Age-specific diastolic dysfunction improves prediction of symptomatic heart failure by Stage B heart failure

Aims: We investigated whether addition of diastolic dysfunction (DD) and longitudinal strain (LS) to Stage B heart failure (SBHF) criteria (structural or systolic abnormality) improves prediction of symptomatic HF in participants of the SCReening Evaluation of the Evolution of New Heart Failure study, a self-selected population at increased cardiovascular disease risk recruited from members of a health insurance fund in Melbourne and Shepparton, Australia. Both American Society of Echocardiography and European Association of Cardiovascular Imaging (ASE/EACVI) criteria and age-specific Atherosclerosis Risk in Communities (ARIC) study criteria, for SBHF and DD, and ARIC criteria for abnormal LS, were examined. Methods and results: Inclusion criteria were age ≥60 years with one or more of self-reported ischaemic or other heart disease, irregular or rapid heart rhythm, cerebrovascular disease, renal impairment, or treatment for hypertension or diabetes for ≥2 years. Exclusion criteria were known HF, or ejection fraction mild valve abnormality detected on previous echocardiography or other imaging. Echocardiography was performed in 3190 participants who were followed for a median of 3.9 (interquartile range: 3.4, 4.5) years after echocardiography. Symptomatic HF was diagnosed in 139 participants at a median of 3.1 (interquartile range: 2.1, 3.9) years after echocardiography. ARIC structural, systolic, and diastolic abnormalities predicted HF in univariate and multivariable proportional hazards analyses, whereas ASE/EACVI structural and systolic, but not diastolic, abnormalities predicted HF. ARIC and ASE/EACVI SBHF criteria predicted HF with sensitivities of 81% and 55%, specificities of 39% and 76%, and C statistics of 0.60 (95% confidence interval: 0.57, 0.64) and 0.66 (0.61, 0.71), respectively. Adding ARIC DD to SBHF increased sensitivity to 94% with specificity of 24% and C statistic of 0.59 (0.57, 0.61), whereas addition of ASE/EACVI DD to SBHF increased sensitivity to 97% but reduced specificity to 9% and the C statistic to 0.52 (0.50, 0.54, P < 0.0001). Addition of LS to ARIC or ASE/EACVI SBHF criteria had minimal impact on prediction of HF. Conclusions: Age-specific ARIC DD criteria, but not ASE/EACVI DD criteria, predicted symptomatic HF, and addition of age-specific ARIC DD criteria to ARIC SBHF criteria improved prediction of symptomatic HF in asymptomatic individuals with cardiovascular disease risk factors. Addition of LS to ASE/EACVI or ARIC SBHF criteria did not improve prediction of symptomatic HF

Risk factors for incident heart failure with preserved or reduced ejection fraction, and valvular heart failure, in a community-based cohort

Background: The lack of effective therapies for heart failure with preserved ejection fraction (HFpEF) reflects an incomplete understanding of its pathogenesis. Design: We analysed baseline risk factors for incident HFpEF, heart failure with reduced ejection fraction (HFrEF) and valvular heart failure (VHF) in a community-based cohort. Methods: We recruited 2101 men and 1746 women =60 years of age with hypertension, diabetes, ischaemic heart disease (IHD), abnormal heart rhythm, cerebrovascular disease or renal impairment. Exclusion criteria were known heart failure, left ventricular ejection fraction mild in severity. Median follow-up was 5.6 (IQR 4.6-6.3) years. Results: Median time to heart failure diagnosis in 162 participants was 4.5 (IQR 2.7-5.4) years, 73 with HFpEF, 53 with HFrEF and 36 with VHF. Baseline age and amino-terminal pro-B-type natriuretic peptide levels were associated with HFpEF, HFrEF and VHF. Pulse pressure, IHD, waist circumference, obstructive sleep apnoea and pacemaker were associated with HFpEF and HFrEF; atrial fibrillation (AF) and warfarin therapy were associated with HFpEF and VHF and peripheral vascular disease and low platelet count were associated with HFrEF and VHF. Additional risk factors for HFpEF were body mass index (BMI), hypertension, diabetes, renal dysfunction, low haemoglobin, white cell count and ß-blocker, statin, loop diuretic, non-steroidal anti-inflammatory and clopidogrel therapies, for HFrEF were male gender and cigarette smoking and for VHF were low diastolic blood pressure and alcohol intake. BMI, diabetes, low haemoglobin, white cell count and warfarin therapy were more strongly associated with HFpEF than HFrEF, whereas male gender and low platelet count were more strongly associated with HFrEF than HFpEF. Conclusions: Our data suggest a major role for BMI, hypertension, diabetes, renal dysfunction, and inflammation in HFpEF pathogenesis; strategies directed to prevention of these risk factors may prevent a sizeable proportion of HFpEF in the community. Trial registration number: NCT00400257, NCT00604006 and NCT01581827

