The instability of carotid and coronary plaques has been reported to be associated with acute coronary syndrome, strokes and other cerebrovascular events. Therefore, recognition of the tissue ...characteristics of carotid and coronary plaques is important to understand and prevent coronary and cerebral artery disease. Recently, an ultrasound integrated backscatter (IB) technique has been developed. The ultrasound IB power ratio is a function of the difference in acoustic characteristic impedance between the medium and target tissue, and the acoustic characteristic impedance is determined by the density of tissue multiplied by the speed of sound. This concept allows for tissue characterization of carotid and coronary plaques for risk stratification of patients with coronary and cerebral artery disease. Two- and three-dimensional IB color-coded maps for the evaluation of tissue components consist of four major components: fibrous, dense fibrosis, lipid pool and calcification. Although several ultrasound techniques using special mathematical algorithms have been reported, a growing body of literature has shown the reliability and usefulness of the IB technique for the tissue characterization of carotid and coronary plaques. This review summarizes concepts, experimental procedures, image reliability and the application of the IB technique. Furthermore, the IB technique is compared with other techniques.
Delamanid, a bicyclic nitroimidazooxazole, is effective against M. tuberculosis. Previous studies have shown that resistance to a bicyclic nitroimidazooxazine, PA-824, is caused by mutations in an ...F420-dependent bio-activation pathway. We investigated whether the same mechanisms are responsible for resistance to delamanid. Spontaneous resistance frequencies were determined using M. bovis BCG Tokyo (BCG) and M. tuberculosis H37Rv. F420 high-performance liquid chromatography (HPLC) elution patterns of homogenates of delamanid-resistant BCG colonies and two previously identified delamanid-resistant M. tuberculosis clinical isolates were examined, followed by sequencing of genes in the F420-dependent bio-activation pathway. Spontaneous resistance frequencies to delamanid were similar to those of isoniazid and PA-824. Four distinct F420 HPLC elution patterns were observed, corresponding to colonies with mutations on fgd1, fbiA, fbiB, and fbiC with no change in the ddn mutants from the wildtype. Complementation with the wildtype sequence of the mutated gene restored susceptibility. The two delamanid-resistant clinical isolates had ddn mutations and the wildtype F420 HPLC elution pattern. In conclusion, delamanid-resistant bacilli have mutations in one of the 5 genes in the F420-dependent bio-activation pathway with distinct F420 HPLC elution patterns. Both genetic and phenotypic changes may be considered in the development of a rapid susceptibility test for delamanid.
Abstract
Aims
This study aimed to determine the effects of a proprotein convertase subtilisin-kexin type 9 inhibitor (PCSK9i) on coronary plaque volume and lipid components in patients with a history ...of coronary artery disease (CAD).
Methods and results
This prospective, open-label, single-centre study analysed non-culprit coronary segments using near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS) at baseline and follow-up angiography. Following changes in the lipid-lowering treatment based on the most recent guideline, the enrolled subjects were divided into two groups: treatment with PCSK9i and statins (PCSK9i: 21 patients and 40 segments) and statins only (control: 32 patients and 50 segments). The absolute and percent LDL-C reductions were significantly greater in the PCSK9i group than in the control group (between group difference: 59.3 mg/dL and 46.4%; P < 0.001 for both). The percent reduction in normalized atheroma volume and absolute reduction in percent atheroma volume (PAV) were also significantly greater in the PCSK9i group (P < 0.001 for both). Furthermore, the PCSK9i group showed greater regression of maximal lipid core burden index for each of the 4-mm segments (maxLCBI4mm) than the control group (57.0 vs. 25.5; P = 0.010). A significant linear correlation was found between the percent changes in LDL-C and maxLCBI4mm (r = 0.318; P = 0.002), alongside the reduction in PAV (r = 0.386; P < 0.001).
Conclusion
The lipid component of non-culprit coronary plaques was significantly decreased by PCSK9i. The effects of statin combined with PCSK9i might be attributed to the stabilization and regression of residual vulnerable coronary plaques in patients with CAD.
See article vol. 23: 932-939It is generally accepted that morbidity and mortality from cardiovascular disease (CVD) are significantly higher in patients with hyperuricemia than in the general ...population. However, it has been controversial whether hyperuricemia is a risk factor for CVD independent of other risk factors or a confounding factor. This is because randomized double-blind prospective studies that show medications for hyperuricemia reduce the risk of CVD have been scarce.
