Dexamethasone induces apoptosis in pulmonary arterial smooth muscle cells

BACKGROUND: Dexamethasone suppressed inflammation and haemodynamic changes in an animal model of pulmonary arterial hypertension (PAH). A major target for dexamethasone actions is NF-κB, which is activated in pulmonary vascular cells and perivascular inflammatory cells in PAH. Reverse remodelling is an important concept in PAH disease therapy, and further to its anti-proliferative effects, we sought to explore whether dexamethasone augments pulmonary arterial smooth muscle cell (PASMC) apoptosis. METHODS: Analysis of apoptosis markers (caspase 3, in-situ DNA fragmentation) and NF-κB (p65 and phospho-IKK-α/β) activation was performed on lung tissue from rats with monocrotaline (MCT)-induced pulmonary hypertension (PH), before and after day 14–28 treatment with dexamethasone (5 mg/kg/day). PASMC were cultured from this rat PH model and from normal human lung following lung cancer surgery. Following stimulation with TNF-α (10 ng/ml), the effects of dexamethasone (10(−8)–10(−6) M) and IKK2 (NF-κB) inhibition (AS602868, 0–3 μM (0-3×10(−6) M) on IL-6 and CXCL8 release and apoptosis was determined by ELISA and by Hoechst staining. NF-κB activation was measured by TransAm assay. RESULTS: Dexamethasone treatment of rats with MCT-induced PH in vivo led to PASMC apoptosis as displayed by increased caspase 3 expression and DNA fragmentation. A similar effect was seen in vitro using TNF-α-simulated human and rat PASMC following both dexamethasone and IKK2 inhibition. Increased apoptosis was associated with a reduction in NF-κB activation and in IL-6 and CXCL8 release from PASMC. CONCLUSIONS: Dexamethasone exerted reverse-remodelling effects by augmenting apoptosis and reversing inflammation in PASMC possibly via inhibition of NF-κB. Future PAH therapies may involve targeting these important inflammatory pathways

miR-322-5p targets IGF-1 and is suppressed in the heart of rats with pulmonary hypertension

Pulmonary arterial hypertension (PAH) is characterised by remodelling of the pulmonary vasculature leading to right ventricular hypertrophy. Here we show that miR-322-5p (the rodent orthologue of miR-424-5p) expression is decreased in the right ventricle of monocrotaline-treated rats, a model of PAH, whereas a putative target insulin-like growth factor 1 (IGF-1) is increased. IGF-1 mRNA was enriched 16-fold in RNA immunoprecipitated with Ago2, indicating binding to miR-322-5p. In cell transfection experiments, miR-322-5p suppressed the activity of a luciferase reporter containing a section of the IGF-1 3′ untranslated region (UTR) as well as IGF-1 mRNA and protein levels. Taken together, these data suggest that miR-322 targets IGF-1, a process downregulated in PAH-related RV hypertrophy

Climate prediction of El Niño malaria epidemics in north-west Tanzania

Malaria is a significant public health problem in Tanzania. Approximately 16 million malaria cases are reported every year and 100,000 to 125,000 deaths occur. Although most of Tanzania is endemic to malaria, epidemics occur in the highlands, notably in Kagera, a region that was subject to widespread malaria epidemics in 1997 and 1998. This study examined the relationship between climate and malaria incidence in Kagera with the aim of determining whether seasonal forecasts may assist in predicting malaria epidemics. A regression analysis was performed on retrospective malaria and climatic data during each of the two annual malaria seasons to determine the climatic factors influencing malaria incidence. The ability of the DEMETER seasonal forecasting system in predicting the climatic anomalies associated with malaria epidemics was then assessed for each malaria season. It was found that malaria incidence is positively correlated with rainfall during the first season (Oct-Mar) (R-squared = 0.73, p < 0.01). For the second season (Apr-Sep), high malaria incidence was associated with increased rainfall, but also with high maximum temperature during the first rainy season (multiple R-squared = 0.79, p < 0.01). The robustness of these statistical models was tested by excluding the two epidemic years from the regression analysis. DEMETER would have been unable to predict the heavy El Niño rains associated with the 1998 epidemic. Nevertheless, this epidemic could still have been predicted using the temperature forecasts alone. The 1997 epidemic could have been predicted from observed temperatures in the preceding season, but the consideration of the rainfall forecasts would have improved the temperature-only forecasts over the remaining years. These results demonstrate the potential of a seasonal forecasting system in the development of a malaria early warning system in Kagera region

