Cardiac Biomarkers and Risk of Atrial Fibrillation in Chronic Kidney Disease: The CRIC Study.

Background We tested associations of cardiac biomarkers of myocardial stretch, injury, inflammation, and fibrosis with the risk of incident atrial fibrillation (AF) in a prospective study of chronic kidney disease patients. Methods and Results The study sample was 3053 participants with chronic kidney disease in the multicenter CRIC (Chronic Renal Insufficiency Cohort) study who were not identified as having AF at baseline. Cardiac biomarkers, measured at baseline, were NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity troponin T, galectin-3, growth differentiation factor-15, and soluble ST-2. Incident AF ("AF event") was defined as a hospitalization for AF. During a median follow-up of 8 years, 279 (9%) participants developed a new AF event. In adjusted models, higher baseline log-transformed NT-proBNP (N-terminal pro-B-type natriuretic peptide) was associated with incident AF (adjusted hazard ratio [HR] per SD higher concentration: 2.11; 95% CI, 1.75, 2.55), as was log-high-sensitivity troponin T (HR 1.42; 95% CI, 1.20, 1.68). These associations showed a dose-response relationship in categorical analyses. Although log-soluble ST-2 was associated with AF risk in continuous models (HR per SD higher concentration 1.35; 95% CI, 1.16, 1.58), this association was not consistent in categorical analyses. Log-galectin-3 (HR 1.05; 95% CI, 0.91, 1.22) and log-growth differentiation factor-15 (HR 1.16; 95% CI, 0.96, 1.40) were not significantly associated with incident AF. Conclusions We found strong associations between higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity troponin T concentrations, and the risk of incident AF in a large cohort of participants with chronic kidney disease. Increased atrial myocardial stretch and myocardial cell injury may be implicated in the high burden of AF in patients with chronic kidney disease

Functional characterization of a melon alcohol acyl-transferase gene family involved in the biosynthesis of ester volatiles. Identification of the crucial role of a threonine residue for enzyme activity

Volatile esters, a major class of compounds contributing to the aroma of many fruit, are synthesized by alcohol acyl-transferases (AAT). We demonstrate here that, in Charentais melon (Cucumis melo var. cantalupensis), AAT are encoded by a gene family of at least four members with amino acid identity ranging from 84% (Cm-AAT1/Cm-AAT2) and 58% (Cm-AAT1/Cm-AAT3) to only 22% (Cm-AAT1/Cm-AAT4). All encoded proteins, except Cm-AAT2, were enzymatically active upon expression in yeast and show differential substrate preferences. Cm-AAT1 protein produces a wide range of short and long-chain acyl esters but has strong preference for the formation of E-2-hexenyl acetate and hexyl hexanoate. Cm-AAT3 also accepts a wide range of substrates but with very strong preference for producing benzyl acetate. Cm-AAT4 is almost exclusively devoted to the formation of acetates, with strong preference for cinnamoyl acetate. Site directed mutagenesis demonstrated that the failure of Cm-AAT2 to produce volatile esters is related to the presence of a 268-alanine residue instead of threonine as in all active AAT proteins. Mutating 268-A into 268-T of Cm-AAT2 restored enzyme activity, while mutating 268-T into 268-A abolished activity of Cm-AAT1. Activities of all three proteins measured with the prefered substrates sharply increase during fruit ripening. The expression of all Cm-AAT genes is up-regulated during ripening and inhibited in antisense ACC oxidase melons and in fruit treated with the ethylene antagonist 1-methylcyclopropene (1-MCP), indicating a positive regulation by ethylene. The data presented in this work suggest that the multiplicity of AAT genes accounts for the great diversity of esters formed in melon

Protein kinase Cepsilon is important for migration of neuroblastoma cells

<p>Abstract</p> <p>Background</p> <p>Migration is important for the metastatic capacity and thus for the malignancy of cancer cells. There is limited knowledge on regulatory factors that promote the migration of neuroblastoma cells. This study investigates the hypothesis that protein kinase C (PKC) isoforms regulate neuroblastoma cell motility.</p> <p>Methods</p> <p>PKC isoforms were downregulated with siRNA or modulated with activators and inhibitors. Migration was analyzed with scratch and transwell assays. Protein phosphorylation and expression levels were measured with Western blot.</p> <p>Results</p> <p>Stimulation with 12-<it>O</it>-tetradecanoylphorbol-13-acetate (TPA) induced migration of SK-N-BE(2)C neuroblastoma cells. Treatment with the general protein kinase C (PKC) inhibitor GF109203X and the inhibitor of classical isoforms Gö6976 inhibited migration while an inhibitor of PKCβ isoforms did not have an effect. Downregulation of PKCε, but not of PKCα or PKCδ, with siRNA led to a suppression of both basal and TPA-stimulated migration. Experiments using PD98059 and LY294002, inhibitors of the Erk and phosphatidylinositol 3-kinase (PI3K) pathways, respectively, showed that PI3K is not necessary for TPA-induced migration. The Erk pathway might be involved in TPA-induced migration but not in migration driven by PKCε. TPA induced phosphorylation of the PKC substrate myristoylated alanine-rich C kinase substrate (MARCKS) which was suppressed by the PKC inhibitors. Treatment with siRNA oligonucleotides against different PKC isoforms before stimulation with TPA did not influence the phosphorylation of MARCKS.</p> <p>Conclusion</p> <p>PKCε is important for migration of SK-N-BE(2)C neuroblastoma cells. Neither the Erk pathway nor MARCKS are critical downstream targets of PKCε but they may be involved in TPA-mediated migration.</p

Economic analysis including long-term risks and costs of alternative diagnostic strategies to evaluate patients with chest pain

Background: Diagnosis costs for cardiovascular disease waste a large amount of healthcare resources. The aim of the study is to evaluate the clinical and economic outcomes of alternative diagnostic strategies in low risk chest pain patients. Methods: We evaluated direct and indirect downstream costs of 6 strategies: coronary angiography (CA) after positive troponin I or T (cTn-I or cTnT) (strategy 1); after positive exercise electrocardiography (ex-ECG) (strategy 2); after positive exercise echocardiography (ex-Echo) (strategy 3); after positive pharmacologic stress echocardiography (PhSE) (strategy 4); after positive myocardial exercise stress single-photon emission computed tomography with technetium Tc 99m sestamibi (ex-SPECT-Tc) (strategy 5) and direct CA (strategy 6). Results: The predictive accuracy in correctly identifying the patients was 83,1% for cTn-I, 87% for cTn-T, 85,1% for ex-ECG, 93,4% for ex-Echo, 98,5% for PhSE, 89,4% for ex-SPECT-Tc and 18,7% for CA. The cost per patient correctly identified results $2.051 for cTn-I,$2.086 for cTn-T, $1.890 for ex-ECG,$803 for ex-Echo, $533 for PhSE,$1.521 for ex-SPECT-Tc ($1.634 including cost of extra risk of cancer) and$29.673 for CA ($29.999 including cost of extra risk of cancer). The average relative cost-effectiveness of cardiac imaging compared with the PhSE equal to 1 (as a cost comparator), the relative cost of ex-Echo is 1.5×, of a ex-SPECT-Tc is 3.1×, of a ex-ECG is 3.5×, of cTnI is ×3.8, of cTnT is ×3.9 and of a CA is 56.3×. Conclusion: Stress echocardiography based strategies are cost-effective versus alternative imaging strategies and the risk and cost of radiation exposure is void

The docking protein p130Cas regulates cell sensitivity to proteasome inhibition

<p>Abstract</p> <p>Background</p> <p>The focal adhesion protein p130Cas (Cas) activates multiple intracellular signaling pathways upon integrin or growth factor receptor ligation. Full-length Cas frequently promotes cell survival and migration, while its C-terminal fragment (Cas-CT) produced upon intracellular proteolysis is known to induce apoptosis in some circumstances. Here, we have studied the putative role of Cas in regulating cell survival and death pathways upon proteasome inhibition.</p> <p>Results</p> <p>We found that Cas-/- mouse embryonic fibroblasts (MEFs), as well as empty vector-transfected Cas-/- MEFs (Cas-/- (EV)) are significantly resistant to cell death induced by proteasome inhibitors, such as MG132 and Bortezomib. As expected, wild-type MEFs (WT) and Cas-/- MEFs reconstituted with full-length Cas (Cas-FL) were sensitive to MG132- and Bortezomib-induced apoptosis that involved activation of a caspase-cascade, including Caspase-8. Cas-CT generation was not required for MG132-induced cell death, since expression of cleavage-resistant Cas mutants effectively increased sensitivity of Cas-/- MEFs to MG132. At the present time, the domains in Cas and the downstream pathways that are required for mediating cell death induced by proteasome inhibitors remain unknown. Interestingly, however, MG132 or Bortezomib treatment resulted in activation of autophagy in cells that lacked Cas, but not in cells that expressed Cas. Furthermore, autophagy was found to play a protective role in Cas-deficient cells, as inhibition of autophagy either by chemical or genetic means enhanced MG132-induced apoptosis in Cas-/- (EV) cells, but not in Cas-FL cells. Lack of Cas also contributed to resistance to the DNA-damaging agent Doxorubicin, which coincided with Doxorubicin-induced autophagy in Cas-/- (EV) cells. Thus, Cas may have a regulatory role in cell death signaling in response to multiple different stimuli. The mechanisms by which Cas inhibits induction of autophagy and affects cell death pathways are currently being investigated.</p> <p>Conclusion</p> <p>Our study demonstrates that Cas is required for apoptosis that is induced by proteasome inhibition, and potentially by other death stimuli. We additionally show that Cas may promote such apoptosis, at least partially, by inhibiting autophagy. This is the first demonstration of Cas being involved in the regulation of autophagy, adding to the previous findings by others linking focal adhesion components to the process of autophagy.</p

