Role of the aryl hydrocarbon receptor in Sugen 5416-induced experimental pulmonary hypertension

Rationale: Rats dosed with the vascular endothelial growth factor (VEGF) inhibitor Sugen 5416 (Su), placed in hypoxia then restored to normoxia has become a widely used model of pulmonary arterial hypertension (PAH). The mechanism by which Su exaccerbates pulmonary hypertension is, however, unclear. Objectives: We investigated Su-activation of the aryl hydrocarbon receptor (AhR) in patient human pulmonary arterial smooth muscle cells (hPASMCs) and patient blood outgrowth endothelial cells (BOECs). We also examined the effect of AhR on aromatase and estrogen levels in the lung. Methods, Measurements and Main Results: Protein and mRNA analysis demonstrated that CYP1A1 was very highly induced in the lungs of Su/hypoxic (Su/Hx) rats. The AhR antagonist CH223191 (8mg/kg/day) reversed the development of PAH in this model in vivo and normalized lung CYP1A1 expression. Increased lung aromatase and estrogen levels in Su/Hx rats were also normalized by CH223191 as was AhR nuclear translocator (ARNT [HIF-1β]) which is shared by HIF-1α and AhR. Su reduced HIF1α expression in hPASMCs. Su induced proliferation in BOECs and increased apoptosis in human pulmonary microvascular endothelial cells (hPMECs) and also induced translocation of AhR to the nucleus in hPASMCs. Under normoxic conditions, hPASMCs do not proliferate to Su. However when grown in hypoxia (1%) Su induced hPASMC proliferation. Conclusion: In combination with hypoxia, Su is proliferative in patient hPASMCs and patient BOECs and Su/Hx-induced PAH in rats may be facilitated by AhR-induced CYP1A1, ARNT and aromatase. Inhibition of the AhR receptor may be a novel approach to the treatment of pulmonary hypertension

Spectropolarimetry of the Type Ib/c SN 2005bf

We present spectropolarimetric observations of the peculiar Type Ib/c SN 2005bf, in MCG+00-27-005, from 3600-8550\AA. The SN was observed on 2005 April 30.9, 18 days after the first B-band light-curve maximum and 6 days before the second B-band light-curve maximum. The degree of the Interstellar Polarization, determined from depolarized emission lines in the spectrum, is found to be large with $p_{max}(ISP)=1.6$ and $\theta(ISP)=149$\fdg$7\pm4.0$, but this may be an upper limit on the real value of the ISP. After ISP subtraction, significant polarization is observed over large wavelength regions, indicating a significant degree of global asymmetry, $\gtrsim 10$. Polarizations of 3.5% and 4% are observed for absorption components of Ca II H&K and IR triplet, and 1.3% for He I 5876\AA and Fe II. On the $Q-U$ plane clear velocity-dependent loop structure is observed for the He I 5876\AA line, suggestive of departures from an axial symmetry and possible clumping of the SN ejecta. Weak High Velocity components of $\mathrm{H\alpha}$, $\mathrm{H\beta}$ and $\mathrm{H\gamma}$ are observed, with velocities of -15 000\kms. The low degree of polarization observed at H$\beta$ suggests that the polarization observed for the other Balmer lines ($\sim 0.4$ above the background polarization) may rather be due to blending of $\mathrm{H\alpha}$ and $\mathrm{H\gamma}$ with polarized Si II and Fe II lines, respectively. We suggest a model in which a jet of material, that is rich in $\mathrm{^{56}Ni}$, has penetrated the C-O core, but not the He mantle. The jet axis is tilted with respect to the axis of the photosphere. This accounts for the lack of significant polarization of O I 7774\AA, the delayed excitation and, hence, observability of He I and, potentially, the varied geometries of He and Ca.Comment: 12 pages, 7 figures (3 colour), MNRAS accepte

Evolution of a novel orally bioavailable series of PI3Kδ inhibitors from an inhaled lead for the treatment of respiratory disease.

