Recent Changes in U.S. Food and Drug Law: Implications for Drug Development

This paper examines in detail the Waxman/Hatch Act and the NDA Rewrite, from both an implementation point of view and from a world-wide research and development perspective. The central theme of these regulatory changes appears to be consistent with U.S. drug policy of the past two decades, i.e., cost containment, primarily, followed by uniformity and efficiency in the regulatory review process. These recent changes, just as the 1962 Drug Ammendments 22 years earlier, will continue to have profound effects upon the sites at which pharmaceutical research and development is carried out.     

Radiation initiated grafting on fluoro polymers II. Grafting of N-vinylpyrrolidone on copolymers of vinyl fluoride and vinylidene fluoride by accelerated electrons

The radiation initiated grafting of N-vinylpyrrolidone (NVP) onto copolymers of vinyl fluoride/vinylidene fluoride (VF/VF₂) with compositions of 75/25 mol-%, 50/50 mol-% and 20/80 mol-% VF/VF₂ has been investigated. The active species, initiating the grafting, have been created by accelerated electrons (160 keV) applying preirradiation technique in vacuo. The time conversion curves present a characteristic temperature dependence. Increasing grafting temperature rises the initial grafting rate. The final (saturation) grafting yield increases with temperature up to 333 K, and then declines. This behaviour was described by the influences of glass transition on the rate of termination in the semicrystalline trunk polymers. The grafting rate (at constant irradiation dose and grafting temperature) decreases with increasing VF₂ content in the copolymers. The reason is discussed by means of a semiquantitative mathematical analysis of the graft kinetics applying “non-steady-state”-conditions. The grafting rate does not depend on dose rate, but strongly depends on irradiation dose passing a maximum. This maximum has been interpreted by means of “Differential-Interference-Contrast”-microscopy. The enthalpies of melting ΔH_m of the semicrystalline copolymers decrease after grafting with increasing grafting yield. This change is due to the partial destroying of crystalline regions in the trunk copolymers caused by stresses arising from grafted polymer chains. The membrane resistance of films grafted through is <10 Ω cm². The membranes proved to be permeable for urea.     

Das Zustandsdiagramm Mn3O4-MnO und die in ihm auftretenden Zersetzungsdrücke

Die Sauerstoffdrücke im System Mn₃O₄-MnO-O₂. Beschreibung einer Versuchsanordnung zur statischen Gleichgewichtsmessung bei hohen Temperaturen. Isothermische Aufbauten und Messung der Zersetzungsdrücke im univarianten Bereich des Systems. Homogenitätsbereiche des MnO und Mn₃O₄ zwischen 1345 bis 1560 °C. Berechnung der Schmelz- und Erstarrungslinie des MnO. Bestimmung des Eutektikums MnO–Mn₃O₄. Erörterung zum Schmelzpunkt des Mn₃O₄.     

Ontogenetic scaling of foot musculoskeletal anatomy in elephants

This study quantifies the shape change in elephant manus and pes anatomy with increasing body mass, using computed tomographic scanning. Most manus and pes bones, and manus tendons, maintain their shape, or become more gracile, through ontogeny. Contrary to this, tendons of the pes become significantly more robust, suggesting functional adaptation to increasingly high loads. Ankle tendon cross-sectional area (CSA) scales the highest in the long digital extensor, proportional to body mass(1.08+/-0.21), significantly greater than the highest-scaling wrist tendon (extensor carpi ulnaris, body mass(0.69+/-0.09)). These patterns of shape change relate to the marked anatomical differences between the pillar-like manus and tripod-like pes, consistent with differences in fore- and hindlimb locomotor function. The cartilaginous predigits (prepollux and prehallux) of the manus and pes also become relatively more robust through ontogeny, and their pattern of shape change does not resemble that seen in any of the 10 metacarpals and metatarsals. Their CSAs scale above isometry proportional to body mass(0.73+/-0.09) and body mass(0.82+/-0.07) respectively. We infer a supportive function for these structures, preventing collapse of the foot pad during locomotion.     

