EMEA and Gene Therapy Medicinal Products Development in the European Union

The evaluation of quality, safety, and efficacy of medicinal products by the European Medicines Evaluation Agency (EMEA) via the centralized procedure is the only available regulatory procedure for obtaining marketing authorization for gene therapy (GT) medicinal products in the European Union. The responsibility for the authorization of clinical trials remains with the national competent authorities (NCA) acting in a harmonized framework from the scientific viewpoint. With the entry into force of a new directive on good clinical practice implementation in clinical trials as of 1 May 2004, procedural aspects will also be harmonized at EU level. Scientifically sound development of medicinal products is the key for the successful registration of dossiers and for contributing to the promotion and protection of public health. The objective of this paper is to introduce the EMEA regulatory processes and scientific activities relevant to GT medicinal products

POLLUX : a database of synthetic stellar spectra

Synthetic spectra are needed to determine fundamental stellar and wind parameters of all types of stars. They are also used for the construction of theoretical spectral libraries helpful for stellar population synthesis. Therefore, a database of theoretical spectra is required to allow rapid and quantitative comparisons to spectroscopic data. We provide such a database offering an unprecedented coverage of the entire Hertzsprung-Russell diagram. We present the POLLUX database of synthetic stellar spectra. For objects with Teff < 6 000 K, MARCS atmosphere models are computed and the program TURBOSPECTRUM provides the synthetic spectra. ATLAS12 models are computed for stars with 7 000 K <Teff <15 000 K. SYNSPEC gives the corresponding spectra. Finally, the code CMFGEN provides atmosphere models for the hottest stars (Teff > 25 000 K). Their spectra are computed with CMF_FLUX. Both high resolution (R>150 000) optical spectra in the range 3 000 to 12 000 A and spectral energy distributions extending from the UV to near--IR ranges are presented. These spectra cover the HR diagram at solar metallicity. We propose a wide variety of synthetic spectra for various types of stars in a format that is compliant with the Virtual Observatory standards. A user--friendly web interface allows an easy selection of spectra and data retrieval. Upcoming developments will include an extension to a large range of metallicities and to the near--IR high resolution spectra, as well as a better coverage of the HR diagram, with the inclusion of models for Wolf-Rayet stars and large datasets for cool stars. The POLLUX database is accessible at http://pollux.graal.univ-montp2.fr/ and through the Virtual Observatory.Comment: 9 pages, 5 figures, accepted for publication in Astronomy ans Astrophysic

The Physical Properties of the Red Supergiant WOH G64: The Largest Star Known?

WOH G64 is an unusual red supergiant (RSG) in the Large Magellanic Cloud (LMC), with a number of properties that set it apart from the rest of the LMC RSG population, including a thick circumstellar dust torus, an unusually late spectral type, maser activity, and nebular emission lines. Its reported physical properties are also extreme, including the largest radius for any star known and an effective temperature that is much cooler than other RSGs in the LMC, both of which are at variance with stellar evolutionary theory. We fit moderate-resolution optical spectrophotometry of WOH G64 with the MARCS stellar atmosphere models, determining an effective temperature of 3400 +/- 25 K. We obtain a similar result from the star's broadband V - K colors. With this effective temperature, and taking into account the flux contribution from the aysmmetric circumstellar dust envelope, we calculate log(L/L_sun) = 5.45 +/- 0.05 for WOH G64, quite similar to the luminosity reported by Ohnaka and collaborators based on their radiative transfer modeling of the star's dust torus. We determine a radius of R/R_sun = 1540, bringing the size of WOH G64 and its position on the H-R diagram into agreement with the largest known Galactic RSGs, although it is still extreme for the LMC. In addition, we use the Ca II triplet absorption feature to determine a radial velocity of 294 +/- 2 km/s for the star; this is the same radial velocity as the rotating gas in the LMC's disk, which confirms its membership in the LMC and precludes it from being an unusual Galactic halo giant. Finally, we describe the star's unusual nebula emission spectrum; the gas is nitrogen-rich and shock-heated, and displays a radial velocity that is significantly more positive than the star itself by 50 km/s.Comment: 25 pages, 5 figures; accepted for publication in The Astronomical Journa

