Contrast echocardiography for the diagnosis of left ventricular thrombus in anterior myocardial infarction

Although detecting left ventricular thrombus in anterior myocardial infarction is important for the prevention of embolic events, imaging of apical thrombus is often difficult using conventional echocardiography. We examined whether contrast echocardiography improves sensitivity and specificity in detecting thrombus in the left ventricle in comparison with conventional echocardiography alone in patients with anterior myocardial infarction. Participants in this single-center prospective study comprised 392 patients with anterior myocardial infarction admitted between 2000 and 2006. After conventional echocardiography, all patients underwent contrast echocardiography (left ventricular opacification and myocardial contrast echocardiography) during intravenous drip infusion of contrast media at rest. Left ventricular thrombus was diagnosed based on left ventriculography or multidetector-row computed tomography (MDCT). Mural left ventricular thrombus was confirmed by left ventriculography and/or MDCT in 32 of 393 patients (8 %). Sensitivity and specificity of conventional echocardiography alone were 88 % and 96 %, respectively, compared with 100 % each with contrast echocardiography. Among the 32 patients with left ventricular thrombus, 25 patients (78 %) showed no perfusion in the anterior wall on myocardial contrast echocardiography, even with a four-beat interval. In conclusion, contrast echocardiography offers a clinically feasible and useful method for noninvasively evaluating left ventricular thrombus in anterior myocardial infarction.     

Limited value of the international staging system for predicting long-term outcome of transplant-ineligible,newly diagnosed,symptomatic multiple myeloma in the era of novel agents

We retrospectively investigated clinical outcomes and prognostic factors of 131 patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) who received melphalan and prednisolone (MP) as first-line therapy from 2006 to 2013. Eighty-one patients received salvage therapies incorporating bortezomib, lenalidomide, and/or thalidomide. The overall response rate to MP was 54.2 %, including 9.2 % of better than very good partial response. With a median follow-up period of 30.2 months, median overall survival (OS) and median time to next treatment (TNT) were 54.4 and 19.0 months, respectively. Univariate analysis revealed that performance status and serum calcium level significantly associated with both OS and TNT, and multivariate analysis revealed that the higher serum calcium level had a significantly unfavorable impact on OS and TNT. Importantly, staging informed by the international staging system (ISS) was not predictive for OS or TNT in the analyzed cohort. Our study revealed that, in the context of first-line MP therapy for NDMM, the salvage therapy incorporating novel agents produced a survival period of >30 months after the initiation of second-line therapy, suggesting that the predictive value of ISS for OS and TNT may be limited in the era of novel agents.     

Inhibition of cysteine cathepsin B and L activation in astrocytes contributes to neuroprotection against cerebral ischemia via blocking the tBid‐mitochondrial apoptotic signaling pathway

The roles of cathepsins in the ischemic astrocytic injury remain unclear. Here, we test the hypothesis that activation of cathepsin B and L contributes to the ischemic astrocyte injury via the tBid‐mitochondrial apoptotic signaling pathways. In the rat models of pMCAO, CA‐074Me or Clik148, a selective inhibitor of cathepsin B or cathepsin L, reduced the infarct volume, improved the neurological deficits and increased the MAP₂ and GFAP levels. In OGD‐induced astrocyte injury, CA‐074Me or Clik148 decreased the LDH leakage and increased the GFAP levels. In the ischemic cortex or OGD‐induced astrocytes injury, Clik148 or CA‐074Me reversed pMCAO or OGD‐induced increase in active cathepsin L or cathepsin B at 3 h or 6 h, increase in tBid, reduction in mitochondrial cytochrome‐c (Cyt‐c) and increase in cytoplastic Cyt‐c and active caspase‐3 at 12–24 h of the late stage of pMCAO or OGD. CA‐074Me or Clik148 also reduced cytosolic and mitochondrial tBid, increased mitochondrial Cyt‐c and decreased cytoplastic Cyt‐c and active caspase‐3 at 6 h of the early stage of Bid activation. CA‐074Me or Clik148 blocked the pMCAO‐induced release of cathepsin B or L from the lysosomes into the cytoplasm and activation of caspase‐3 in ischemic astrocytes at 12 h after ischemia. Concurrent inhibition of cathepsin B and cathepsin L provided better protection on the OGD‐induced astrocytic apoptosis than obtained with separate use of each inhibitor. These results suggest that inhibition of the cysteine cathepsin B and cathepsin L activation in ischemic astrocytes contributes to neuroprotection via blocking the tBid‐mitochondrial apoptotic signaling pathway. GLIA 2014;62:855–880     

Soy β-conglycinin improves glucose uptake in skeletal muscle and ameliorates hepatic insulin resistance in Goto-Kakizaki rats

