Histone deacetylases – a new target for suppression of cartilage degradation?

Increased expression of metalloproteinases is a fundamental aspect of arthritispathology and its control is a major therapeutic objective. In cartilage cultured in the presence of the cytokines interleukin-1 and oncostatin M, chondrocytes produce enhanced levels of metalloproteinases of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and MMP (matrix metalloproteinase) families, resulting in the degradation of aggrecan and collagen. The histone deacetylase inhibitors trichostatin A and butyrate were shown to drastically reduce expression of these enzymes relatively selectively, with concomitant inhibition of breakdown of matrix components. This family of enzymes is therefore a promising target for therapeutic intervention

The potential role of hybridization in diversification and speciation in an insular plant lineage: insights from synthetic interspecific hybrids

Hybridization is recognized as an important process in plant evolution, and this may be particularly true for island plants where several biotic and abiotic factors facilitate interspecific hybridization. Although rarely done, experimental studies could provide insights into the potential of natural hybridization to generate diversity when species come into contact in the dynamic island setting. The potential of hybridization to generate morphological variation was analysed within and among 12 families (inbred lines) of an F4 hybrid generation between two species of Tolpis endemic to the Canary Islands. Combinations of characters not seen in the parents were present in hybrids. Several floral and vegetative characters were transgressive relative to their parents. Morphometric studies of floral, vegetative and fruit characters revealed that several F4 families were phenotypically distinct from other families, and from their parents. The study demonstrates that morphologically distinct pollen-fertile lines, potentially worthy of taxonomic recognition if occurring in nature, can be generated in four generations. The ability of the hybrid lines to set self-seed would reduce gene flow among the lines, and among the hybrids and their parental species. Selfing would also facilitate the fixation of characters within each of the lines. Overall, the results show the considerable potential of hybridization for generating diversity and distinct phenotypes in island lineages

Normal X-inactivation mosaicism in corneas of heterozygous FlnaDilp2/+ female mice--a model of human Filamin A (FLNA) diseases

<p>Abstract</p> <p>Background</p> <p>Some abnormalities of mouse corneal epithelial maintenance can be identified by the atypical mosaic patterns they produce in X-chromosome inactivation mosaics and chimeras. Human <it>FLNA</it>/+ females, heterozygous for X-linked, filamin A gene (<it>FLNA</it>) mutations, display a range of disorders and X-inactivation mosaicism is sometimes quantitatively unbalanced. <it>Flna</it>^{<it>Dilp2/+ </it>}mice, heterozygous for an X-linked filamin A (<it>Flna</it>) nonsense mutation have variable eye, skeletal and other abnormalities, but X-inactivation mosaicism has not been investigated. The aim of this study was to determine whether X-inactivation mosaicism in the corneal epithelia of <it>Flna</it>^{<it>Dilp2/+ </it>}mice was affected in any way that might predict abnormal corneal epithelial maintenance.</p> <p>Results</p> <p>X-chromosome inactivation mosaicism was studied in the corneal epithelium and a control tissue (liver) of <it>Flna</it>^{<it>Dilp2/+ </it>}and wild-type (WT) female X-inactivation mosaics, hemizygous for the X-linked, <it>LacZ </it>reporter H253 transgene, using β-galactosidase histochemical staining. The corneal epithelia of <it>Flna</it>^{<it>Dilp2/+ </it>}and WT X-inactivation mosaics showed similar radial, striped patterns, implying epithelial cell movement was not disrupted in <it>Flna</it>^{<it>Dilp2/+ </it>}corneas. Corrected stripe numbers declined with age overall (but not significantly for either genotype individually), consistent with previous reports suggesting an age-related reduction in stem cell function. Corrected stripe numbers were not reduced in <it>Flna</it>^{<it>Dilp2/+ </it>}compared with WT X-inactivation mosaics and mosaicism was not significantly more unbalanced in the corneal epithelia or livers of <it>Flna</it>^{<it>Dilp2/+ </it>}than wild-type <it>Flna^+/+</it>X-inactivation mosaics.</p> <p>Conclusions</p> <p>Mosaic analysis identified no major effect of the mouse <it>Flna^Dilp2</it>mutation on corneal epithelial maintenance or the balance of X-inactivation mosaicism in the corneal epithelium or liver.</p

Comparison of the Airtraq® and Truview® laryngoscopes to the Macintosh laryngoscope for use by Advanced Paramedics in easy and simulated difficult intubation in manikins

