Significant increase in the prevalence of Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus, particularly the USA300 variant ΨUSA300, in the Japanese community.

IMPORTANCE: USA300 is an MRSA clone producing PVL, a toxin associated with SSTIs. ΨUSA300 is a USA300 variant recently identified in Japan by Takadama et al. (15). Here, we found that the prevalence rate of PVL-positive MRSA in S. aureus was elevated in the Japanese community, and ΨUSA300 accounted for most of them. ΨUSA300 strains have been isolated from several areas in Japan and were associated with deep-seated SSTIs. This study highlighted the emerging threat posed by ΨUSA300 in Japan.

Current status of Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus isolated from patients with skin and soft tissue infections in Japan.

The USA300 clone, which produces Panton-Valentine leukocidin (PVL), is a major pathogenic community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) clone that causes intractable skin infections. Recently, PVL-positive CA-MRSA, including USA300 clones, have emerged in both communities and hospitals in Japan. To prevent an outbreak of PVL-positive MRSA, infected patients should be treated with effective antimicrobial agents at community clinics. Herein, we investigate molecular epidemiological characteristics of PVL-positive MRSA isolated from outpatients with skin and soft tissue infections (SSTI), which are common community-onset infectious diseases. The detection rate of MRSA was 24.9% (362 strains) out of 1455 S. aureus strains isolated between 2013 and 2017. Among the MRSA strains, 15.5% (56 strains) were PVL-positive strains and associated with deep-seated skin infections. Molecular epidemiological analyses of PVL-positive MRSA showed that USA300 was the predominant clone (53.6%, 30 strains) and was identified in Kanto (18 strains), Kagawa (nine strains), Tohoku (two strains) and Hokkaido (one strain). Notably, minocycline and fusidic acid were effective against all PVL-positive MRSA strains. Hence, our data reveals the current status of PVL-positive MRSA isolated from patients with SSTI in Japan. Continuous surveillance of CA-MRSA is necessary to monitor latest prevalence rates and identify effective antimicrobial agents for PVL-positive MRSA strains.

Prevalence of skin infections caused by Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus in Japan, particularly in Ishigaki, Okinawa.

The prevalence of Panton-Valentine leukocidin gene (pvl)-positive community-acquired methicillin-resistant Staphylococcus aureus USA300 clone, which is designated as the ST8-staphylococcal cassette chromosome (SCC) mec type IV (ST8-IV) lineage, is a major public health concern worldwide. Thus, to elucidate the prevalence and characteristics of pvl-positive community-onset MRSA in Japan, we conducted a molecular epidemiological analysis for 854 S. aureus isolates obtained from outpatients with skin infections during 2013 and 2014. The isolation rate of MRSA was 25.6% (219 isolates), and the ratio of pvl-positive MRSA was 13.2% (29 isolates). Notably, the proportion (93.8%) of pvl-positive isolates was particularly high among MRSA isolates from Ishigaki island in Okinawa. Pulsed-field gel electrophoresis and multilocus sequence typing showed that the pulsotype C isolates (11 isolates) were typical USA300 clones with arginine catabolic mobile element (ACME) type I-CC8-IV lineages and prevalent on the main island of Japan (Honshu). Pulsotypes A (11 isolates) and B (four isolates) consisted of ACME-negative CC8-IV clones and were specific for Ishigaki island. Both USA300 and Okinawa-Ishigaki specific clones were associated with deep-seated skin infections, such as furuncle and cellulitis. Pulsotypes D (two isolates) and E (one isolate) were ACME-negative clonal complex (CC) 59-IV clones and were related to superficial skin infections, such as impetigo. Our findings revealed that pvl-positive MRSA associated with deep-seated skin infections are spreading in Japanese communities, particularly in Ishigaki, Okinawa.

Echocardiographic evaluation of the effects of stem cell therapy on perfusion and function in ischemic cardiomyopathy.