Background:Multilineage differentiating stress-enduring (Muse) cells are SSEA3+and CD105+double-positive pluripotent-like stem cells. We aimed to examine the mobilization of Muse cells into ...peripheral blood after acute myocardial infarction (AMI) and their effects on left ventricular (LV) function and remodeling.Methods and Results:In 79 patients with AMI, 44 patients with coronary artery disease (CAD), and 64 normal subjects (Control), we measured the number of Muse cells in the peripheral blood by fluorescence-activated cell sorting. Muse cells were measured on days 0, 1, 7, 14, and 21 after AMI. Plasma sphingosine-1-phosphate (S1P) levels were measured. Cardiac echocardiography was performed in the acute (within 7 days) and chronic (6 months) phases of AMI. Muse cell number on day 1 was significantly higher in the AMI (276±137 cells/100 μL) than in the CAD (167±89 cells/100 μL) and Control (164±125 cells/100 μL) groups. Muse cell number peaked on day 1, and had gradually decreased on day 21. Muse cell number positively correlated with plasma S1P levels. Patients with a higher increase in the number of Muse cells in the peripheral blood but not those with a lower increase in number of Muse cells in the acute phase showed improved LV function and remodeling in the chronic phase.Conclusions:Endogenous Muse cells were mobilized into the peripheral blood after AMI. The number of Muse cells could be a predictor of prognosis in patients with AMI.
Little is known about the association between autophagy and diabetic cardiomyopathy. Also unknown are possible distinguishing features of cardiac autophagy in type 1 and type 2 diabetes. In hearts ...from streptozotocin-induced type 1 diabetic mice, diastolic function was impaired, though autophagic activity was significantly increased, as evidenced by increases in microtubule-associated protein 1 light chain 3/LC3 and LC3-II/-I ratios, SQSTM1/p62 (sequestosome 1) and CTSD (cathepsin D), and by the abundance of autophagic vacuoles and lysosomes detected electron-microscopically. AMP-activated protein kinase (AMPK) was activated and ATP content was reduced in type 1 diabetic hearts. Treatment with chloroquine, an autophagy inhibitor, worsened cardiac performance in type 1 diabetes. In addition, hearts from db/db type 2 diabetic model mice exhibited poorer diastolic function than control hearts from db/+ mice. However, levels of LC3-II, SQSTM1 and phosphorylated MTOR (mechanistic target of rapamycin) were increased, but CTSD was decreased and very few lysosomes were detected ultrastructurally, despite the abundance of autophagic vacuoles. AMPK activity was suppressed and ATP content was reduced in type 2 diabetic hearts. These findings suggest the autophagic process is suppressed at the final digestion step in type 2 diabetic hearts. Resveratrol, an autophagy enhancer, mitigated diastolic dysfunction, while chloroquine had the opposite effects in type 2 diabetic hearts. Autophagy in the heart is enhanced in type 1 diabetes, but is suppressed in type 2 diabetes. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy, which is essential for the development of new treatment strategies.
RATIONALE:Muse cells, pluripotent marker SSEA-3 cells, are non-tumorigenic endogenous pluripotent-like stem cells obtainable from various tissues including the bone marrow (BM). Their therapeutic ...efficiency has not been validated in the acute myocardial infarction (AMI).
OBJECTIVE:To clarify the efficiency of intravenously infused rabbit autograft, allograft, and xenograft (human) BM-Muse cells in a rabbit AMI model and their mechanisms of tissue repair.
METHODS AND RESULTS:In vivo dynamics of Nano-lantern-labeled Muse cells showed preferential homing of the cells to the post-infarct heart at 3 days and 2 weeks, with ~14.5% of injected GFP-Muse cells estimated to be engrafted into the heart at 3 days. The migration and homing of the Muse cells was confirmed pharmacologically (S1P receptor 2 S1PR2-specific antagonist JTE-013 co-injection) and genetically (S1PR2-siRNA-introcuded Muse cells) to be mediated through the S1P-S1PR2 axis. They spontaneously differentiated into cells positive for cardiac markers, such as cardiac troponin-I, sarcomeric α-actinin, and connexin43, as well as vascular markers. GCaMP3-labeled Muse cells that engrafted into the ischemic region exhibited increased GCaMP3 fluorescence during systole and decreased fluorescence during diastole. Infarct size was reduced by ~52% and the ejection fraction was increased by ~38% compared with vehicle injection at 2 months, ~2.5 and ~2.1 times higher, respectively, than induced by mesenchymal stem cells. These effects were partially attenuated by the administration of GATA4-gene silenced-Muse cells. Muse cell allografts and xenografts efficiently engrafted and recovered functions, and allografts remained in the tissue and sustained functional recovery for up to 6 months without immunosuppression.