<p>Abstract</p> <p>Background</p> <p>Paramedics are frequently required to perform tracheal intubation, a potentially life-saving manoeuvre in severely ill patients, in the prehospital setting. However, direct laryngoscopy is often more difficult in this environment, and failed tracheal intubation constitutes an important cause of morbidity. Novel indirect laryngoscopes, such as the Airtraq^®and Truview^®laryngoscopes may reduce this risk.</p> <p>Methods</p> <p>We compared the efficacy of these devices to the Macintosh laryngoscope when used by 21 Paramedics proficient in direct laryngoscopy, in a randomized, controlled, manikin study. Following brief didactic instruction with the Airtraq^®and Truview^®laryngoscopes, each participant took turns performing laryngoscopy and intubation with each device, in an easy intubation scenario and following placement of a hard cervical collar, in a SimMan^®manikin.</p> <p>Results</p> <p>The Airtraq^®reduced the number of optimization manoeuvres and reduced the potential for dental trauma when compared to the Macintosh, in both the normal and simulated difficult intubation scenarios. In contrast, the Truview^®increased the duration of intubation attempts, and required a greater number of optimization manoeuvres, compared to both the Macintosh and Airtraq^®devices.</p> <p>Conclusion</p> <p>The Airtraq^®laryngoscope performed more favourably than the Macintosh and Truview^®devices when used by Paramedics in this manikin study. Further studies are required to extend these findings to the clinical setting.</p

Comparison of the Airtraq® and Truview® laryngoscopes to the Macintosh laryngoscope for use by Advanced Paramedics in easy and simulated difficult intubation in manikins

<p>Abstract</p> <p>Background</p> <p>Paramedics are frequently required to perform tracheal intubation, a potentially life-saving manoeuvre in severely ill patients, in the prehospital setting. However, direct laryngoscopy is often more difficult in this environment, and failed tracheal intubation constitutes an important cause of morbidity. Novel indirect laryngoscopes, such as the Airtraq^®and Truview^®laryngoscopes may reduce this risk.</p> <p>Methods</p> <p>We compared the efficacy of these devices to the Macintosh laryngoscope when used by 21 Paramedics proficient in direct laryngoscopy, in a randomized, controlled, manikin study. Following brief didactic instruction with the Airtraq^®and Truview^®laryngoscopes, each participant took turns performing laryngoscopy and intubation with each device, in an easy intubation scenario and following placement of a hard cervical collar, in a SimMan^®manikin.</p> <p>Results</p> <p>The Airtraq^®reduced the number of optimization manoeuvres and reduced the potential for dental trauma when compared to the Macintosh, in both the normal and simulated difficult intubation scenarios. In contrast, the Truview^®increased the duration of intubation attempts, and required a greater number of optimization manoeuvres, compared to both the Macintosh and Airtraq^®devices.</p> <p>Conclusion</p> <p>The Airtraq^®laryngoscope performed more favourably than the Macintosh and Truview^®devices when used by Paramedics in this manikin study. Further studies are required to extend these findings to the clinical setting.</p

Effects of Aberrant Pax6 Gene Dosage on Mouse Corneal Pathophysiology and Corneal Epithelial Homeostasis

Background: Altered dosage of the transcription factor PAX6 causes multiple human eye pathophysiologies. PAX6(+/-) heterozygotes suffer from aniridia and aniridia-related keratopathy (ARK), a corneal deterioration that probably involves a limbal epithelial stem cell (LESC) deficiency. Heterozygous Pax6(+/Sey-Neu) (Pax6(+/-)) mice recapitulate the human disease and are a good model of ARK. Corneal pathologies also occur in other mouse Pax6 mutants and in PAX77(Tg/-) transgenics, which over-express Pax6 and model human PAX6 duplication. Methodology/Principal Findings: We used electron microscopy to investigate ocular defects in Pax6(+/-) heterozygotes (low Pax6 levels) and PAX77(Tg/-) transgenics (high Pax6 levels). As well as the well-documented epithelial defects, aberrant Pax6 dosage had profound effects on the corneal stroma and endothelium in both genotypes, including cellular vacuolation, similar to that reported for human macular corneal dystrophy. We used mosaic expression of an X-linked LacZ transgene in X-inactivation mosaic female (XLacZ(Tg/-)) mice to investigate corneal epithelial maintenance by LESC clones in Pax6(+/-) and PAX77(Tg/-) mosaic mice. PAX77(Tg/-) mosaics, over-expressing Pax6, produced normal corneal epithelial radial striped patterns (despite other corneal defects), suggesting that centripetal cell movement was unaffected. Moderately disrupted patterns in Pax6(+/-) mosaics were corrected by introducing the PAX77 transgene (in Pax6(+/-), PAX77(Tg/-) mosaics). Pax6(Leca4/+), XLacZ(Tg/-) mosaic mice (heterozygous for the Pax6(Leca4) missense mutation) showed more severely disrupted mosaic patterns. Corrected corneal epithelial stripe numbers (an indirect estimate of active LESC clone numbers) declined with age (between 15 and 30 weeks) in wild-type XLacZ(Tg/-) mosaics. In contrast, corrected stripe numbers were already low at 15 weeks in Pax6(+/-) and PAX77(Tg/-) mosaic corneas, suggesting Pax6 under-and over-expression both affect LESC clones. Conclusions/Significance: Pax6(+/-) and PAX77(Tg/-) genotypes have only relatively minor effects on LESC clone numbers but cause more severe corneal endothelial and stromal defects. This should prompt further investigations of the pathophysiology underlying human aniridia and ARK