BACKGROUND: Small animal models of ischemic left ventricular (LV) dysfunction are important for the preclinical optimization of stem cell therapy. The aim of this study was to test the hypothesis that temporal changes in LV function and regional perfusion after cell therapy can be assessed in mice using echocardiographic imaging. METHODS: Wild-type mice (n = 25) were studied 7 and 28 days after permanent ligation of the left anterior descending coronary artery. Animals were randomized to receive closed-chest ultrasound-guided intramyocardial delivery of saline (n = 13) or 5 × 10(5) multipotential adult progenitor cells (MAPCs; n = 12) on day 7. LV end-diastolic and end-systolic volumes, LV ejection fraction, and stroke volume were measured using high-frequency echocardiography. Multiplanar assessments of perfusion and defect area size were made using myocardial contrast echocardiography. RESULTS: Between days 7 and 28, MAPC-treated animals had 40% to 50% reductions in defect size (P < .001) and 20% to 30% increases in total perfusion (P < .01). Perfusion did not change in nontreated controls. Both LV end-diastolic and end-systolic volumes increased between days 7 and 28 in both groups, but LV end-systolic volume increased to a lesser degree in MAPC-treated compared with control mice (+4.2 ± 7.9 vs +19.2 ± 22.0 µL, P < .05). LV ejection fraction increased in the MAPC-treated mice and decreased in control mice (+3.0 ± 4.3% vs -5.6 ± 5.9%, P < .01). There was a significant linear relation between the change in LV ejection fraction and the change in either defect area size or total perfusion. CONCLUSIONS: High-frequency echocardiography and myocardial contrast echocardiography in murine models of ischemic LV dysfunction can be used to assess the response to stem cell therapy and to characterize the relationship among spatial flow, ventricular function, and ventricular remodeling.

Renal retention of lipid microbubbles: a potential mechanism for flank discomfort during ultrasound contrast administration.

BACKGROUND: The etiology of flank pain sometimes experienced during the administration of ultrasound contrast agents is unknown. The aim of this study was to investigate whether microbubble ultrasound contrast agents are retained within the renal microcirculation, which could lead to either flow disturbance or local release of vasoactive and pain mediators downstream from complement activation. METHODS: Retention of lipid-shelled microbubbles in the renal microcirculation of mice was assessed by confocal fluorescent microscopy and contrast-enhanced ultrasound imaging with dose-escalating intravenous injection. Studies were performed with size-segregated microbubbles to investigate physical entrapment, after glycocalyx degradation and in wild-type and C3-deficient mice to investigate complement-mediated retention. Urinary bradykinin was measured before and after microbubble administrations. Renal contrast-enhanced ultrasound in human subjects (n = 13) was performed 7 to 10 min after the completion of lipid microbubble administration. RESULTS: In both mice and humans, microbubble retention was detected in the renal cortex by persistent contrast-enhanced ultrasound signal enhancement. Microbubble retention in mice was linearly related to dose and occurred almost exclusively in cortical glomerular microvessels. Microbubble retention did not affect microsphere-derived renal blood flow. Microbubble retention was not influenced by glycocalyx degradation or by microbubble size, thereby excluding lodging, but was reduced by 90% (P < .01) in C3-deficient mice. Urinary bradykinin increased by 65% 5 min after microbubble injection. CONCLUSIONS: Lipid-shelled microbubbles are retained in the renal cortex because of complement-mediated interactions with glomerular microvascular endothelium. Microbubble retention does not adversely affect renal perfusion but does generate complement-related intermediates that are known to mediate nociception and could be responsible for flank pain.

Molecular imaging of inflammation and platelet adhesion in advanced atherosclerosis effects of antioxidant therapy with NADPH oxidase inhibition.

BACKGROUND: In atherosclerosis, local generation of reactive oxygen species amplifies the inflammatory response and contributes to plaque vulnerability. We used molecular imaging to test whether inhibition of NADPH oxidase with apocynin would reduce endothelial inflammatory activation and endothelial-platelet interactions, thereby interrupting progression to high-risk plaque phenotype. METHODS AND RESULTS: Mice deficient for both the low-density lipoprotein receptor and Apobec-1 were studied at 30 weeks of age and again after 10 weeks with or without apocynin treatment (10 or 50 mg/kg per day orally). In vivo molecular imaging of vascular cell adhesion molecule-1 (VCAM 1) P-selectin, and platelet glycoprotein-1bα (GPIbα) in the thoracic aorta was performed with targeted contrast-enhanced ultrasound molecular imaging. Arterial elastic modulus and pulse wave transit time were assessed using ultrahigh frequency ultrasound and invasive hemodynamic measurements. Plaque size and composition were assessed by histology. Molecular imaging in nontreated mice detected a 2-fold increase in P-selectin expression, VCAM-1 expression, and platelet adhesion between 30 and 40 weeks of age. Apocynin reduced all of these endothelial events in a dose-dependent fashion (25% and 50% reduction in signal at 40 weeks for low- and high-dose apocynin). Apocynin also decreased aortic elastic modulus and increased the pulse transit time. On histology, apocynin reduced total monocyte accumulation in a dose-dependent manner as well as platelet adhesion, although total plaque area was reduced in only the high-dose apocynin treatment group. CONCLUSIONS: Inhibition of NADPH oxidase in advanced atherosclerosis reduces endothelial activation and platelet adhesion, which are likely responsible for the arrest of plaque growth and improvement of vascular mechanical properties.

