Assessment of left atrial volume before and after pulmonary thromboendarterectomy in chronic thromboembolic pulmonary hypertension.

BackgroundImpaired left ventricular diastolic filling is common in chronic thromboembolic pulmonary hypertension (CTEPH), and recent studies support left ventricular underfilling as a cause. To investigate this further, we assessed left atrial volume index (LAVI) in patients with CTEPH before and after pulmonary thromboendarterectomy (PTE).MethodsForty-eight consecutive CTEPH patients had pre- & post-PTE echocardiograms and right heart catheterizations. Parameters included mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index, LAVI, & mitral E/A ratio. Echocardiograms were performed 6 ± 3 days pre-PTE and 10 ± 4 days post-PTE. Regression analyses compared pre- and post-PTE LAVI with other parameters.ResultsPre-op LAVI (mean 19.0 ± 7 mL/m2) correlated significantly with pre-op PVR (R = -0.45, p = 0.001), mPAP (R = -0.28, p = 0.05) and cardiac index (R = 0.38, p = 0.006). Post-PTE, LAVI increased by 18% to 22.4 ± 7 mL/m2 (p = 0.003). This change correlated with change in PVR (765 to 311 dyne-s/cm5, p = 0.01), cardiac index (2.6 to 3.2 L/min/m2, p = 0.02), and E/A (.95 to 1.44, p = 0.002).ConclusionIn CTEPH, smaller LAVI is associated with lower cardiac output, higher mPAP, and higher PVR. LAVI increases by ~20% after PTE, and this change correlates with changes in PVR and mitral E/A. The rapid increase in LAVI supports the concept that left ventricular diastolic impairment and low E/A pre-PTE are due to left heart underfilling rather than inherent left ventricular diastolic dysfunction

Evidence for mechanisms underlying the functional benefits of a myocardial matrix hydrogel for post-MI treatment

Background There is increasing need for better therapies to prevent the development of heart failure after myocardial infarction (MI). An injectable hydrogel derived from decellularized porcine ventricular myocardium has been shown to halt the post-infarction progression of negative left ventricular remodeling and decline in cardiac function in both small and large animal models. Objectives This study sought to elucidate the tissue-level mechanisms underlying the therapeutic benefits of myocardial matrix injection. Methods Myocardial matrix or saline was injected into infarcted myocardium 1 week after ischemia-reperfusion in Sprague-Dawley rats. Cardiac function was evaluated by magnetic resonance imaging and hemodynamic measurements at 5 weeks after injection. Whole transcriptome microarrays were performed on RNA isolated from the infarct at 3 days and 1 week after injection. Quantitative polymerase chain reaction and histologic quantification confirmed expression of key genes and their activation in altered pathways. Results Principal component analysis of the transcriptomes showed that samples collected from myocardial matrix-injected infarcts are distinct and cluster separately from saline-injected control subjects. Pathway analysis indicated that these differences are due to changes in several tissue processes that may contribute to improved cardiac healing after MI. Matrix-injected infarcted myocardium exhibits an altered inflammatory response, reduced cardiomyocyte apoptosis, enhanced infarct neovascularization, diminished cardiac hypertrophy and fibrosis, altered metabolic enzyme expression, increased cardiac transcription factor expression, and progenitor cell recruitment, along with improvements in global cardiac function and hemodynamics. Conclusions These results indicate that the myocardial matrix alters several key pathways after MI creating a pro-regenerative environment, further demonstrating its promise as a potential post-MI therapy

Comparison of two- and three-dimensional echocardiography with cineventriculography for measurement of left ventricular volume in patients