Bottleneck co-ownership as a regulatory alternative

This paper proposes a regulatory mechanism for vertically related industries in which the upstream “bottleneck” segment faces significant returns to scale while other (downstream) segments may be more competitive. In the proposed mechanism, the ownership of the upstream firm is allocated to downstream firms in proportion to their shares of input purchases. This mechanism, while preserving downstream competition, partially internalizes the benefits of exploiting economies of scale resulting from an increase in downstream output. We show that this mechanism is more efficient than a disintegrated market structure in which the upstream natural monopoly bottleneck sets a price equal to average cost

Histone deacetylase inhibitor, butyrate, attenuates lipopolysaccharide-induced acute lung injury in mice

<p>Abstract</p> <p>Background</p> <p>Histone deacetylase (HDAC) inhibitors, developed as promising anti-tumor drugs, exhibit their anti-inflammatory properties due to their effects on reduction of inflammatory cytokines.</p> <p>Objective</p> <p>To investigate the protective effect of butyrate, a HDAC inhibitor, on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice.</p> <p>Methods</p> <p>ALI was induced in Balb/c mice by intratracheally instillation of LPS (1 mg/kg). Before 1 hour of LPS administration, the mice received butyrate (10 mg/kg) orally. The animals in each group were sacrificed at different time point after LPS administration. Pulmonary histological changes were evaluated by hematoxylin-eosin stain and lung wet/dry weight ratios were observed. Concentrations of interleukin (IL)-1β and tumor necrosis factor (TNF)-α in bronchoalveolar lavage fluid (BALF) and concentrations of nitric oxide (NO) and myeloperoxidase (MPO) activity in lung tissue homogenates were measured by enzyme-linked immunosorbent assay (ELISA). Expression of nuclear factor (NF)-κB p65 in cytoplasm and nucleus was determined by Western blot analysis respectively.</p> <p>Results</p> <p>Pretreatment with butyrate led to significant attenuation of LPS induced evident lung histopathological changes, alveolar hemorrhage, and neutrophils infiltration with evidence of reduced MPO activity. The lung wet/dry weight ratios, as an index of lung edema, were reduced by butyrate administration. Butyrate also repressed the production of TNF-α, IL-1β and NO. Furthermore, the expression of NF-κB p65 in nucleus was markedly suppressed by butyrate pretreatment.</p> <p>Conclusions</p> <p>Butyrate had a protective effect on LPS-induced ALI, which may be related to its effect on suppression of inflammatory cytokines production and NF-κB activation.</p

The Extended Cleavage Specificity of Human Thrombin

Thrombin is one of the most extensively studied of all proteases. Its central role in the coagulation cascade as well as several other areas has been thoroughly documented. Despite this, its consensus cleavage site has never been determined in detail. Here we have determined its extended substrate recognition profile using phage-display technology. The consensus recognition sequence was identified as, P2-Pro, P1-Arg, P1′-Ser/Ala/Gly/Thr, P2′-not acidic and P3′-Arg. Our analysis also identifies an important role for a P3′-arginine in thrombin substrates lacking a P2-proline. In order to study kinetics of this cooperative or additive effect we developed a system for insertion of various pre-selected cleavable sequences in a linker region between two thioredoxin molecules. Using this system we show that mutations of P2-Pro and P3′-Arg lead to an approximate 20-fold and 14-fold reduction, respectively in the rate of cleavage. Mutating both Pro and Arg results in a drop in cleavage of 200–400 times, which highlights the importance of these two positions for maximal substrate cleavage. Interestingly, no natural substrates display the obtained consensus sequence but represent sequences that show only 1–30% of the optimal cleavage rate for thrombin. This clearly indicates that maximal cleavage, excluding the help of exosite interactions, is not always desired, which may instead cause problems with dysregulated coagulation. It is likely exosite cooperativity has a central role in determining the specificity and rate of cleavage of many of these in vivo substrates. Major effects on cleavage efficiency were also observed for residues as far away as 4 amino acids from the cleavage site. Insertion of an aspartic acid in position P4 resulted in a drop in cleavage by a factor of almost 20 times

Thermodynamics of mixing in diopside-jadeite, CaMgSi2O6-NaAlSi2O6, solid solution from staticlattice energy calculations

Static lattice energy calculations (SLEC), based on empirical interatomic potentials, have beenperformed for a set of 800 different structures in a 2 2 4 supercell of C2/c diopside with compositionsbetween diopside and jadeite, and with different states of order of the exchangeable Na/Ca and Mg/Al cations. Excess static energies of these structures have been cluster expanded in a basis set of 37 pair-interaction parameters. These parameters have been used to constrain Monte Carlo simulations of temperature-dependent properties in the range of 273?2,023 K and to calculate a temperature?composition phase diagram. The simulations predict the order?disorder transition in omphacite at1,150 20C in good agreement with the experimental data of Carpenter (Mineral Petrol 78:433?440, 1981). The stronger ordering of Mg/Al within the M1 site than of Ca/Na in the M2 site is attributed to the shorter M1?M1 nearest-neighbor distance, and, consequently, the stronger ordering force. The comparison of the simulated relationship between the order parameters corresponding to M1 and M2 sites with the X-ray refinement data on natural omphacites (Boffa Ballaran et al. in Am Mineral83:419?433, 1998) suggests that the cation ordering becomes kinetically ineffective at about 600C