Personal Dental Services--a practitioner's point of view.

NHS dentistry has seen many changes recently. The latest has been the introduction of Personal Dental Services. This article describes the experiences of two general dental practitioners in their practice who entered as a first wave pilot. The article explains the steps involved in generating a proposal and preparing a practice to run as a pilot. The authors have highlighted areas of particular concern for others to consider before embarking on a similar journey.

The Yin-Yang of TCF/beta-catenin signaling.

Wingless/Wnt signaling directs cell-fate choices during embryonic development. In Drosophila, Wingless signaling mediates endoderm induction and the establishment of segment polarity in the developing embryo. The fly Wingless cascade is strikingly similar to the vertebrate Wnt signaling pathway, which controls a number of key developmental decisions such as dorsal-ventral patterning in Xenopus. Factors of the TCF/LEF HMG domain family (Tcfs) have recently been established as the downstream effectors of the Wingless/Wnt signal transduction pathways. Upon Wingless/Wnt signaling, a cascade is initiated that results in the accumulation of cytoplasmic beta-catenin (or its fly homolog, Armadillo). There is also a concomitant translocation of beta-catenin/Armadillo to the nucleus, where it interacts with a specific sequence motif at the N terminus of Tcfs to generate a transcriptionally active complex. This bipartite transcription factor is targeted to the upstream regulatory regions of Tcf target genes including Siamois and Nodal related gene-3 in Xenopus, engrailed and Ultrabithorax in Drosophila via the sequence-specific HMG box, and mediates their transcriptional activation by virtue of transactivation domains contributed by beta-catenin/Armadillo. In the absence of Wingless/Wnt signals, a key negative regulator of the pathway, GSK3 beta, is activated, which mediates the downregulation of cytoplasmic beta-catenin/Armadillo via the ubiquitin-proteasome pathway. In the absence of nuclear beta-catenin, the Tcfs recruit the corepressor protein Groucho to the target gene enhancers and actively repress their transcription. An additional corepressor protein, CREB-binding protein (CBP), may also be involved in this repression of Tcf target gene activity. Several other proteins, including adenomatous polyposis coli (APC), GSK3 beta, and Axin/Conductin, are instrumental in the regulation of beta-catenin/Armadillo. In APC-deficient colon carcinoma cell lines, beta-catenin accumulates and is constitutively complexed with nuclear Tcf-4. A proportion of APC wild-type colon carcinomas and melanomas also contains constitutive nuclear Tcf-4/beta-catenin complexes as a result of dominant mutations in the N terminus of beta-catenin that render it insensitive to downregulation by APC, GSK3 beta, and Axin/Conductin. This results in the unregulated expression of Tcf-4 target genes such as c-myc. Based on the established role for Tcf-4 in maintaining intestinal stem cells it is likely that deregulation of c-myc expression as a result of constitutive Tcf-4/beta-catenin activity promotes uncontrolled intestinal cell proliferation. This would readily explain the formation of intestinal polyps during colon carcinogenesis. Similar mechanisms leading to deregulation of Tcf target gene activity are likely to be involved in melanoma and other forms of cancer.

Manchineel keratoconjunctivitis.

The Manchineel tree is an evergreen widely distributed in tropical regions. The toxic nature of Manchineel has been known since the early sixteenth century. Contact with its milky sap (latex) produces bullous dermatitis and acute keratoconjunctivitis. We identified 19 patients who had ocular injuries caused by Manchineel between 1985 and 1990 and were able to review 12. All of these patients had been treated by lavage, cycloplegia, and topical antibiotics. Of 20 episodes of exposure 14 affected both eyes. The cornea was damaged in 16 episodes, the extent varying from large corneal epithelial defects to superficial punctate keratitis. The epithelial changes had resolved in a mean period of 3.75 days (range 1 to 14 days). Two episodes caused stromal infiltration to appear and in one of these a stromal opacity remained 5 years later. The final visual acuity was 6/9 or better in all eyes except in one patient who had visual impairment because of glaucoma. Our results suggest that despite the severity of the acute reaction, the long term visual prognosis is excellent in Manchineel keratoconjunctivitis. The historical and toxicological literature on Manchineel is reviewed.