Molecular imaging of disease with targeted contrast ultrasound imaging.

To enhance clinical care for patients, methods for noninvasive imaging of specific disease-related molecular changes are being developed to expand and improve diagnostic capabilities. These new techniques are used in research programs to characterize pathophysiology and as a surrogate end point for therapeutic efficacy. Molecular imaging with contrast-enhanced ultrasound relies on the detection of microbubbles or other acoustically active particulate agents that are targeted to and retained at sites of disease. This review describes the progress that has been made in the development and testing of methods for contrast ultrasound molecular imaging with a specific focus on cardiovascular disease. Specific topics addressed include probe development, detection methods, and specific biologic processes that are important in clinical cardiovascular medicine and that have been targeted with microbubble contrast agents.

Carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysis.

OBJECTIVES: We conducted the meta-analysis to compare the diagnostic accuracies of carotid plaque and carotid intima-media thickness (CIMT) measured by B-mode ultrasonography for the prediction of coronary artery disease (CAD) events. METHODS: Two reviewers independently searched electronic databases to identify relevant studies through April 2011. Both population-based longitudinal studies with the outcome measure of myocardial infarction (MI) events and diagnostic cohort studies for the detection of CAD were identified and analyzed separately. Weighted summary receiver-operating characteristic (SROC) plots, with pertinent areas under the curves (AUCs), were constructed using the Moses-Shapiro-Littenberg model. Meta-regression analyses, using parameters of relative diagnostic odds ratio (DOR), were conducted to compare the diagnostic performance after adjusting other study-specific covariates. RESULTS: The meta-analysis of 11 population-based studies (54,336 patients) showed that carotid plaque, compared with CIMT, had a significantly higher diagnostic accuracy for the prediction of future MI events (AUC 0.64 vs. 0.61, relative DOR 1.35; 95%CI 1.1-1.82, p=0.04). The 10-year event rates of MI after negative results were lower with carotid plaque (4.0%; 95% CI 3.6-4.7%) than with CIMT (4.7%; 95% CI 4.2-5.5%). The meta-analysis of 27 diagnostic cohort studies (4.878 patients) also showed a higher, but non-significant, diagnostic accuracy of carotid plaque compared with CIMT for the detection of CAD (AUC 0.76 vs. 0.74, p=0.21 for relative DOR). CONCLUSIONS: The present meta-analysis showed that the ultrasound assessment of carotid plaque, compared with that of CIMT, had a higher diagnostic accuracy for the prediction of future CAD events.

Quantity of viable myocardium required to improve survival with revascularization in patients with ischemic cardiomyopathy: A meta-analysis.

BACKGROUND: This meta-analysis was conducted to determine optimal cutoff values for the assessment of viability using various imaging techniques for which revascularization would offer a survival benefit in patients with ischemic cardiomyopathy (ICM). METHODS AND RESULTS: We searched five electronic databases to identify relevant studies through December 2008. Relative risks of cardiac death, both in patients with and without viability, were calculated in each study. In order to estimate the optimal threshold for the presence of viability, we assumed a linear relationship between the amount of viable myocardium and survival benefit of revascularization. Twenty-nine studies (4,167 patients) met the inclusion criteria. The optimal threshold for the presence of viability was estimated to be 25.8% (95% CI: 16.6-35.0%) by positron emission tomography using 18F-fluorodeoxyglucose-perfusion mismatch, 35.9% (95% CI: 31.6-40.3%) by stress echocardiography using contractile reserve or ischemic responses, and 38.7% (95% CI: 27.7-49.7%) by single photon emission computed tomography using thallium-201 or technetium-99m MIBI myocardial perfusion. CONCLUSIONS: The calculated amount of viable myocardium determined to lead to improved survival was different among imaging techniques. Thus, separate cutoff values for imaging modalities may be helpful in determining which patients with ICM benefit from revascularization.

Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis.

BACKGROUND: We conducted a meta-analysis of observational studies which examined the association between flow-mediated dilatation (FMD) of brachial artery, a noninvasive measure of endothelial function, and future cardiovascular events. METHODS: Electronic databases were searched using a predefined search strategy. Data was independently abstracted on study characteristics, study quality, and outcomes by two reviewers. The multivariate relative risks, adjusted for confounding factors, were calculated from individual studies and then pooled using random-effects models. Statistical heterogeneity was evaluated using I2 statistics. Subgroup analyses and meta-regression analyses were conducted to assess the robustness of the meta-analysis. Publication bias was examined with funnel plot analysis and Egger's test. RESULTS: Four population-based cohort studies and ten convenience-cohort studies, involving 5,547 participants, were included in the meta-analysis. The pooled relative risks of cardiovascular events per 1% increase in brachial FMD, adjusted for confounding risk factors, was 0.87 (95% CI, 0.83- 0.91). The significant associations between brachial FMD and cardiovascular events were consistent among all subgroups evaluated, suggesting the robustness of the meta-analysis. However, the presence of heterogeneity in study quality, the remaining confounding factors, and publication bias in the available literature prevent a definitive evaluation of the additional predictive value of brachial FMD beyond traditional cardiovascular risk factors. CONCLUSIONS: The meta-analysis of heterogeneous studies with moderate methodological quality suggested that impairment of brachial FMD is significantly associated with future cardiovascular events. Further prospective randomized trials are warranted to confirm the efficacy of the usage of brachial FMD in the management of cardiovascular diseases.

