[Susceptibility surveillance of clinical isolates to fluoroquinolone antimicrobial agents from 2003 to 2008: post-marketing study of prulifloxacin].

Yearly changes in the susceptibility of clinical isolates to ulifloxacin (UFX) and other fluoroquinolones were examined through surveys over 3 periods. In the first survey, 534 strains derived from 19 species were collected from clinical specimens during 6 months from December 2003 to May 2004. In the same way, 805 strains were collected from December 2005 to May 2006 in the second survey, and 863 strains were from December 2007 to May 2008 in the third survey. Over these 3 study periods, the susceptibilities of fluoroquinolones against methicillin-susceptible Staphylococcus aureus and Escherichia coli were decreased. The isolation frequency of levofloxacin-nonsusceptible strain was increased from 0% to 11.8% and from 14.6% to 20.8%, respectively. MIC90s of UFX against these pathogens were also increased, but its MIC90 for E. coli was 2 to 4 times lower than that of levofloxacin. On the other hand, the susceptibility of strains of Klebsiella pneumoniae to UFX was increased. Among the fluoroquinolones tested, UFX showed the most potent activity against Pseudomonas aeruginosa, and no changes in the MIC90s occurred during the surveillance. Although one strain of Streptococcus pneumoniae isolated in the third study period showed levofloxacin-resistance (MIC, 8 microg/mL), there were nearly no changes in the MIC90s of any agents tested including UFX against S. pneumoniae during the surveillance. As for other bacterial species, a tendency to increase in resistance to UFX was not observed. The activity of UFX against Salmonella spp. and Shigella spp. was superior/equal to those of fluoroquinolones tested.

Core protein of hepatitis C virus induces cardiomyopathy.

Hepatitis C virus (HCV) has been reported to be associated with cardiomyopathy. However, the mechanism of cardiomyopathy in chronic HCV infection is still unclear. Therefore, we investigate the development of cardiomyopathy in mice transgenic for the HCV-core gene. After the age of 12 months, mice developed cardiomyopathy that appeared as left ventricular dilatation, and systolic and diastolic dysfunction assessed by Doppler echocardiography. Histologically, hypertrophy of cardiomyocytes, cardiac fibrosis, disarray and scarcity of myofibrils, vacuolization and deformity of nuclei, myofibrillar lysis, streaming of Z-bands, and an increased number of bizarre-shaped mitochondria were found in HCV-core transgenic mice. These histological changes are just consistent with cardiomyopathy. In conclusion, the HCV-core protein directly plays an important role in the development of cardiomyopathy.

Acute hemodynamic benefits of bi-atrial atrioventricular sequential pacing with the optimal atrioventricular delay.

OBJECTIVES: We evaluate the acute effects on hemodynamics of bi-atrial (BiA) pacing with the optimal atrioventricular (AV) delays, in comparison with high right atrial (HRA) pacing and coronary sinus (CS) pacing. BACKGROUND: Bi-atrial pacing has been suggested as one of the alternative therapy for preventing the recurrence of atrial fibrillation (AF). There are, however, few reports on the hemodynamic effects of BiA pacing, and the results that exist are controversial. METHODS: Twenty patients were paced from HRA, left lateral site of CS, and both sites with the optimal AV delays at 80 and 100 beats/min, in random order. After 5-min pacing, maximal P-wave duration in a 12-lead electrocardiogram, cardiac output (CO), pulmonary capillary wedge pressure (PCWP), and the transmitral flow pattern by transthoracic echocardiography were measured. RESULTS: Compared with HRA and CS pacing, BiA pacing delivered the shortest P-wave duration (HRA: 130 +/- 14 ms, CS: 132 +/- 19 ms, and BiA: 94 +/- 8 ms, respectively, p < 0.001) and the most improvement in CO and PCWP (HRA: 3.63 +/- 0.67 l/min and 9.2 +/- 4.3 mm Hg, CS: 3.71 +/- 0.70 l/min and 8.8 +/- 3.4 mmHg, and BiA: 3.88 +/- 0.63 l/min and 8.0 +/- 3.1 mmHg, respectively, p < 0.01). Bi-atrial pacing also significantly increased the mitral flow time velocity integral and peak A-wave velocity by transthoracic echocardiography, compared with HRA and CS pacing (HRA: 7.6 +/- 1.4 cm and 68.8 +/- 12.2 cm/s, CS: 7.8 +/- 1.4 cm and 70.5 +/- 14.5 cm/s, and BiA: 8.2 +/- 1.2 cm and 76.3 +/- 14.2 cm/s, respectively, p < 0.01). Bi-atrial pacing most significantly decreased the intervals between the atrial pacing spike and the peak of A-wave (HRA: 180 +/- 28 ms, CS: 165 +/- 21 ms, and BiA: 157 +/- 19 ms, respectively, p < 0.01). These improvements in hemodynamics significantly correlated with interatrial conduction delay. CONCLUSIONS: Bi-atrial pacing made the most significant improvements of hemodynamics. These benefits may be due to the improvements in interatrial conduction delay and atrial dyssynchrony.