Asymptotic wave-splitting in anisotropic linear acoustics

Linear acoustic wave-splitting is an often used tool in describing sound-wave propagation through earth's subsurface. Earth's subsurface is in general anisotropic due to the presence of water-filled porous rocks. Due to the complexity and the implicitness of the wave-splitting solutions in anisotropic media, wave-splitting in seismic experiments is often modeled as isotropic. With the present paper, we have derived a simple wave-splitting procedure for an instantaneously reacting anisotropic media that includes spatial variation in depth, yielding both a traditional (approximate) and a `true amplitude' wave-field decomposition. One of the main advantages of the method presented here is that it gives an explicit asymptotic representation of the linear acoustic-admittance operator to all orders of smoothness for the smooth, positive definite anisotropic material parameters considered here. Once the admittance operator is known we obtain an explicit asymptotic wave-splitting solution.Comment: 20 page

Effect of antiandrogen flutamide on measures of hepatic regeneration in rats

Male rat liver undergoes a process of demasculinization during hepatic regeneration following partial hepatectomy. The possibility that antiandrogens might potentiate this demasculinization process and in so doing augment the hepatic regenerative response was investigated. Adult male Wistar rats were treated with the antiandrogen flutamide (2 mg/rat/day or 5 mg/rat/day subcutaneously) or vehicle for three days prior to and daily after a 70% partial hepatectomy. At various times after hepatectomy, the liver remnants were removed and weighed. Rates of DNA and polyamine synthesis were assessed by measuring thymidine kinase and ornithine decarboxylase activities, respectively. Hepatic estrogen receptor status and the activity of alcohol dehydrogenase, an androgen-sensitive protein, were measured. Prior to surgery, the administration of 5 mg/day flutamide reduced the hepatic cytosolic androgen receptor activity by 98% and hepatic cytosolic estrogen receptor content by 92% compared to that present in vehicle-treated controls. After hepatectomy, however, all differences in sex hormone receptor activity between the treatment groups were abolished. The rate of liver growth after partial hepatectomy in the three groups was identical. Moreover, hepatectomy-induced increases in ornithine decarboxylase activity and thymidine kinase activity were comparable. These data demonstrate that, although flutamide administration initially alters the sex hormone receptor status of the liver, these affects have no effect on the hepatic regenerative response following a partial hepatectomy. © 1989 Plenum Publishing Corporation

Algebraic Models of Hadron Structure II. Strange Baryons

The algebraic treatment of baryons is extended to strange resonances. Within this framework we study a collective string-like model in which the radial excitations are interpreted as rotations and vibrations of the strings. We derive a mass formula and closed expressions for strong and electromagnetic decay widths and use these to analyze the available experimental data.Comment: 60 pages, 8 figures, 30 tables, Annals of Physics (N.Y.), in pres

Modulation of NTC frequencies by Pc5 ULF pulsations : experimental test of the generation mechanism and magnetoseismology of the emitting surface

Nonthermal continuum (NTC) radiation is believed to be emitted by the conversion of an electrostatic wave into an electromagnetic one, which takes place at the Earth's magnetic equator. It is generally accepted that the frequency of the electrostatic wave at the source meets a local characteristic frequency placed in between two multiples of the electron cyclotron frequency, fce, which results in emission of a narrow band frequency element. In an event on 14 August 2003, we compare oscillations of the central frequency of distinct NTC frequency elements observed from Cluster orbiting near perigee, with simultaneous Pc5 Ultra Low Frequency (ULF) pulsations in the magnetic field observed from the same platform. The latter magnetic perturbations are interpreted as magnetohydrodynamic poloidal waves, where fundamental and second harmonic modes coexist. The NTC oscillation and the fundamental wave have similar periods, but are phase shifted by a quarter of period. From the correlation between both signals, and the proximity of the NTC source (localized via triangulation) with Cluster, we infer that the poloidal perturbations are spatially uniform between the source and the satellites. From the phase shift between signals, we conclude that the electrostatic wave which converts into NTC is mainly governed by the plasma density, affected by movements of the magnetic field lines. Furthermore, we demonstrate that the observations can be used to perform a magnetoseismology of the emitting surface. The results show a steepening of the plasmapause density profile near the satellites, which can be responsible for the generation of NTC emission