Prognostic value of myocardial metabolic imaging with BMIPP in the spectrum of coronary artery disease: a systematic review.

BACKGROUND: We conducted a systematic review to summarize the current literature on the prognostic value of BMIPP imaging, fatty-acid metabolic imaging, for the prediction of cardiovascular events in coronary artery disease. METHODS AND RESULTS: Electronic databases (including Japanese medical literature search engines) were searched by a Japanese investigator using a predefined search strategy. Eleven studies, all conducted in Japan, were included in the meta-analysis. In three studies involving 541 patients with suspected acute coronary syndrome who were excluded for acute myocardial infarction (AMI), an abnormal finding on BMIPP imaging was significantly associated with future hard events (cardiac death or non-fatal myocardial infarction). The negative predictive value of BMIPP imaging for future hard events was 98.9% (96.8-99.7%) over 3.5 years. In six studies involving 542 patients with AMI, a larger defect on BMIPP imaging was significantly associated with future hard events. The prognostic value of perfusion-metabolism mismatch compared with myocardial perfusion imaging was dependent upon the relative timing of BMIPP imaging, revascularization, and myocardial perfusion damage. CONCLUSIONS: BMIPP imaging is useful for the risk stratification of patients with coronary artery disease, particularly patients with acute chest pain.

Impact of single or multicentre study design on the results of trials examining the efficacy of adjunctive devices to prevent distal embolisation during acute myocardial infarction.

AIMS: We investigated using meta-analytic techniques, whether, and to what degree, single or multicentre study design affects clinical outcomes in randomised controlled trials examining the efficacy of adjunctive devices to prevent distal embolisation during acute myocardial infarction (AMI). METHODS AND RESULTS: We searched electronic databases, conference proceedings, and internet-based sources of information to identify relevant studies through March 2009. The pooled summary effect was estimated with a random effects model. Subgroup and meta-regression analyses were conducted to examine the impact of single or multicentre design on trial outcomes compared with other variables. A total of 25 randomised trials (5,919 patients) were included in the analysis. The major sources of heterogeneity in trial outcomes were single or multicentre design, type of device used, study size, study region, and presence of conflicts of interest, of which the most influential source of heterogeneity was single or multicentre design (p-values of regression coefficient on meta-regression analyses were 0.09 for mortality, 0.001 for incomplete ST-segment resolution, and 0.07 for impaired myocardial blush grade, respectively). CONCLUSIONS: Single or multicentre study design has a significant impact on outcomes in trials examining the efficacy of adjunctive devices in AMI.

Diagnostic accuracy of beta-methyl-p-[123I]-iodophenyl-pentadecanoic acid (BMIPP) imaging: a meta-analysis.

BACKGROUND: beta-Methyl-p-[(123)I]-iodophenyl-pentadecanoic acid (BMIPP) imaging has been used extensively to detect coronary artery disease (CAD), primarily in Japan. However, the reported sensitivity and specificity vary considerably from study to study. This meta-analysis was conducted to summarize the evidence for the diagnostic accuracy of resting BMIPP imaging in the detection of CAD. METHODS AND RESULTS: A MEDLINE search of the literature published through the end of 2006 was performed. Seven studies (528 patients) met the inclusion criteria. Using random-effects models, the overall sensitivity and specificity to detect CAD were 78% (95% confidence interval, 73% to 81%) and 84% (95% confidence interval, 77% to 89%), respectively. A significant threshold effect was identified among studies, which was expected given the between-study variability in study methodology. A summary receiver-operating characteristic curve yielded an asymmetric curve with an area under the curve of 0.91 (SE, 0.020), indicating excellent diagnostic performance. CONCLUSIONS: Imaging with BMIPP at rest exhibits a moderate sensitivity and high specificity to detect CAD in patients with a high prevalence of CAD. Thus, this tracer may be of great value for patients with acute chest pain and those with relative contraindications to exercise or pharmacologic stress myocardial perfusion imaging (MPI).