BCAR1 Protein Plays Important Roles in Carcinogenesis and Predicts Poor Prognosis in Non-Small-Cell Lung Cancer

Objective: Our previous study suggested the potential clinical implications of BCAR1 in non-small-cell lung cancer (NSCLC) (Mol Diagn Ther. 2011. 15(1): 31–40). Herein, we aim to evaluate the predictive power of BCAR1 as a marker for poor prognosis in NSCLC cases, verify the carcinogenic roles of BCAR1 in the A549 lung adenocarcinoma cell line, and testify to the BCAR1/phospho-p38 axis. Methods: Between January 2006 and June 2010, there were a total of 182 patients with NSCLC (151 cases with available follow up data, and 31 cases lost to follow-up due to the invalid contact information). We inspected BCAR1, phospho-BCAR1(Tyr410), phospho-p38(Thr180/Tyr182) and p38 expression in NSCLC tissues and matched adjacent normal tissues by immunoblotting and IHC. After BCAR1-RNA interference in A549 cells, we inspected the protein expression (BCAR1, phospho-BCAR1, phospho-p38 and p38) and performed cell biology experiments (cell growth, migration and cycle). Results: BCAR1 was overexpressed in NSCLC tissues (177/182) and cell lines (A549 and Calu-3). However, it was not detected in the normal adjacent tissue in 161 of the 182 cases. Higher BCAR1 levels were strongly associated with more poorly differentiated NSCLC and predicted poorer prognosis. BCAR1 knockdown caused cell growth arrest, cell migration inhibition and cell cycle arrest of A549 cells. Overexpression of BCAR1 was associated with activation of p38 in NSCLC cases, and BCAR1 knockdown caused reduction of phospho-p38 levels in A549 cells

Chronic Kidney Disease and Coronary Artery Disease: JACC State-of-the-Art Review

Chronic kidney disease (CKD) is a major risk factor for coronary artery disease (CAD). As well as their high prevalence of traditional CAD risk factors, such as diabetes and hypertension, persons with CKD are also exposed to other nontraditional, uremia-related cardiovascular disease risk factors, including inflammation, oxidative stress, and abnormal calcium-phosphorus metabolism. CKD and end-stage kidney disease not only increase the risk of CAD, but they also modify its clinical presentation and cardinal symptoms. Management of CAD is complicated in CKD patients, due to their\ua0likelihood of comorbid conditions and potential for side effects during interventions. This summary of the Kidney\ua0Disease: Improving Global Outcomes (KDIGO) Controversies Conference on CAD and CKD (including end-stage\ua0kidney disease and\ua0transplant recipients) seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and\ua0treatment of CAD in CKD and to identify knowledge gaps, areas of controversy, and\ua0priorities for research

Prescribing patterns in dementia: a multicentre observational study in a German network of CAM physicians

<p>Abstract</p> <p>Background</p> <p>Dementia is a major and increasing health problem worldwide. This study aims to investigate dementia treatment strategies among physicians specialised in complementary and alternative medicine (CAM) by analysing prescribing patterns and comparing them to current treatment guidelines in Germany.</p> <p>Methods</p> <p>Twenty-two primary care physicians in Germany participated in this prospective, multicentre observational study. Prescriptions and diagnoses were reported for each consecutive patient. Data were included if patients had at least one diagnosis of dementia according to the 10th revision of the International Classification of Diseases during the study period. Multiple logistic regression was used to determine factors associated with a prescription of any anti-dementia drug including <it>Ginkgo biloba</it>.</p> <p>Results</p> <p>During the 5-year study period (2004-2008), 577 patients with dementia were included (median age: 81 years (IQR: 74-87); 69% female). Dementia was classified as unspecified dementia (57.2%), vascular dementia (25.1%), dementia in Alzheimer's disease (10.4%), and dementia in Parkinson's disease (7.3%). The prevalence of anti-dementia drugs was 25.6%. The phytopharmaceutical <it>Ginkgo biloba </it>was the most frequently prescribed anti-dementia drug overall (67.6% of all) followed by cholinesterase inhibitors (17.6%). The adjusted odds ratio (AOR) for receiving any anti-dementia drug was greater than 1 for neurologists (AOR = 2.34; CI: 1.59-3.47), the diagnosis of Alzheimer's disease (AOR = 3.28; CI: 1.96-5.50), neuroleptic therapy (AOR = 1.87; CI: 1.22-2.88), co-morbidities hypertension (AOR = 2.03; CI: 1.41-2.90), and heart failure (AOR = 4.85; CI: 3.42-6.88). The chance for a prescription of any anti-dementia drug decreased with the diagnosis of vascular dementia (AOR = 0.64; CI: 0.43-0.95) and diabetes mellitus (AOR = 0.55; CI: 0.36-0.86). The prescription of <it>Ginkgo biloba </it>was associated with sex (female: AOR = 0.41; CI: 0.19-0.89), patient age (AOR = 1.06; CI: 1.02-1.10), treatment by a neurologist (AOR = 0.09; CI: 0.03-0.23), and the diagnosis of Alzheimer's disease (AOR = 0.07; CI: 0.04-0.16).</p> <p>Conclusions</p> <p>This study provides a comprehensive analysis of everyday practice for treatment of dementia in primary care in physicians with a focus on CAM. The prescribing frequency for anti-dementia drugs is equivalent to those found in other German studies, while the administration of <it>Ginkgo biloba </it>is significantly higher.</p