CONCLUSIONS:Muse cells may provide reparative effects and robust functional recovery, and may thus provide a novel strategy for the treatment of AMI.
Background:The results of previous clinical trials on the effects of ezetimibe-statin combination therapy on atherosclerosis are inconsistent, and the anti-atherosclerotic effect of ezetimibe remains ...controversial.Methods and Results:We conducted a prospective, randomized open-label study at 10 centers. One hundred and twenty-eight statin-naïve patients with acute coronary syndrome (ACS) undergoing intravascular ultrasound (IVUS)-guided percutaneous coronary intervention were randomized to receive either 2 mg/day pitavastatin plus 10 mg/day ezetimibe, or 2 mg/day pitavastatin. One hundred and 3 patients had evaluable IVUS of non-culprit coronary lesions at baseline and at follow-up. The primary endpoint was the percentage change in non-culprit coronary plaque volume (PV) and lipid PV on integrated backscatter IVUS. Mean low-density lipoprotein cholesterol was reduced from 123 mg/dL to 64 mg/dL in the combination therapy group (n=50) and 126 mg/dL to 87 mg/dL in the statin alone group (n=53; between-group difference, 16.9%, P<0.0001). The percent change in PV was −5.1% in the combination therapy group and −6.2% in the statin alone group (P=0.66), although both groups had reduction of PV compared with baseline (both P<0.01). The percent change in lipid PV did not differ between the groups (4.3 vs. −3.0%, P=0.37).Conclusions:In statin-naïve patients with ACS, combined therapy with ezetimibe and statin did not result in a significant change in coronary plaque regression or tissue component compared with statin alone. Clinical Trial Registration: www.clinicaltrials.gov (NCT00549926)
Tuberculosis (TB) is still a leading cause of death worldwide. Almost a third of the world's population is infected with TB bacilli, and each year approximately 8 million people develop active TB and ...2 million die as a result. Today's TB treatment, which dates back to the 1970s, is long and burdensome, requiring at least 6 mo of multidrug chemotherapy. The situation is further compounded by the emergence of multidrug-resistant TB (MDR-TB) and by the infection's lethal synergy with HIV/AIDS. Global health and philanthropic organizations are now pleading for new drug interventions that can address these unmet needs in TB treatment.
Here we report OPC-67683, a nitro-dihydro-imidazooxazole derivative that was screened to help combat the unmet needs in TB treatment. The compound is a mycolic acid biosynthesis inhibitor found to be free of mutagenicity and to possess highly potent activity against TB, including MDR-TB, as shown by its exceptionally low minimum inhibitory concentration (MIC) range of 0.006-0.024 microg/ml in vitro and highly effective therapeutic activity at low doses in vivo. Additionally, the results of the post-antibiotic effect of OPC-67683 on intracellular Mycobacterium tuberculosis showed the agent to be highly and dose-dependently active also against intracellular M. tuberculosis H37Rv after a 4-h pulsed exposure, and this activity at a concentration of 0.1 microg/ml was similar to that of the first-line drug rifampicin (RFP) at a concentration of 3 microg/ml. The combination of OPC-67683 with RFP and pyrazinamide (PZA) exhibited a remarkably quicker eradication (by at least 2 mo) of viable TB bacilli in the lung in comparison with the standard regimen consisting of RFP, isoniazid (INH), ethambutol (EB), and PZA. Furthermore, OPC-67683 was not affected by nor did it affect the activity of liver microsome enzymes, suggesting the possibility for OPC-67683 to be used in combination with drugs, including anti-retrovirals, that induce or are metabolized by cytochrome P450 enzymes.
We concluded that based on these properties OPC-67683 has the potential to be used as a TB drug to help combat the unmet needs in TB treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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