Acute myocardial infarction: clinical characteristics and plaque morphology between expansive remodeling and constrictive remodeling by intravascular ultrasound.

BACKGROUND: According to recent intravascular ultrasound (IVUS) studies, expansive remodeling (ER) at the culprit lesion has been observed in almost 50% of patients with acute coronary syndrome and constrictive remodeling (CR) in 30%. The purpose of this study is to investigate the difference between ER and CR at the culprit lesion in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: Preinterventional IVUS images of 73 patients with AMI were identified. The remodeling index (RI) was defined as the ratio of the external elastic membrane (EEM) areas at the culprit lesion to the EEM areas at the proximal reference site. Expansive remodeling was defined as an RI > 1.05; CR, as an RI < 0.95. In patients with AMI, 40 patients (55%) showed ER on IVUS, whereas CR was observed in 18 patients (25%). Patients with ER were significantly older than those with CR (P < .005). The frequency of the presence of calcifications was higher in patients with ER than in those with CR (P < .0005). In patients with AMI with ER, soft plaque with small calcium was the most frequent (58%). Multivariate analysis revealed that age and the presence of calcifications remained as independent predictors of ER. CONCLUSIONS: These findings suggest that ER relates to old age and calcification, and CR may contribute to early plaque progression than ER in patients with AMI.

Vascular endothelial growth factor-expressing mesenchymal stem cell transplantation for the treatment of acute myocardial infarction.

OBJECTIVE: Vascular endothelial growth factor (VEGF) plays an important role in inducing angiogenesis. Mesenchymal stem cells (MSCs) may have potential for differentiation to several types of cells, including myocytes. We hypothesized that transplantation of VEGF-expressing MSCs could effectively treat acute myocardial infarction (MI) by providing enhanced cardioprotection, followed by angiogenic effects in salvaging ischemic myocardium. METHODS AND RESULTS: The human VEGF165 gene was transfected to cultured MSCs of Lewis rats using an adenoviral vector. Six million VEGF-transfected and LacZ-transfected MSCs (VEGF group), LacZ-transfected MSCs (control group), or serum-free medium only (medium group) were injected into syngeneic rat hearts 1 hour after left coronary artery occlusion. At 1 week after MI, MSCs were detected by X-gal staining in infarcted region. High expression of VEGF was immunostained in the VEGF group. At 28 days after MI, infarct size, left ventricular dimensions, ejection fraction, E wave/A wave ratio and capillary density of the infarcted region were most improved in the VEGF group, compared with the medium group. Immunohistochemically, alpha-smooth muscle actin-positive cells were most increased in the VEGF group. CONCLUSIONS: This combined strategy of cell transplantation with gene therapy could be a useful therapy for the treatment of acute MI.

Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study.

BACKGROUND: Calcification is a common finding in human coronary arteries; however, the relationship between calcification patterns, plaque morphology, and patterns of remodeling of culprit lesions in a comparison of patients with acute coronary syndromes (ACS) and those with stable conditions has not been documented. METHODS AND RESULTS: Preinterventional intravascular ultrasound (IVUS) images of 178 patients were studied, 61 with acute myocardial infarction (AMI), 70 with unstable angina pectoris (UAP), and 47 with stable angina pectoris (SAP). The frequency of calcium deposits within an arc of less than 90 degrees for all calcium deposits was significantly different in culprit lesions of patients with AMI, UAP, and SAP (P<0.0001). Moreover, the average number of calcium deposits within an arc of <90 degrees per patient was significantly higher in AMI than in SAP (P<0.0005; mean+/-SD, AMI 1.4+/-1.3, SAP 0.5+/-0.8). Conversely, calcium deposits were significantly longer in SAP patients (P<0.0001; mean+/-SD, AMI 2.2+/-1.6, UAP 1.9+/-1.8, and SAP 4.3+/-3.2 mm). In AMI patients, the typical pattern was spotty calcification, associated with a fibrofatty plaque and positive remodeling. In ACS patients showing negative remodeling, no calcification was the most frequent observation. Conversely, SAP patients had the highest frequency of extensive calcification. CONCLUSIONS: Our observations show that IVUS allows the identification of vulnerable plaques in coronary arteries, not only by identifying a fibrofatty plaque and positive remodeling, but also by identifying a spotty pattern of calcification.

Neutrophil infiltration of culprit lesions in acute coronary syndromes.

BACKGROUND: Neutrophils in unstable atherosclerotic lesions have not received much consideration, despite accumulating evidence suggesting a link between systemic inflammation and acute coronary syndromes. METHODS AND RESULTS: Coronary artery segments were obtained at autopsy from 13 patients with acute myocardial infarction (AMI); 8 had a ruptured and 5 an eroded plaque. Patients (n=45) who had died of noncardiovascular diseases served as reference. Atherectomy specimens were obtained from 35 patients with stable angina pectoris (SAP) and from 32 patients with unstable angina pectoris (UAP). Antibodies against CD66b, elastase, myeloperoxidase, and CD11b identified neutrophils; CD10 identified neutral endopeptidase (NEP). CD66b-positive and NEP-positive neutrophils were counted and expressed as a number per square millimeter of tissue. All specimens with plaque rupture or erosion showed distinct neutrophil infiltration; the number did not differ between ruptured and eroded plaques. However, the number of NEP-positive neutrophils was significantly higher (P<0.0001) in ruptured plaques than in eroded plaques. UAP patients showed neutrophils in 14 of 32 culprit lesions; in SAP only 2 of 35 lesions contained neutrophils. The number of neutrophils and NEP-positive cells in patients with UAP was significantly higher (neutrophils, P<0.0005; NEP-positive cells, P<0.005) than in patients with SAP. CONCLUSIONS: The observations suggest that neutrophil infiltration is actively associated with acute coronary events. The high number of NEP-positive neutrophils in ruptured plaques, compared with eroded plaques, may reflect differences in the underlying pathophysiological mechanisms.

Protective effect of high diastolic blood pressure during exercise against exercise-induced myocardial ischemia.