Perovskite-Type Strontium Zirconate as a New Material for Thermal Barrier Coatings

Perovskite-type SrZrO₃ was investigated as an alternative to yttria-stabilized zirconia (YSZ) material for thermal barrier coating (TBC) applications. Three phase transformations (orthorhombic↔pseudo-tetragonal↔tetragonal↔cubic) were found only by heat capacity measurement, whereas the phase transformation from orthorhombic to pseudo-tetragonal was found in thermal expansion measurements. The thermal expansion coefficients (TECs) of SrZrO₃ coatings were at least 4.5% larger than YSZ coatings up to 1200°C. Mechanical properties (Young's modulus, hardness, and fracture toughness) of dense SrZrO₃ showed lower Young's modulus, hardness, and comparable fracture toughness with respect to YSZ. The "steady-state" sintering rate of a SrZrO₃ coating at 1200°C was 1.04 × 10⁻⁹ s⁻¹, which was less than half that of YSZ coating at 1200°C. Plasma-sprayed coatings were produced and characterized. Thermal cycling with a gas burner showed that at operating temperatures ∼1250°C the cycling lifetime of SrZrO₃/YSZ double-layer coating (DLC) was more than twice as long as SrZrO₃ coating and comparable to YSZ coating. However, at operating temperatures >1300°C, the cycling lifetime of SrZrO₃/YSZ DLC was comparable to the optimized YSZ coating, indicating SrZrO₃ might be a promising material for TBC applications at higher temperatures compared with YSZ.     

MEDOR, a didactic tool to support interpretation of bioassay data after internal contamination by actinides

A didactic software, MEthodes DOsimètriques de REférence (MEDOR), is being developed to provide help in the interpretation of biological data. Its main purpose is to evaluate the pertinence of the application of different models. This paper describes its first version that is focused on inhalation exposure to actinide aerosols. With this tool, sensitivity analysis on different parameters of the ICRP models can be easily done for aerosol deposition, in terms of activity and particle number, actinide biokinetics and doses. The user can analyse different inhalation cases showing either that dose per unit intake cannot be applied if the aerosol contains a low number of particles or that an inhibition of the late pulmonary clearance by particle transport can occur which contributes to a 3-4 fold increase in effective dose as compared with application of default parameters. This underlines the need to estimate systematically the number of deposited particles, as well as to do chest monitoring as long as possible.     

<Superscript>29</Superscript>Si NMR Chemical Shift Tensor and Electronic Structure of 7-Silanorbornadienes

The structure and bonding of 7-silanorbornadienes was investigated using X-ray Diffraction (XRD), solid-state NMR spectroscopy and density functional calculations. The solid state structures of four benzo-7-silanorbornadienes (4a, c, d, e) and of one dibenzo-7-silabenzonorbornadiene (5a) are reported and compared with the results of previous structural investigations. The most prominent features of the molecular structures of all 7-silanorbornadienes are very long Si-C(bridgehead) bonds (d(SiC) = 190.6–196.8 pm) and very acute CSiC bond angles α (α(CSiC) = 78.7–83.9°). All newly investigated 7-silanorborndienes show for tetracoordinated silicon nuclei extremely deshielded ²⁹Si NMR resonances (δ²⁹Si = 65.6–31.6). Solid State NMR investigations for 7-silanorbornadienes anti-4a, b reveal highly anisotropic chemical shift tensors of axial or nearly axial symmetry (4a: δ₁₁ = 161, δ₂₂ = δ₃₃ = −11; 4b: δ₁₁ = 113, δ₂₂ = 14, δ₃₃ = −15). The dominating, strongly deshielding δ₁₁ component is oriented almost perpendicular to the plane spanned by the two bridgehead carbon atoms and the bridging silicon atom. The DFT calculations suggest that the origin of the strong deshielding is a small energy difference between the frontier orbitals, which are strongly localized at the silicon atom. In addition the computations reveal that both the long SiC bonds and the strongly deshielded ²⁹Si NMR chemical shift are direct consequences of the bonding situation in 7-silanorbornadienes which are characterized by through space interaction of the C=C double bonds and by hyperconjugation between the SiC σ-bonds and the unoccupied orbitals of the C=C double bonds.     

How does industry specialization affect the efficiency of regional innovation systems?

This study analyzes the relationship between the specialization of a region in certain industries and the efficiency of the region in generating new knowledge. The efficiency measure is constructed by relating regional R&D input and output. An inversely u-shaped relationship is found between regional specialization and R&D efficiency, indicating the presence of externalities of both Marshall and Jacobs’ type. Further factors influencing efficiency are externalities resulting from high R&D intensity of the local private sector as well as knowledge from local public research institutions. The impact of both the specialization and the additional factors is, however, different for regions at different efficiency levels.