Hyperthermia induced by transient receptor potential vanilloid-1 (TRPV1) antagonists in human clinical trials: Insights from mathematical modeling and meta-analysis

Antagonists of the transient receptor potential vanilloid-1 (TRPV1) channel alter body temperature (Tb) in laboratory animals and humans: most cause hyperthermia; some produce hypothermia; and yet others have no effect. TRPV1 can be activated by capsaicin (CAP), protons (low pH), and heat. First-generation (polymodal) TRPV1 antagonists potently block all three TRPV1 activation modes. Second-generation (mode-selective) TRPV1 antagonists potently block channel activation by CAP, but exert different effects (e.g., potentiation, no effect, or low-potency inhibition) in the proton mode, heat mode, or both. Based on our earlier studies in rats, only one mode of TRPV1 activation - by protons - is involved in thermoregulatory responses to TRPV1 antagonists. In rats, compounds that potently block, potentiate, or have no effect on proton activation cause hyperthermia, hypothermia, or no effect on Tb, respectively. A Tb response occurs when a TRPV1 antagonist blocks (in case of hyperthermia) or potentiates (hypothermia) the tonic TRPV1 activation by protons somewhere in the trunk, perhaps in muscles, and - via the acido-antithermogenic and acido-antivasoconstrictor reflexes - modulates thermogenesis and skin vasoconstriction. In this work, we used a mathematical model to analyze Tb data from human clinical trials of TRPV1 antagonists. The analysis suggests that, in humans, the hyperthermic effect depends on the antagonist's potency to block TRPV1 activation not only by protons, but also by heat, while the CAP activation mode is uninvolved. Whereas in rats TRPV1 drives thermoeffectors by mediating pH signals from the trunk, but not Tb signals, our analysis suggests that TRPV1 mediates both pH and thermal signals driving thermoregulation in humans. Hence, in humans (but not in rats), TRPV1 is likely to serve as a thermosensor of the thermoregulation system. We also conducted a meta-analysis of Tb data from human trials and found that polymodal TRPV1 antagonists (ABT-102, AZD1386, and V116517) increase Tb, whereas the mode-selective blocker NEO6860 does not. Several strategies of harnessing the thermoregulatory effects of TRPV1 antagonists in humans are discussed

Leptonic and charged kaon decay modes of the ϕ\phi meson measured in heavy-ion collisions at the CERN SPS

We report a measurement of $\phi$ meson production in central Pb+Au collisions at E$_{lab}$/A=158 GeV. For the first time in heavy-ion collisions, $\phi$ mesons were reconstructed in the same experiment both in the K$^+$K$^-$ and the dilepton decay channel. Near mid-rapidity, this yields rapidity densities, corrected for production at the same rapidity value, of 2.05 +- 0.14(stat) +- 0.25(syst) and 2.04 +- 0.49(stat)+-{0.32}(syst), respectively. The shape of the measured transverse momentum spectra is also in close agreement in both decay channels. The data rule out a possible enhancement of the $\phi$ yield in the leptonic over the hadronic channel by a factor larger than 1.6 at 95% CL.Comment: 11 pages, 4 figures,submitted to Phys. Rev. Let

Flow and non-flow event anisotropies at the SPS

A study of differential elliptic event anisotropies (v_2) of charged particles and high-pt pions in 158 AGeV/c Pb+Au collisions is presented. Results from correlations with respect to the event plane and from two-particle azimuthal correlations are compared. The latter give systematically higher v_2 values at pt>1.2GeV/c providing possibly an evidence of a non-flow semihard component.Comment: 4 pages, 6 figures, Quark Matter 2002, Nantes, to appear in Nucl. Phys.

Azimuthal dependence of pion source radii in Pb+Au collisions at 158 A GeV

We present results of a two-pion correlation analysis performed with the Au+Pb collision data collected by the upgraded CERES experiment in the fall of 2000. The analysis was done in bins of the reaction centrality and the pion azimuthal emission angle with respect to the reaction plane. The pion source, deduced from the data, is slightly elongated in the direction perpendicular to the reaction plane, similarly as was observed at the AGS and at RHIC.Comment: 5 pages, 2 figure

Elliptic flow of charged pions, protons and strange particles emitted in Pb+Au collisions at top SPS energy