BACKGROUND: Hypertension is one of the risk factors for coronary artery disease. However, because most coronary blood flow to the left ventricle occurs during diastole, high diastolic blood pressure during exercise may have a protective effect against exercise-induced myocardial ischemia. The aim of the present study was to test this hypothesis. METHODS AND RESULTS: We identified 469 patients with sinus rhythm and known or suspected coronary artery disease who underwent exercise thallium-201 myocardial single-photon emission computed tomography and coronary arteriography. High diastolic blood pressure during exercise was defined as diastolic blood pressure at peak exercise > or = 90 mm Hg. There was no significant difference in medications, number of diseased vessels, or Gensini score between patients with high (n = 228) and normal (n = 241) diastolic blood pressure during exercise, whereas patients with high diastolic blood pressure during exercise exhibited a higher pressure-rate product during exercise than patients with normal diastolic blood pressure during exercise. The reversibility score on thallium-201 myocardial scan was significantly smaller in patients with high diastolic blood pressure during exercise than in patients with normal diastolic blood pressure during exercise (P = .021). CONCLUSIONS: High diastolic blood pressure during exercise has a potential protective effect against exercise-induced ischemia, although the mechanism of such effects remains to be determined.

Involvement of apoptosis signal-regulating kinase-1 on angiotensin II-induced monocyte chemoattractant protein-1 expression.

OBJECTIVE: Monocyte chemoattractant protein 1 (MCP-1) could contribute to enhanced leukocyte recruitment and activation resulting in chronic tissue damage. However, little is known about the molecular mechanisms of cardiac MCP-1 expression. To elucidate these molecular mechanisms, angiotensin II-induced expression of MCP-1 was examined in cultured rat neonatal ventricular cardiomyocytes and fibroblasts by adenovirus gene transfer. METHODS AND RESULTS: MCP-1 mRNA increased 3.6-fold in cardiac fibroblasts at 3 hours after 100 nmol/L angiotensin-II stimulation (P<0.01), whereas MCP-1 mRNA in cardiomyocytes was unchanged. Angiotensin II significantly enhanced JNK, p38MAPK, and nuclear factor-kappaB (NF-kappaB) activities of cardiac fibroblasts. Wild-type ASK-1 increased MCP-1 expression of cardiac fibroblasts, whereas dominant negative mutant of ASK-1 (DN-ASK), dominant negative mutant of p38MAPK (DN-p38MAPK), and pyrrolidine dithiocarbamate significantly inhibited such expression. The increased MCP-1 mRNA expression in wild-type ASK-1 transfected fibroblasts was inhibited by cotransfection with adenovirus expressing DN-p38MAPK. On the contrary, the decreased MCP-1 mRNA expression in DN-ASK transfected cells was increased by cotransfection with adenovirus expressing constitutively active MKK6. CONCLUSIONS: Angiotensin II induced MCP-1 gene expression in cardiac fibroblasts. The angiotensin II-induced activation of ASK-1 followed by p38MAPK and NF-kappaB signaling in cardiac fibroblasts is partially involved in myocardial MCP-1 expression.

Effects of granulocyte-colony stimulating factor on cardiac remodeling after myocardial infarction.

BACKGROUND: Recent studies suggest that granulocyte colony-stimulating factor (G-CSF) may be beneficial in the treatment of myocardial infarction (MI). However, the effects of G-CSF on MI are still controversial and the molecular mechanism of G-CSF treatment for repair of the infarcted heart is not fully understood. METHODS: Mice were divided into three groups: Control, MI and MI treated with G-CSF. Four weeks after MI, we examined cardiac function by Doppler echocardiography and measured non-infarcted myocardial mRNA expression by northern blot analysis. RESULTS: Cardiac function decreased significantly in the MI groups compared with the sham-operated groups. Additionally, the ratios of E wave to A wave peak velocity (E/A) in the MI groups were higher than in the control group. E/A in G-CSF MI mice was significantly lower than in control MI mice (p<0.01). Matrix metalloproteinase-2 (MMP-2) mRNA expression was significantly increased in the MI groups compared with the control group (p<0.01). Furthermore, mRNA expression in the G-CSF MI group was significantly higher than in the Control MI group (p<0.05). CONCLUSIONS: G-CSF can prevent the LV remodeling process after MI that accompanies progressive cardiac dysfunction. One of the mechanisms of G-CSF treatment for cardiac remodeling after MI may be overexpression of MMP-2 in non-infarcted myocardium.