AbstractObjectives. We compared two- and three-dimensional echocardiopaphy with cineventriculography for measurement of left ventricular volume in patients.Background. Three-dimensional echocardiography has been shown to be highly accurate and superior to two-dimensional echocardiography in measuring left ventricular volume in vitro. However, there has been little comparison of the two methods in patients.Methods. Two- and three-dimensional echocardiography were performed in 35 patients (mean age 48 years) 1 to 3 h before left ventricular cineventriculography. Three-dimensional echocardiography used an acoustic spatial locator to register image position. Volume was computed using a polyhedral surface reconstruction algorithm based on multiple nonparallel, unevenly spaced short-axis cross sections. Two-dimensional echocardiography used the apical biplane summation of disks method. Single-plane cineventriculographic volumes were calculated using the summation of disks algorithm. The methods were compared by linear regression and a limits of agreement analysis. For the latter, systematic error was assessed by the mean of the deferences (cineventriculography minus echocardiography), and the limits of agreement were defined as ±2 SD from the mean difference.Results. Three-dimensional echocardiographic volumes demonstrated excellent correlation (end-diastole r = 0.97; end-systole r = 0.98) with cineventriculography. Standard errors of the estimate were approximately half those of two-dimensional echocardiography (end-diastole ±11.0 ml vs. ±21.5 ml; end-systole ±10.2 ml vs. ±17.0 ml). By limits of agreement analysis the end-diastolic mean diferences for two- and three-dimensional echocardiography were 21.1 and 12.9 ml, respectively. The limits of agreement (±2 SD) were ±54.0 and ±24.8 ml, respectively. For end-systole, comparable improvement was obtained by three-dimensional echocardiography. Results for ejection fraction by the two methods were similar.Conclusions. Three-dimensional echocardiography correlates highly with cineventriculography for estimation of ventricular volumes in patients and has approximately half the variability of two-dimensional echocardiography for these measurements. On the basis of this study, three-dimensional echocardiography is the preferred echocardiographic technique for measurement of ventricular volume. Three-dimensional echocardiography is equivalent to two-dimensional echocardiography for measuring ejection fraction

STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity.

Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma

Interleukin 23-Helper T Cell 17 Axis as a Treatment Target for Pityriasis Rubra Pilaris.

Treatment of pityriasis rubra pilaris (PRP) is solely based on its resemblance to psoriasis rather than any knowledge of its pathomechanism. Insight into pathogenic mediators of inflammation is essential for targeted and valid treatment options that could replace previous serendipitous therapeutic approaches in refractory PRP. To determine whether blockade of the interleukin 23-helper T cell 17 (IL-23-TH17) pathway with ustekinumab represents an efficacious and, based on its proinflammatory cytokine profile, targeted treatment option in PRP. In this case report, a patient with PRP received outpatient treatment at a university hospital department of dermatology with ustekinumab according to the dosing regimen approved for psoriasis. Lesional skin biopsy samples were taken from this patient and 2 others with refractory PRP. Messenger RNA (mRNA) expression of proinflammatory innate and T-cell-derived cytokines were measured and compared with skin samples from patients with psoriasis and healthy donors. From 1 patient, lesional skin samples were taken before ustekinumab treatment and 4 and 28 weeks after treatment initiation. Follow-up was completed after 6 months. Subcutaneous ustekinumab, 45 mg, at weeks 0 and 4 and quarterly thereafter. The primary outcome was to determine the changes in expression of proinflammatory innate and T-cell-derived cytokines during ustekinumab therapy. The secondary objective was to evaluate the clinical and histopathologic phenotype in relation to the mRNA expression profile of proinflammatory cytokines. In lesional PRP skin samples from a single patient, upregulated expression levels were found for most proinflammatory innate cytokines, including tumor necrosis factor (TNF), IL-6, IL-12, IL-23, and IL-1β. Among adaptive T-cell cytokines, an increase of TH1 cytokines and, in particular, TH17 cytokines IL-17A, IL-17F, and IL-22 was seen in PRP. The patient with PRP who received ustekinumab showed regression of skin lesions after 2 weeks and almost complete resolution after 1 month. Clinical and histopathologic improvement paralleled the expression levels of TH17 cytokines but not of interferon-γ and TNF, which lagged behind the amelioration. In this case report, a role of the IL-23-TH17-axis in PRP was identified, suggesting a shared pathogenic inflammatory pathway with psoriasis, despite evident clinical and histopathologic differences. In addition, this report provides a rationale for targeting the IL-23-TH17-pathway as a treatment option for refractory PRP

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum

Combined search for the quarks of a sequential fourth generation

Results are presented from a search for a fourth generation of quarks produced singly or in pairs in a data set corresponding to an integrated luminosity of 5 inverse femtobarns recorded by the CMS experiment at the LHC in 2011. A novel strategy has been developed for a combined search for quarks of the up and down type in decay channels with at least one isolated muon or electron. Limits on the mass of the fourth-generation quarks and the relevant Cabibbo-Kobayashi-Maskawa matrix elements are derived in the context of a simple extension of the standard model with a sequential fourth generation of fermions. The existence of mass-degenerate fourth-generation quarks with masses below 685 GeV is excluded at 95% confidence level for minimal off-diagonal mixing between the third- and the fourth-generation quarks. With a mass difference of 25 GeV between the quark masses, the obtained limit on the masses of the fourth-generation quarks shifts by about +/- 20 GeV. These results significantly reduce the allowed parameter space for a fourth generation of fermions.Comment: Replaced with published version. Added journal reference and DO