PURPOSE.To characterize the genetic basis and phenotype of inherited Fuchs corneal dystrophy (FCD). METHODS.DNA from blood was used for genome-wide linkage scans with tandem repeat polymorphisms. Mutation detection involved sequencing PCR-amplified exons. Families with FCD were clinically evaluated and graded on the Krachmer severity scale. Confocal specular microscopy visualized the morphology of endothelial guttae, small protrusions of Descemet's membrane that are characteristic of FCD. RESULTS.Linkage was obtained to 1p34.3-p32 for the autosomal dominant kindred originally reported by Magovern in 1979. All 21 cases with FCD and one with posterior polymorphous dystrophy were heterozygous for L450W, a novel point mutation in the COL8A2 gene. Of 62 independent cases of familial FCD, none had the previously reported mutations in COL8A2. Corneal guttae in COL8A2 patients were small, rounded, and associated with the endothelial cell center. This contrasts with common FCD, in which guttae were larger, sharply peaked, and initially positioned at edges of endothelial cells. The profile of age and disease severity for the L450W FCD kindred suggested that disease onset occurred in infancy, compared with an average age of onset of 50 years estimated for 201 familial FCD patients in 62 other families. CONCLUSIONS.A novel pathogenic L450W COL8A2 mutation was identified and its highly distinctive pathology characterized. This indicates that COL8A2 mutations give rise to a rare subtype of FCD. This study also provides the first direct evidence that COL8A2-FCD progresses from early to late stages in 25 years, a rate similar to that estimated for late-onset FCD. (Invest Ophthalmol Vis Sci. 2005;46:1934 -1939) DOI: 10.1167/iovs.04-0937 F uchs corneal dystrophy (FCD) is a primary disorder of the endothelium that leads to progressive edema of the corneal stroma (OMIM 136800; Online Mendelian Inheritance in Man; http://www.ncbi.nlm.nih.gov/Omim/ provided in the public domain by the National Center for Biotechnology Information, Bethesda, MD). Visual disability from this disease is currently the major reason for corneal transplantation.1 The initial stages of FCD typically begin in the fifth through seventh decades of life and are characterized by localized thickening of Descemet's membrane and the development of nodular excrescences called guttae. This early phase is followed by long-term decreases in the density and ion transport functions of the overlying corneal endothelial cells, which allows excess water to accumulate in the cornea.2-8 Several reports, including the original description by Fuchs, have indicated that two to three times as many females as males are affected by the disease. 2,7,9 As many as 50% of clinical cases of FCD may show familial clustering, 9 and the disease generally follows an autosomal dominant pattern of inheritance. 10 -15 Nearly all these families show inheritance of late-onset FCD, whereas rare cases 12,14 show disease onset as early as the first decade, with extensive corneal edema by the third ...

There is currently much interest in examining climatic tipping points, to see if it is feasible to predict them in advance. Using techniques from bifurcation theory, recent work looks for a slowing down of the intrinsic transient responses, which is predicted to occur before an instability is encountered. This is done, for example, by determining the short-term autocorrelation coefficient ARC(1) in a sliding window of the time-series: this stability coefficient should increase to unity at tipping. Such studies have been made both on climatic computer models and on real paleoclimate data preceding ancient tipping events. The latter employ reconstituted time-series provided by ice cores, sediments, etc., and seek to establish whether the actual tipping could have been accurately predicted in advance. One such example is the end of the Younger Dryas event, about 11 500 years ago, when the Arctic warmed by 7• C in 50 yrs. A second gives an excellent prediction for the end of "greenhouse" Earth about 34 million years ago when the climate tipped from a tropical state into an icehouse state, using data from tropical Pacific sediment cores. This prediction science is very young, but some encouraging results are already being obtained. Future analyses will clearly need to embrace both real data from improved monitoring instruments, and simulation data generated from increasingly sophisticated predictive models.

Infection is a major complication of implantable medical devices, which provide a scaffold for biofilm formation, thereby reducing susceptibility to antibiotics and complicating treatment. Hematogenous implant-related infections following bacteremia are particularly problematic because they can occur at any time in a previously stable implant. Herein, we developed a model of hematogenous infection in which an orthopedic titanium implant was surgically placed in the legs of mice followed 3 wk later by an i.v. exposure to Staphylococcus aureus. This procedure resulted in a marked propensity for a hematogenous implant-related infection comprised of septic arthritis, osteomyelitis, and biofilm formation on the implants in the surgical legs compared with sham-operated surgical legs without implant placement and with contralateral nonoperated normal legs. Neutralizing human monoclonal antibodies against α-toxin (AT) and clumping factor A (ClfA), especially in combination, inhibited biofilm formation in vitro and the hematogenous implant-related infection in vivo. Our findings suggest that AT and ClfA are pathogenic factors that could be therapeutically targeted against S. aureus hematogenous implant-related infections.hematogenous | implant | Staphylococcus aureus | biofilm | orthopedic

We propose an archetypal system to investigate transitions from smooth to discontinuous dynamics. In the smooth regime, the system bears significant similarities to the Duffing oscillator, exhibiting the standard dynamics governed by the hyperbolic structure associated with the stationary state of the double well. At the discontinuous limit, however, there is a substantial departure in the dynamics from the standard one. In particular, the velocity flow suffers a jump in crossing from one well to another, caused by the loss of local hyperbolicity due to the collapse of the stable and unstable manifolds of the stationary state. In the presence of damping and external excitation, the system has coexisting attractors and also a chaotic saddle which becomes a chaotic attractor when a smoothness parameter drops to zero. This attractor can bifurcate to a high-period periodic attractor or a chaotic sea with islands of quasiperiodic attractors depending on the strength of damping.

Routine measurement of i.v. agents, analogous to that for volatile anaesthetic agents, may be possible.

No abstract

No abstract

No abstract