Growth/differentiation factor 15 causes TGFβ activated kinase 1 dependent muscle atrophy in pulmonary arterial hypertension

Introduction Skeletal muscle dysfunction is a clinically important complication of pulmonary arterial hypertension (PAH). Growth/differentiation factor 15 (GDF-15), a prognostic marker in PAH, has been associated with muscle loss in other conditions. We aimed to define the associations of GDF-15 and muscle wasting in PAH, to assess its utility as a biomarker of muscle loss and to investigate its downstream signalling pathway as a therapeutic target. Methods GDF-15 levels and measures of muscle size and strength were analysed in the monocrotaline (MCT) rat, Sugen/hypoxia mouse and in 30 patients with PAH. In C2C12 myotubes the downstream targets of GDF-15 were identified. The pathway elucidated was then antagonised in vivo. Results Circulating GDF-15 levels correlated with tibialis anterior (TA) muscle fibre diameter in the MCT rat (Pearson r=−0.61, p=0.003). In patients with PAH, plasma GDF-15 levels of <564 pg/L predicted those with preserved muscle strength with a sensitivity and specificity of ≥80%. In vitro GDF-15 stimulated an increase in phosphorylation of TGFβ-activated kinase 1 (TAK1). Antagonising TAK1, with 5(Z)-7-oxozeaenol, in vitro and in vivo led to an increase in fibre diameter and a reduction in mRNA expression of atrogin-1 in both C2C12 cells and in the TA of animals who continued to grow. Circulating GDF-15 levels were also reduced in those animals which responded to treatment. Conclusions Circulating GDF-15 is a biomarker of muscle loss in PAH that is responsive to treatment. TAK1 inhibition shows promise as a method by which muscle atrophy may be directly prevented in PAH

Mesons in the massive Schwinger model on the light-cone

We investigate mesons in the bosonized massive Schwinger model in the light-front Tamm-Dancoff approximation in the strong coupling region. We confirm that the three-meson bound state has a few percent fermion six-body component in the strong coupling region when expressed in terms of fermion variables, consistent with our previous calculations. We also discuss some qualitative features of the three-meson bound state based on the information about the wave function.Comment: 19 pages, RevTex, included 6 figures which are compressed and uuencode

Plasma Metabolomics Implicate Modified Transfer RNAs and Altered Bioenergetics in the Outcome of Pulmonary Arterial Hypertension.

BACKGROUND: -Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality. METHODS: -We conducted a comprehensive study of plasma metabolites using ultra-performance liquid chromatography mass-spectrometry to (1) identify patients at high risk of early death, (2) identify patients who respond well to treatment and (3) provide novel molecular insights into disease pathogenesis. RESULTS: -53 circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy controls (n=121) following correction for multiple testing (p<7.3e-5) and confounding factors, including drug therapy, renal and hepatic impairment. A subset of 20/53 metabolites also discriminated PAH patients from disease controls (symptomatic patients without pulmonary hypertension, n=139). 62 metabolites were prognostic in PAH, with 36/62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), TCA cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan and polyamine metabolites and decreased levels of steroids, sphingomyelins and phosphatidylcholines distinguished patients from controls. The largest differences correlated with increased risk of death and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to healthy controls. CONCLUSIONS: -Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterisation of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients

Nonperturbative Light-Front QCD

In this work the determination of low-energy bound states in Quantum Chromodynamics is recast so that it is linked to a weak-coupling problem. This allows one to approach the solution with the same techniques which solve Quantum Electrodynamics: namely, a combination of weak-coupling diagrams and many-body quantum mechanics. The key to eliminating necessarily nonperturbative effects is the use of a bare Hamiltonian in which quarks and gluons have nonzero constituent masses rather than the zero masses of the current picture. The use of constituent masses cuts off the growth of the running coupling constant and makes it possible that the running coupling never leaves the perturbative domain. For stabilization purposes an artificial potential is added to the Hamiltonian, but with a coefficient that vanishes at the physical value of the coupling constant. The weak-coupling approach potentially reconciles the simplicity of the Constituent Quark Model with the complexities of Quantum Chromodynamics. The penalty for achieving this perturbative picture is the necessity of formulating the dynamics of QCD in light-front coordinates and of dealing with the complexities of renormalization which such a formulation entails. We describe the renormalization process first using a qualitative phase space cell analysis, and we then set up a precise similarity renormalization scheme with cutoffs on constituent momenta and exhibit calculations to second order. We outline further computations that remain to be carried out. There is an initial nonperturbative but nonrelativistic calculation of the hadronic masses that determines the artificial potential, with binding energies required to be fourth order in the coupling as in QED. Next there is a calculation of the leading radiative corrections to these masses, which requires our renormalization program. Then the real struggle of finding the right extensions to perturbation theory to study the strong-coupling behavior of bound states can begin.Comment: 56 pages (REVTEX), Report OSU-NT-94-28. (figures not included, available via anaonymous ftp from pacific.mps.ohio-state.edu in subdirectory pub/infolight/qcd

Pulmonary hypertension in interstitial lung disease: Limitations of echocardiography compared to cardiac catheterization

BACKGROUND AND OBJECTIVE: In interstitial lung disease (ILD), pulmonary hypertension (PH) is a major adverse prognostic determinant. Transthoracic echocardiography (TTE) is the most widely used tool when screening for PH, although discordance between TTE and right heart catheter (RHC) measured pulmonary haemodynamics is increasingly recognized. We evaluated the predictive utility of the updated European Society of Cardiology/European Respiratory Society (ESC/ERS) TTE screening recommendations against RHC testing in a large, well-characterized ILD cohort. METHODS: Two hundred and sixty-five consecutive patients with ILD and suspected PH underwent comprehensive assessment, including RHC, between 2006 and 2012. ESC/ERS recommended tricuspid regurgitation (TR) velocity thresholds for assigning high (>3.4 m/s), intermediate (2.9-3.4 m/s) and low (3.4 m/s, and excluded PH in 60% of ILD subjects with a TR velocity <2.8 m/s. Thus, the ESC/ERS guidelines misclassified 40% of subjects as 'low probability' of PH, when PH was confirmed on subsequent RHC. Evaluating alternative TR velocity thresholds for assigning a low probability of PH did not significantly improve the ability of TR velocity to exclude a diagnosis of PH. CONCLUSION: In patients with ILD and suspected PH, currently recommended ESC/ERS TR velocity screening thresholds were associated with a high positive predictive value (86%) for confirming PH, but were of limited value in excluding PH, with 40% of patients misclassified as low probability when PH was confirmed at subsequent RHC

Application of Pauli-Villars Regularization and Discretized Light-Cone Quantization to a (3+1)-Dimensional Model

We apply Pauli-Villars regularization and discrete light-cone quantization to the nonperturbative solution of a (3+1)-dimensional model field theory. The matrix eigenvalue problem is solved for the lowest-mass state with use of the complex symmetric Lanczos algorithm. This permits the calculation of each Fock-sector wave function, and from these we obtain values for various quantities, such as average multiplicities and average momenta of constituents, structure functions, and a form factor slope.Comment: RevTex, 27 page