Accuracy of Self-Reported Heart Failure. The Atherosclerosis Risk in Communities (ARIC) Study

Objective The aim of this work was to estimate agreement of self-reported heart failure (HF) with physician-diagnosed HF and compare the prevalence of HF according to method of ascertainment. Methods and Results ARIC cohort members (60–83 years of age) were asked annually whether a physician indicated that they have HF. For those self-reporting HF, physicians were asked to confirm their patients' HF status. Physician-diagnosed HF included surveillance of hospitalized HF and hospitalized and outpatient HF identified in administrative claims databases. We estimated sensitivity, specificity, positive predicted value, kappa, prevalence and bias–adjusted kappa (PABAK), and prevalence. Compared with physician-diagnosed HF, sensitivity of self-report was low (28%–38%) and specificity was high (96%–97%). Agreement was poor (kappa 0.32–0.39) and increased when adjusted for prevalence and bias (PABAK 0.73–0.83). Prevalence of HF measured by self-report (9.0%), ARIC-classified hospitalizations (11.2%), and administrative hospitalization claims (12.7%) were similar. When outpatient HF claims were included, prevalence of HF increased to 18.6%. Conclusions For accurate estimates HF burden, self-reports of HF are best confirmed by means of appropriate diagnostic tests or medical records. Our results highlight the need for improved awareness and understanding of HF by patients, because accurate patient awareness of the diagnosis may enhance management of this common condition

Bupleurum chinense Roots: a Bioactivity-Guided Approach toward Saponin-Type NF-κB Inhibitors

The roots of Bupleurum chinense have a long history in traditional medicine to treat infectious diseases and inflammatory disorders. Two major compounds, saikosaponins A and D, were reported to exert potent anti-inflammatory activity by inhibiting NF-κB. In the present study, we isolated new saikosaponin analogues from the roots of B. chinese interfering with NF-κB activity in vitro. The methanol-soluble fraction of the dichloromethane extract of Radix Bupleuri was subjected to activity-guided isolation yielding 18 compounds, including triterpenoids and polyacetylenes. Their structures were determined by spectroscopic methods as saikogenin D (1), prosaikogenin D (2), saikosaponins B2 (3), W (4), B1 (5), Y (6), D (7), A (8), E (9), B4 (10), B3 (11), and T (12), saikodiyne A (13), D (14), E (15) and F (16), falcarindiol (17), and 1-linoleoyl-sn-glycero-3-phosphorylcholine (18). Among them, 4, 15, and 16 are new compounds, whereas 6, previously described as a semi-synthetic compound, is isolated from a natural source for the first time, and 13–17 are the first reports of polyacetylenes from this plant. Nine saponins/triterpenoids were tested for inhibition of NF-κB signaling in a cell-based NF-κB-dependent luciferase reporter gene model in vitro. Five of them (1, 2, 4, 6, and 8) showed strong (> 50%, at 30 µM) NF-κB inhibition, but also varying degrees of cytotoxicity, with compounds 1 and 4 (showing no significant cytotoxicity) presenting IC50 values of 14.0 µM and 14.1 µM in the cell-based assay, respectively

Polyacetylenes from Notopterygium incisum–New Selective Partial Agonists of Peroxisome Proliferator-Activated Receptor-Gamma

Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of glucose and lipid metabolism and therefore an important pharmacological target to combat metabolic diseases. Since the currently used full PPARγ agonists display serious side effects, identification of novel ligands, particularly partial agonists, is highly relevant. Searching for new active compounds, we investigated extracts of the underground parts of Notopterygium incisum, a medicinal plant used in traditional Chinese medicine, and observed significant PPARγ activation using a PPARγ-driven luciferase reporter model. Activity-guided fractionation of the dichloromethane extract led to the isolation of six polyacetylenes, which displayed properties of selective partial PPARγ agonists in the luciferase reporter model. Since PPARγ activation by this class of compounds has so far not been reported, we have chosen the prototypical polyacetylene falcarindiol for further investigation. The effect of falcarindiol (10 µM) in the luciferase reporter model was blocked upon co-treatment with the PPARγ antagonist T0070907 (1 µM). Falcarindiol bound to the purified human PPARγ receptor with a Ki of 3.07 µM. In silico docking studies suggested a binding mode within the ligand binding site, where hydrogen bonds to Cys285 and Glu295 are predicted to be formed in addition to extensive hydrophobic interactions. Furthermore, falcarindiol further induced 3T3-L1 preadipocyte differentiation and enhanced the insulin-induced glucose uptake in differentiated 3T3-L1 adipocytes confirming effectiveness in cell models with endogenous PPARγ expression. In conclusion, we identified falcarindiol-type polyacetylenes as a novel class of natural partial PPARγ agonists, having potential to be further explored as pharmaceutical leads or dietary supplements

Plant extracts in cell-based anti-inflammatory assays—Pitfalls and considerations related to removal of activity masking bulk components

Plants used in traditional medicine represent an important source of new lead compounds. However, cell-based in vitro screening assays with plant material are hampered by the complex nature of plant extracts as mixtures of active and inactive components. Bulk constituents, such as chlorophyll and polyphenols were previously shown to interfere with several biological in vitro assays. Their influence on anti-inflammatory cell-based testing systems has not been thoroughly investigated. Hence, the present study was aimed at comparing different procedures for the removal of bulk constituents from plant extracts and examining the influence of their elimination on selected cell-based anti-inflammatory assays. Malva sp. and Glechoma hederacea L., two plants used in traditional European medicine for the treatment of inflammatory disorders, were subjected to three different methods for the removal of chlorophyll and polyphenols, respectively. Removal of bulk constituents was confirmed by HPLC and mass spectrometry. Extracts were tested before and after the purification procedure, to determine their potential to inhibit the activation of the transcription factor NF-κB in reporter gene assay and to interfere with the secretion of the chemokine IL-8 after stimulation of endothelial cells with tumor necrosis factor (TNF-α) or lipopolysaccharide (LPS). Removal of chlorophyll from tested extracts led to a strong decrease in the anti-inflammatory activities, due to loss of bioactive constituents. In contrast, the effect of the polyphenol-free extracts was either not changed or significantly increased, depending on the purification method used. The study concluded that clearance of bulk compounds represents a valuable strategy for cell-based in vitro anti-inflammatory evaluation of plant extracts. Liquid–liquid partitioning was identified as the optimal method for the elimination of both chlorophyll and polyphenols. It is recommended that removal of chlorophyll from extracts always be accompanied by HPLC profiling to detect a possible loss of active constituents

Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium

Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stageGWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with totalmortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3). Conclusions QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders

Application of the Euler method EUFLEX to a fighter-type airplane configuration at transonic speed

With 10 refs., 23 figs.Copy held by FIZ Karlsruhe; available from UB/TIB Hannover / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman