A mouse model for Sorsby fundus dystrophy

purpose. Sorsby fundus dystrophy (SFD) is a rare, late-onset macular dystrophy caused by mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) gene. The known mutations introduce potentially unpaired cysteine residues in the C terminus of the protein and result in the formation of higher-molecular-weight protein complexes of as yet unknown composition and functional consequences in the pathologic course of SFD. To facilitate in vivo investigation of mutant TIMP3, the authors generated a knock-in mouse carrying a disease-related Ser156Cys mutation in the orthologous murine Timp3 gene. methods. Site-directed mutagenesis and homologous recombination in embryonic stem (ES) cells was used to generate mutant ES cells carrying the Timp3 S156C allele. Chimeric animals were obtained, of which two displayed germline transmission of the mutated allele. Molecular genetic, biochemical, electron microscopic, and electrodiagnostic techniques were used for characterization. results. At 8 months of age, knock-in mice showed abnormalities in the inner aspect of Bruch’s membrane and in the organization of the adjacent basal microvilli of the retinal pigment epithelium (RPE). Changes resembling those in the mutant animals were also present to some extent in normal littermates, but only at an advanced age of 30 months. Long-term electrodiagnostic recordings indicated normal retinal function throughout life. The biochemical characteristics of the mutant protein appear similar in humans and knock-in mice, suggesting common molecular pathways in the two species. The localization of the mutant protein in the eye is normal, although there is evidence of increased Timp3 levels in Bruch’s membrane of mutant animals. conclusions. The knock-in mice display early features of age-related changes in Bruch’s membrane and the RPE that may represent the primary clinical manifestations of SFD. In addition, our immunolabeling studies and biochemical data support a model proposing that site-specific excess rather than absence or deficiency of functional Timp3 may be the primary consequence of the known Timp3 mutations

Particle transport in magnetized media around black holes and associated radiation

Galactic black hole coronae are composed of a hot, magnetized plasma. The spectral energy distribution produced in this component of X-ray binaries can be strongly affected by different interactions between locally injected relativistic particles and the matter, radiation and magnetic fields in the source. We study the non-thermal processes driven by the injection of relativistic particles into a strongly magnetized corona around an accreting black hole. We compute in a self-consistent way the effects of relativistic bremsstrahlung, inverse Compton scattering, synchrotron radiation, and the pair-production/annihilation of leptons, as well as hadronic interactions. Our goal is to determine the non-thermal broadband radiative output of the corona. The set of coupled kinetic equations for electrons, positrons, protons, and photons are solved and the resulting particle distributions are computed self-consistently. The spectral energy distributions of transient events in X-ray binaries are calculated, as well as the neutrino production. We show that the application to Cygnus X-1 of our model of non-thermal emission from a magnetized corona yields a good fit to the observational data. Finally, we show that the accumulated signal produced by neutrino bursts in black hole coronae might be detectable for sources within a few kpc on timescales of years. Our work leads to predictions for non-thermal photon and neutrino emission generated around accreting black holes, that can be tested by the new generation of very high energy gamma-ray and neutrino instruments.Comment: 13 pages, 10 figures, accepted for publication in A&

Modifying effect of dual antiplatelet therapy on incidence of stent thrombosis according to implanted drug-eluting stent type

Aim To investigate the putative modifying effect of dual antiplatelet therapy (DAPT) use on the incidence of stent thrombosis at 3 years in patients randomized to Endeavor zotarolimus-eluting stent (E-ZES) or Cypher sirolimus-eluting stent (C-SES). Methods and results Of 8709 patients in PROTECT, 4357 were randomized to E-ZES and 4352 to C-SES. Aspirin was to be given indefinitely, and clopidogrel/ticlopidine for ≥3 months or up to 12 months after implantation. Main outcome measures were definite or probable stent thrombosis at 3 years. Multivariable Cox regression analysis was applied, with stent type, DAPT, and their interaction as the main outcome determinants. Dual antiplatelet therapy adherence remained the same in the E-ZES and C-SES groups (79.6% at 1 year, 32.8% at 2 years, and 21.6% at 3 years). We observed a statistically significant (P = 0.0052) heterogeneity in treatment effect of stent type in relation to DAPT. In the absence of DAPT, stent thrombosis was lower with E-ZES vs. C-SES (adjusted hazard ratio 0.38, 95% confidence interval 0.19, 0.75; P = 0.0056). In the presence of DAPT, no difference was found (1.18; 0.79, 1.77; P = 0.43). Conclusion A strong interaction was observed between drug-eluting stent type and DAPT use, most likely prompted by the vascular healing response induced by the implanted DES system. These results suggest that the incidence of stent thrombosis in DES trials should not be evaluated independently of DAPT use, and the optimal duration of DAPT will likely depend upon stent type (Clinicaltrials.gov number NCT00476957

Approaching 3-D modelling of the global climate system on paleo-climatic time scales

A strategy for 3-d modelling of the global climate system on paleo-climatic time scales is proposed. Presently available models of the general circulation type for the three major physical climate components (atmosphere, ocean and ice sheets) are quite able to simulate the present climate. They also seem to behave realistically when paleo-climatic boundary conditions are applied. However, these models are still not precise enough to define the exchange fluxes in numerical, coupled atmosphere-ocean-ice experiments. Furthermore, typical multi-level Atmospheric General Circulation Models (AGCMs) consume too much computer time to allow integrations on paleo-climatic time scales. It is suggested to replace the AGCM by a two-level atmospheric model, including a simple parameterization of the hydrological cycle, formulated to yield the stationary state for prescribed boundary conditions. With such a simplified model atmosphere, coupled integrations of the climate system over several thousand years will be possible. © 1992