A four step process of high quality modelling of existing data, deconstruction, identification of replacement cores and an innovative synthetic re-growth strategy led to the rapid discovery of a novel oral series of PI3K δ inhibitors with promising selectivity and excellent in vivo characteristics

Spectropolarimetry of the Type Ib Supernova iPTF 13bvn: revealing the complex explosion geometry of a stripped-envelope core-collapse supernova

We present six epochs of spectropolarimetric observations and one epoch of spectroscopy of the Type Ib SN iPTF 13bvn. The epochs of these observations correspond to −10 to +61 d with respect to the r-band light-curve maximum. The continuum is intrinsically polarized to the 0.2–0.4 per cent level throughout the observations, implying asphericities of ∼10 per cent in the shape of the photosphere. We observe significant line polarization associated with the spectral features of Ca II IR3, He I/Na I D, He I λλ6678, 7065, Fe II λ4924 and O I λ7774. We propose that an absorption feature at ∼6200 Å, usually identified as Si II λ6355, is most likely to be high-velocity H α at −16 400 km s−1. Two distinctly polarized components, separated in velocity, are detected for both He I/Na I D and Ca II IR3 , indicating the presence of two discrete line-forming regions in the ejecta in both radial velocity space and in the plane of the sky. We use the polarization of He I λ5876 as a tracer of sources of non-thermal excitation in the ejecta; finding that the bulk of the radioactive nickel was constrained to lie interior to ∼50–65 per cent of the ejecta radius. The observed polarization is also discussed in the context of the possible progenitor system of iPTF 13bvn, with our observations favouring the explosion of a star with an extended, distorted envelope rather than a compact Wolf–Rayet star

Platelet Factor 4 Regulation of Monocyte KLF4 in Experimental Cerebral Malaria

Cerebral malaria continues to be a difficult to treat complication of Plasmodium falciparum infection in children. We have shown that platelets can have major deleterious immune functions in experimental cerebral malaria (ECM). One of the platelet derived mediators we have identified as particularly important is platelet factor 4/CXCL4. Our prior work demonstrated that PF4−/− mice are protected from ECM, have reduced plasma cytokines, and have reduced T-cell trafficking to the brain. We now show that PF4 drives monocyte cytokine production in a Kruppel like factor 4 (KLF4) dependent manner. Monocyte depleted Plasmodium berghei infected mice have improved survival, and KLF4 is greatly increased in control, but not monocyte depleted mice. PF4−/− mice have less cerebral monocyte trafficking and no change in KLF4 expression. These data indicate that PF4 induction of monocyte KLF4 expression may be an important step in the pathogenesis of ECM

Hydrogen peroxide regulation of endothelial exocytosis by inhibition of N-ethylmaleimide sensitive factor

Although an excess of reactive oxygen species (ROS) can damage the vasculature, low concentrations of ROS mediate intracellular signal transduction pathways. We hypothesized that hydrogen peroxide plays a beneficial role in the vasculature by inhibiting endothelial exocytosis that would otherwise induce vascular inflammation and thrombosis. We now show that endogenous H2O2 inhibits thrombin-induced exocytosis of granules from endothelial cells. H2O2 regulates exocytosis by inhibiting N-ethylmaleimide sensitive factor (NSF), a protein that regulates membrane fusion events necessary for exocytosis. H2O2 decreases the ability of NSF to hydrolyze adenosine triphosphate and to disassemble the soluble NSF attachment protein receptor complex. Mutation of NSF cysteine residue C264T eliminates the sensitivity of NSF to H2O2, suggesting that this cysteine residue is a redox sensor for NSF. Increasing endogenous H2O2 levels in mice decreases exocytosis and platelet rolling on venules in vivo. By inhibiting endothelial cell exocytosis, endogenous H2O2 may protect the vasculature from inflammation and thrombosis

β2M Signals Monocytes Through Non-Canonical TGFβ Receptor Signal Transduction.