Elevated plasma levels of cardiac troponin-I predict left ventricular systolic dysfunction in patients with myotonic dystrophy type 1:A multicentre cohort follow-up study

Objective: High sensitivity plasma cardiac troponin-I (cTnI) is emerging as a strong predictor of cardiac events in a variety of settings. We have explored its utility in patients with myotonic dystrophy type 1 (DM1). Methods: 117 patients with DM1 were recruited from routine outpatient clinics across three health boards. A single measurement of cTnI was made using the ARCHITECT STAT Troponin I assay. Demographic, ECG, echocardiographic and other clinical data were obtained from electronic medical records. Follow up was for a mean of 23 months. Results: Fifty five females and 62 males (mean age 47.7 years) were included. Complete data were available for ECG in 107, echocardiography in 53. Muscle Impairment Rating Scale score was recorded for all patients. A highly significant excess (p = 0.0007) of DM1 patients presented with cTnI levels greater than the 99th centile of the range usually observed in the general population (9 patients; 7.6%). Three patients with elevated troponin were found to have left ventricular systolic dysfunction (LVSD), compared with four of those with normal range cTnI (33.3% versus 3.7%; p = 0.001). Sixty two patients had a cTnI level &#60; 5ng/L, of whom only one had documented evidence of LVSD. Elevated cTnI was not predictive of severe conduction abnormalities on ECG, or presence of a cardiac device, nor did cTnI level correlate with muscle strength expressed by Muscle Impairment Rating Scale score. Conclusions: Plasma cTnI is highly elevated in some ambulatory patients with DM1 and shows promise as a tool to aid cardiac risk stratification, possibly by detecting myocardial involvement. Further studies with larger patient numbers are warranted to assess its utility in this setting

Association of Glomerular Filtration Rate with High-Sensitivity Cardiac Troponin T in a Community-Based Population Study in Beijing

BACKGROUND: Reduced renal function is an independent risk factor for cardiovascular disease mortality, and persistently elevated cardiac troponin T (cTnT) is frequently observed in patients with end-stage renal disease. In the general population the relationship between renal function and cTnT levels may not be clear because of the low sensitivity of the assay. In this study, we investigated the level of cTnT using a highly sensitive assay (hs-cTnT) and evaluated the association of estimated glomerular filtration rate (eGFR) with detectable hs-cTnT levels in a community-based population. METHODS: The serum hs-cTnT levels were measured in 1365 community dwelling population aged ≥45 years in Beijing, China. eGFR was determined by the Chinese modifying modification of diet in renal disease (C-MDRD) equation. RESULTS: With the highly sensitive assay, cTnT levels were detectable (≥3pg/mL) in 744 subjects (54.5%). The result showed that eGFR was associated with Log hs-cTnT (r = -0.14, P<0.001). After adjustment for the high predicted Framingham Coronary Heart Disease (CHD) risk (10-year risk >20%) and other prognostic indicators, moderate to severe reduced eGFR was independently associated with detectable hs-cTnT, whereas normal to mildly reduced eGFR was not independently associated with detectable hs-cTnT. In addition, after adjustment for other risk factors, the high predicted Framingham CHD risk was associated with detectable hs-cTnT in the subjects with different quartile levels of eGFR. CONCLUSION: The levels of hs-cTnT are detectable in a community-based Chinese population and low eGFR is associated with detectable hs-cTnT. Moreover, eGFR and high predicted Framingham CHD risk are associated with detectable hs-cTnT in subjects with moderate-to-severe reduced renal function