Modelflow estimates of cardiac output compared with Doppler ultrasound during acute changes in vascular resistance in women

We compared Modelflow (MF) estimates of cardiac stroke volume (SV) from the finger pressure-pulse waveform (Finometer®) with pulsed Doppler ultrasound (DU) of the ascending aorta during acute changes in total peripheral resistance (TPR) in the supine and head-up-tilt (HUT) postures. Twenty-four women were tested during intravenous infusion of 0.005 or 0.01 μg kg -1 min-1 isoprenaline, 10 or 50 ng kg-1 min-1 noradrenaline and 0.3 mg sublingual nitroglycerine. Responses to static hand-grip exercise (SHG), graded lower body negative pressure (LBNP, from -20 to -45 mmHg) and 45 deg HUT were evaluated on separate days. Bland-Altman analysis indicated that SVMF yielded lower estimates than SVDU during infusion of 0.01 μg kg-1 min -1 isoprenaline (SVMF 92.7 ± 15.5 versus SV DU 104.3 ± 22.9 ml, P = 0.03) and SHG (SVMF 78.8 ± 12.0 versus SVDU 106.1 ± 28.5 ml, P \u3c 0.01), while larger estimates were recorded with SVMF during -45 mmHg LBNP (SVMF 52.6 ± 10.7 versus SVDU 46.2 ± 14.5 ml, P = 0.04) and HUT (SVMF 59.3 ± 13.6 versus SVDU 45.2 ± 11.3 ml, P \u3c 0.01). Linear regression analysis revealed a relationship (r2 = 0.41, P \u3c 0.01) between the change in TPR from baseline and the between-methods discrepancy in SV measurements. This relationship held up under all of the experimental protocols (regression for fixed effects, P = 0.46). These results revealed a discrepancy in MF estimates of SV, in comparison with those measured by DU, during acute changes in TPR. © 2010 The Physiological Society

Molecular and Atomic Excitation Stratification in the Outflow of the Planetary Nebula M27

High resolution spectroscopy with FUSE and STIS of atomic and molecular velocity stratification in the nebular outflow of M27 challenge models for the abundance kinematics in planetary nebulae. The simple picture of a very high speed (~ 1000 km/s), high ionization, radiation driven stellar wind surrounded by a slower (~ 10 km/s) mostly molecular outflow, with low ionization and neutral atomic species residing at the wind interaction interface, is not supported... We find ...there is a fast (33 -- 65 km/s) low ionization zone, surrounding a slower (<~ 33 km/s) high ionization zone and, at the transition velocity (33 km/s), vibrationally excited H_2 is intermixed with a predominately neutral atomic medium... Far-UV continuum fluorescence of H_2 is not detected, but Lyman alpha (Lya) fluorescence is present. The diffuse nebular medium is inhospitable to molecules and dust. Maintaining the modest equilibrium abundance of H_2 (N(H_2)/N(HI) << 1) in the diffuse nebular medium requires a source of H_2, mostly likely the clumpy nebular medium. The stellar SED shows no signs of reddening (E(B-V) < 0.01), but paradoxically measurements of Ha/Hb ... indicate E(B-V) ~ 0.1. ...the apparent enhancement of Ha/Hb in the absence of dust may result from a two step process of H_2 ionization by Lyman continuum (Lyc) photons followed by dissociative recombination (H_2 + gamma -> H_2^+ + e -> H(1s) + H (nl)), which ultimately produces fluorescence of Ha and Lya. In the optically thin limit at the inferred radius of the velocity transition we find dissociation of H_2 by stellar Lyc photons is an order of magnitude more efficient than spontaneous dissociation by far-UV photons. We suggest that the importance of this H_2 destruction process in HII regions has been overlooked.Comment: In emulateapj 2 column, 28 pages total, 18 figures. Accepted for publication in the Astrophysical Journal on 5 January 2007. Abstract abridge

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

EMU and economic governance in Germany

This article argues the value of models of policy analysis which focus on the role of endogenous variables in explaining policy change. Studies of EMU and studies of German public policy in general have tended to be preoccupied with contextual variables as explanations of change. Whilst such variables are important in identifying necessary conditions of policy change, they underestimate the dynamics within the policy process. Policy change in EMU is explored as a negotiation process with two interacting dimensions: a 'nested', 'two-level' bargaining game, involving creative linkage politics and sophisticated bargaining strategies, and a cognitive dimension of individual policy entrepreneurship and learning in the process. The conclusions deal with the character of economic governance in this sector and with the prospects for EMU in 1998-99

Jacques Delors and the relaunch of economic and monetary union: a study of strategic calculation, brokerage and cognitive leadership

The paper employs a contingency mode, stressing the connection between strategic dynamics (bargaining games), cognitive dynamics (learning by interaction, policy entrepreneurship) and the specific institutional milieu, to help explain the nature of the role played by the European Commission and Jacques Delors in relation to the initiation and negotiation of the EMU project. It thus covers the period 1988-91, and the focus is more on agency than on the wider structural factors affecting EMU. It is based on the results of some 250 elite interviews with leading policy actors across Europe and on the contents of private papers concerning the Intergovernmental Conference made available to the authors. The paper stems from research funded by the Economic and Social Research Council in the UK