Although the underlying mechanism is unclear, β-conglycinin (βCG), the major component of soy proteins, regulates blood glucose levels. Here, we hypothesized that consumption of βCG would normalize blood glucose levels by ameliorating insulin resistance and stimulating glucose uptake in skeletal muscles. To test our hypothesis, we investigated the antidiabetic action of βCG in spontaneously diabetic Goto-Kakizaki (GK) rats. Our results revealed that plasma adiponectin levels and adiponectin receptor 1 messenger RNA expression in skeletal muscle were higher in βCG-fed rats than in casein-fed rats. Phosphorylation of adenosine monophosphate–activated protein kinase (AMP kinase) but not phosphatidylinositol-3 kinase was activated in βCG-fed GK rats. Subsequently, βCG increased translocation of glucose transporter 4 to the plasma membrane. Unlike the results in skeletal muscle, the increase in adiponectin receptor 1 did not lead to AMP kinase activation in the liver of βCG-fed rats. The down-regulation of sterol regulatory element-binding factor 1, which is induced by low insulin levels, promoted the increase in hepatic insulin receptor substrate 2 expression. Based on these findings, we concluded that consumption of soy βCG improves glucose uptake in skeletal muscle via AMP kinase activation and ameliorates hepatic insulin resistance and that these actions may help normalize blood glucose levels in GK rats.     

Metabolic changes induced by TGF-β1 via reduced expression of phosphatidylserine decarboxylase during myofibroblast transition

Metabolic alteration is increasingly recognized as an important pathogenic process that underlies fibrosis across many organ types, and metabolically targeted therapies could become important strategies for reducing fibrosis. In present study, target enzymes that are involved in changes in phospholipid metabolism during fibroblast-to-myofibroblast transition induced by transforming growth factor beta 1 (TGF-β1) were examined. Different amounts of phospholipids were found in the 2 groups. In response to TGF-β1 stimulation, 17 lipids decreased and 17 increased. The latter included the phospholipids phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylethanolamine (PE). Furthermore, among the rate-limiting enzymes that regulate these phospholipids, phosphatidylserine decarboxylase (PISD), which controls conversion of PS to PE and is localized in mitochondria, decreased in response to TGF-β1. Knockdown of PISD alone without TGF-β1 stimulation increased expression of α-smooth muscle actin mRNA and production of total collagen. Taken together, these results indicate that PISD is involved in the mechanism of fibrogenesis by regulating phospholipid metabolism.     

Plasma cell leukaemia of non-producer type with missing light chain gene rearrangement

A case of plasma cell leukaemia of non-producer type is described. The patient presented with typical clinical features of plasma cell myeloma, including multiple osteolytic lesions, hypercalcaemia, renal failure and reduced polyclonal immunoglobulins, except that M-component was not detected in either the serum or urine. Morphological examinations showed a plasmacytoid appearance of the neoplastic cells, while immunological studies failed to detect cytoplasmic immunoglobulin or secretory capacity. The surface phenotype of CD38+, PCA-1+, DR-, CD20-, CD24-, CD9-, CD10- and surface immunoglobulin- was compatible with mature plasma cells. Chromosomal analysis showed the 14q+ marker due to translocation (6;14) and deletion of the short arm of chromosome 1. Analysis of immunoglobulin genes revealed the presence of heavy chain gene rearrangement, but the light chain genes, both kappa and lambda, remained in germline configuration. Such defective immunoglobulin gene rearrangement may be responsible for the failure of immunoglobulin biosynthesis and secretion by the neoplastic plasma cells. Furthermore, it is suggested that the morphological and phenotypic development of B cells may not necessarily depend on immunoglobulin light chain gene rearrangement, and that the oncogenic event in myeloma may occur at an earlier stage of B cell differentiation.     

Utility of automated brachial ankle pulse wave velocity measurements in hypertensive patients

BACKGROUND: We examined whether pulse wave velocity (PWV), determined by brachial ankle arterial pressure wave measurements, using a newly developed, fully automated device could be a surrogate measure for carotid femoral PWV. METHODS & RESULTS: This device (AT-form PWV/ABI, Nippon Colin, Komaki, Japan) can simultaneously monitor bilateral brachial and ankle pressure wave forms using the volume plethysmographic method, with two optional tonometry sensors for carotid and femoral arterial wave measurements. We examined the right brachial-right ankle PWV and left carotid-left femoral PWV in 89 normotensive and untreated hypertensive patients. The brachial ankle PWV correlated well with carotid femoral PWV (r = 0.755, P <.00001). The Bland-Altman plots of the two variables, however, showed a significant difference exists between the two techniques over the range of measurement. The within-observer and between-observer coefficients of variation of the brachial ankle PWV were 6.5% +/- 4.1% and 3.6% +/- 3.9%, respectively. To determine the factors affecting brachial ankle PWV, we studied treated and untreated hypertensive patients with World Health Organization stage I (n = 146), stage II (n = 74), or stage III (n = 54). In multiple regression analysis, age, brachial ankle PWV, and the presence of diabetes were significant predictors of the severity of hypertensive organ damage. Age, systolic blood pressure, and the stage of hypertensive organ damage were major determinants of brachial ankle PWV. CONCLUSIONS: Although the brachial ankle PWV does not agree with the carotid femoral PWV, this parameter may yet become a new, useful measure for arterial stiffness. Further longitudinal studies are necessary to confirm the clinical significance of the brachial ankle PWV.