Differential elliptic flow spectra v2(pT) of \pi-, K0short, p, \Lambda have been measured at \sqrt(s NN)= 17.3 GeV around midrapidity by the CERN-CERES/NA45 experiment in mid-central Pb+Au collisions (10% of \sigma(geo)). The pT range extends from about 0.1 GeV/c (0.55 GeV/c for \Lambda) to more than 2 GeV/c. Protons below 0.4 GeV/c are directly identified by dE/dx. At higher pT, proton elliptic flow v2(pT) is derived as a constituent, besides \pi+ and K+, of the elliptic flow of positive pion candidates. The retrieval requires additional inputs: (i) of the particle composition, and (ii) of v2(pT) of positive pions. For (i), particle ratios obtained by NA49 were adapted to CERES conditions; for (ii), the measured v2(pT) of negative pions is substituted, assuming \pi+ and \pi- elliptic flow magnitudes to be sufficiently close. The v2(pT) spectra are compared to ideal-hydrodynamics calculations. In synopsis of the series \pi- - K0short - p - \Lambda, flow magnitudes are seen to fall with decreasing pT progressively even below hydro calculations with early kinetic freeze-out (Tf= 160 MeV) leaving not much time for hadronic evolution. The proton v2(pT) data show a downward swing towards low pT with excursions into negative v2 values. The pion-flow isospin asymmetry observed recently by STAR at RHIC, invalidating in principle our working assumption, is found in its impact on proton flow bracketed from above by the direct proton flow data, and not to alter any of our conclusions. Results are discussed in perspective of recent viscous dynamics studies which focus on late hadronic stages.Comment: 38 pages, 27 figures, 2 tables. Abstract and parts of introduction made more comprehensible; corrected typos; acknowledgement added. To appear in Nucl.Phys.

Lambda production in 40 A GeV/c Pb-Au collisions

During the 1999 lead run, CERES has measured hadron and electron-pair production at 40 A GeV/c beam momentum with the spectrometer upgraded by the addition of a radial TPC. Here the analysis of lambda and antilambda will be presented.Comment: 8 pages, 8 figures. 6th International Conference on Strange Quarks in Matter, Frankfurt 200

Modification of the rho meson detected by low-mass electron-positron pairs in central Pb-Au collisions at 158 A GeV/c

We present a measurement of $e^+e^-$ pair production in central Pb-Au collisions at 158$A$ GeV/$c$. As reported earlier, a significant excess of the $e^+e^-$ pair yield over the expectation from hadron decays is observed. The improved mass resolution of the present data set, recorded with the upgraded CERES experiment at the CERN-SPS, allows for a comparison of the data with different theoretical approaches. The data clearly favor a substantial in-medium broadening of the $\rho$ spectral function over a density-dependent shift of the $\rho$ pole mass. The in-medium broadening model implies that baryon induced interactions are the key mechanism to in-medium modifications of the $\rho$-meson in the hot fireball at SPS energy.Comment: Revised versio

Event-by-event fluctuations at SPS

Results on event-by-event fluctuations of the mean transverse momentum and net charge in Pb-Au collisions, measured by the CERES Collaboration at CERN-SPS, are presented. We discuss the centrality and beam energy dependence and compare our data to cascade calculations.Comment: 4 pages, 4 figures, proceedings to INPC2004 Goteborg, Swede

Abundance analysis of two late A-type stars HD 32115 and HD 37594

We have performed abundance analysis of two slowly rotating, late A-type stars, HD 32115 (HR 1613) and HD 37594 (HR 1940), based on obtained echelle spectra covering the spectral range 4000-9850 AAngstrom. These spectra allowed us to identify an extensive line list for 31 chemical elements, the most complete to date for A-type stars. Two approaches to abundance analysis were used, namely a ``manual'' (interactive) and a semi-automatic procedure for comparison of synthetic and observed spectra and equivalent widths. For some elements non-LTE (NLTE) calculations were carried out and the corresponding corrections have been applied. The abundance pattern of HD 32115 was found to be very close to the solar abundance pattern, and thus may be used as an abundance standard for chemical composition studies in middle and late A stars. Further, its H-alpha line profile shows no core-to-wing anomaly like that found for cool Ap stars and therefore also may be used as a standard in comparative studies of the atmospheric structures of cool, slowly rotating Ap stars. HD 37594 shows a metal deficiency at the level of -0.3 dex for most elements and triangle-like cores of spectral lines. This star most probably belongs to the Delta Scuti group.Comment: 10 pages, 4 figure

Universal Pion Freeze-out in Heavy-Ion Collisions

Based on an evaluation of data on pion interferometry and on particle yields at mid-rapidity, we propose a universal condition for thermal freeze-out of pions in heavy-ion collisions. We show that freeze-out occurs when the mean free path of pions lambda_f reaches a value of about 1 fm, which is much smaller than the spatial extent of the system at freeze-out. This critical mean free path is independent of the centrality of the collision and beam energy from AGS to RHIC.Comment: 5 pages, 3 figures, revised version resubmitted to PR