The mass-loss rates of red supergiants and the de Jager prescription

Mass loss of red supergiants (RSG) is important for the evolution of massive stars, but is not fully explained. Several empirical prescriptions have been proposed, trying to express the mass-loss rate (Mdot) as a function of fundamental stellar parameters (mass, luminosity, effective temperature). Our goal is to test whether the de Jager et al. (1988) prescription, used in some stellar evolution models, is still valid in view of more recent mass-loss determinations. By considering 40 Galactic RSGs presenting an infrared excess and an IRAS 60-mu flux larger than 2 Jy, and assuming a gas-to-dust mass ratio of 200, it is found that the de Jager rate agrees within a factor 4 with most Mdot estimates based on the 60-mu signal. It is also in agreement with 6 of the only 8 Galactic RSGs for which Mdot can be measured more directly through observations of the circumstellar gas. The two objects that do not follow the de Jager prescription (by an order of magnitude) are mu Cep and NML Cyg. We have also considered the RSGs of the Magellanic Clouds. Thanks to the works of Groenewegen et al. (2009) and Bonanos et al. (2010), we find that the RSGs of the SMC have Mdots consistent with the de Jager rate scaled by (Z/Zsun)**(alpha), where Z is the metallicity and alpha is 0.7. The situation is less clear for the LMC RSGs. In particular, for luminosties larger than 1.6E+05 Lsun, one finds numerous RSGs (except WOH-G64) having Mdot significantly smaller than the de Jager rate, and indicating that Mdot would no longer increase with L. Before this odd situation is confirmed through further analysis of LMC RSGs, we suggest to keep the de Jager prescription unchanged at solar metallicity in the stellar evolutionary models and to apply a (Z/Zsun)**0.7 dependence.Comment: 13 pages, 9 figures. Accepted by Astronomy and Astrophysic

Spatially resolved H2 emission from the disk around T Tau N

We report the detection of quiescent H2 emission in a spatially resolved ring-like structure within 100 AU of T Tau N. We present evidence to show that the emission most likely arises from shocks in the atmosphere of a nearly face-on disk around T Tau N. Using high spatial resolution 3D spectroscopic K-band data, we trace the spatial distribution of several H2 NIR rovibrational lines in the vicinity of T Tau N. We detect weak H2 emission from the v=1-0 S(0), S(1), Q(1) lines and the v=2-1 S(1) line in a ring-like structure around T Tau N between 0.1'' (~15 AU) and 0.7'' (~100AU) from the star. The v=1-0 S(0) and v=2-1 S(1) lines are detected only in the outer parts of the ring structure. Closer to the star, the strong continuum limits our sensitivity to these lines. The total flux of the v=1-0 S(1) line is 1.8 *10^{-14} ergs s^{-1}cm^{-2}, similar to previous measurements of H2 in circumstellar disks. The velocity of the H2 emitting gas around T Tau N is consistent with the rest velocity of the star, and the H2 does not seem to be part of a collimated outflow. Both shocks impinging on the surface of a disk and irradiation of a disk by UV-photons and X-rays from the central star are plausible candidates for the H2 excitation mechanism. However, irradiation should not create a large degree of excitation at radii larger than 20 AU. Most likely the H2 emission arises in the atmosphere of a flared disk with radius 85-100 AU and mass 0.005-0.5Msun, where the gas is excited by shocks created when a wide-angle wind impinges on the disk. The H2 emission could also originate from shock excitation in the cavity walls of an envelope, but this requires an unusually high velocity of the wide-angle wind from T Tau N.Comment: Accepted by A&

Serum clara cell protein: a sensitive biomarker of increased lung epithelium permeability caused by ambient ozone.

Ozone in ambient air may cause various effects on human health, including decreased lung function, asthma exacerbation, and even premature mortality. These effects have been evidenced using various clinical indicators that, although sensitive, do not specifically evaluate the O(3)-increased lung epithelium permeability. In the present study, we assessed the acute effects of ambient O(3) on the pulmonary epithelium by a new approach relying on the assay in serum of the lung-specific Clara cell protein (CC16 or CC10). We applied this test to cyclists who exercised for 2 hr during episodes of photochemical smog and found that O(3) induces an early leakage of lung Clara cell protein. The protein levels increased significantly into the serum from exposure levels as low as 0.060-0.084 ppm. Our findings, confirmed in mice exposed to the current U.S. National Ambient Air Quality Standards for O(3) (0.08 ppm for 8 hr) indicate that above the present natural background levels, there is almost no safety margin for the effects of ambient O(3) on airway permeability. The assay of CC16 in the serum represents a new sensitive noninvasive test allowing the detection of early effects of ambient O(3) on the lung epithelial barrier