Rationale: Circulating monocytes can have pro-inflammatory or pro-reparative phenotypes. The endogenous signaling molecules and pathways that regulate monocyte polarization in vivo are poorly understood. We have shown that platelet derived beta-2 microglobulin (β2M) and transforming growth factor beta (TGFβ) have opposing effects on monocytes by inducing inflammatory and reparative phenotypes respectively, but each bind and signal through the same receptor. We now define the signaling pathways involved. Objective: To determine the molecular mechanisms and signal transduction pathways by which β2M and TGFβ regulate monocyte responses both in vitro and in vivo. Methods and Results: Wild-type (WT) and platelet specific β2M knockout (Plt-β2M-/-) mice were treated intravenously with either β2M or TGFβ to increase plasma concentrations to those in cardiovascular diseases. Elevated plasma β2M increased pro-inflammatory monocytes, while increased plasma TGFβ increased pro-reparative monocytes. TGFβ receptor (TGFβR) inhibition blunted monocyte responses to both β2M and TGFβ in vivo. Using imaging flow cytometry, we found that β2M decreased monocyte SMAD2/3 nuclear localization, while TGFβ promoted SMAD nuclear translocation, but decreased noncanonical/ inflammatory (JNK and NFκB nuclear localization). This was confirmed in vitro using both imaging flow cytometry and immunoblots. β2M, but not TGFβ, promoted ubiquitination of SMAD3 and SMAD4, that inhibited their nuclear trafficking. Inhibition of ubiquitin ligase activity blocked noncanonical SMAD-independent monocyte signaling and skewed monocytes towards a pro-reparative monocyte response. Conclusions: Our findings indicate that elevated plasma β2M and TGFβ dichotomously polarize monocytes. Furthermore, these immune molecules share a common receptor, but induce SMAD-dependent canonical signaling (TGFβ) versus non-canonical SMAD-independent signaling (β2M) in a ubiquitin ligase dependent manner. This work has broad implications as β2M is increased in several inflammatory conditions, while TGFβ is increased in fibrotic diseases.pre-print3451 K

Interprofessional faculty teams: Building an effective team to create and implement an interprofessional simulation

This presentation provides an exemplar of how nursing faculty engaged members of different healthcare professions collaboratively in the creation and implementation of an interprofessional learning activity. Participants will be able to consider ways to collaborate with other professions and design an interprofessional learning activity in their own practice setting

High-Dose Isotretinoin Treatment and the Rate of Retrial, Relapse, and Adverse Effects in Patients With Acne Vulgaris

IMPORTANCE: Isotretinoin is the most effective treatment for acne. The ideal dosing regimen is unknown. OBJECTIVE: To determine the rates of relapse of acne vulgaris and retrial of isotretinoin after high cumulative-dose treatment and the changes to the adverse effect profile. DESIGN, SETTING, AND PARTICIPANTS: A prospective, observational, intervention study was conducted from August 1, 2008, to August 31, 2010, in a single academic tertiary care center with multiple providers. A total of 180 patients with acne resistant to other treatments were enrolled. Of these, 116 participated in the 12-month follow-up survey, for a response rate of 64.4%. EXPOSURE: Patients received isotretinoin, with dosing based on the providers' judgment. Patients were divided into 2 groups on the basis of cumulative dosing (<220 mg/kg and ≥ 220 mg/kg). MAIN OUTCOMES AND MEASURES: Relapse (treatment with a prescription topical or oral acne medication after a course of isotretinoin) or retrial (retreatment with isotretinoin) at 12-month follow-up and adverse effects experienced during and after 12 months of treatment. RESULTS The mean age of the participants was 19.3 years, 51.9% were female, and 74.1% were white. At 12 months' follow-up, 97.4% of the patients reported that their acne was improved. Overall, acne in 32.7% of patients in the study relapsed at 12 months, and 1.72% of the patients required a retrial. In the lower-dose treatment group (<220 mg/kg), the relapse rate was 47.4% (95% CI, 32.3%-63.0%) compared with 26.9% (95% CI, 18.3%-37.8%) in the high-dose group (P = .03). Almost 100% of the patients in both treatment groups developed cheilitis and xerosis during treatment. Retinoid dermatitis was significantly more common in the high-dose treatment group (53.8% vs 31.6%; P = .02). None of the other adverse effects was significantly different between the 2 groups. CONCLUSIONS AND RELEVANCE: The dosing regimen used in the present study is considerably higher than that used in previous studies of isotretinoin. At 1 year after completion of isotretinoin treatment, we found that patients receiving 220 mg/kg or more had a significantly decreased risk of relapse. Rash was the only adverse effect that was significantly more common in the high-dose group during treatment. This study suggests that significantly higher doses of isotretinoin are effective for treating acne and decreasing relapse rates without increasing adverse effects