Gas1 Regulates Patterning of the Murine and Human Dentitions through Sonic Hedgehog.

The mammalian dentition is a serially homogeneous structure that exhibits wide numerical and morphological variation among multiple different species. Patterning of the dentition is achieved through complex reiterative molecular signaling interactions that occur throughout the process of odontogenesis. The secreted signaling molecule Sonic hedgehog (Shh) plays a key role in this process, and the Shh coreceptor growth arrest-specific 1 (Gas1) is expressed in odontogenic mesenchyme and epithelium during multiple stages of tooth development. We show that mice engineered with Gas1 loss-of-function mutation have variation in number, morphology, and size of teeth within their molar dentition. Specifically, supernumerary teeth with variable morphology are present mesial to the first molar with high penetrance, while molar teeth are characterized by the presence of both additional and absent cusps, combined with reduced dimensions and exacerbated by the presence of a supernumerary tooth. We demonstrate that the supernumerary tooth in Gas1 mutant mice arises through proliferation and survival of vestigial tooth germs and that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt and downstream FGF signaling in odontogenic epithelium through facilitation of Shh signal transduction. Moreover, regulation of tooth number is independent of the additional Hedgehog coreceptors Cdon and Boc, which are also expressed in multiple regions of the developing tooth germ. Interestingly, further reduction of Hedgehog pathway activity in Shhtm6Amc hypomorphic mice leads to fusion of the molar field and reduced prevalence of supernumerary teeth in a Gas1 mutant background. Finally, we demonstrate defective coronal morphology and reduced coronal dimensions in the molar dentition of human subjects identified with pathogenic mutations in GAS1 and SHH/GAS1, suggesting that regulation of Hedgehog signaling through GAS1 is also essential for normal patterning of the human dentition.

Leaders by example: Best practices and advice on establishing a state-of-the art surgical simulation center that optimizes available resources.

BACKGROUND: The role of simulation-based education continues to expand exponentially. To excel in this environment as a surgical simulation leader requires unique knowledge, skills, and abilities that are different from those used in traditional clinically-based education. METHODS: Leaders in surgical simulation were invited to participate as discussants in a pre-conference course offered by the Association for Surgical Education. Highlights from their discussions were recorded. RESULTS: Recommendations were provided on topics such as building a simulation team, preparing for accreditation requirements, what to ask for during early stages of development, identifying tools and resources needed to meet educational goals, expanding surgical simulation programming, and building educational curricula. CONCLUSION: These recommendations provide new leaders in simulation with a unique combination of up-to-date best practices in simulation-based education, as well as valuable advice gained from lessons learned from the personal experiences of national leaders in the field of surgical simulation and education.

Dose-dependent increase in plasma interleukin-6 after recombinant tumour necrosis factor infusion in humans.

Several studies have shown that the cytokine interleukin-6 (IL-6) is produced in response to tumour necrosis factor (TNF) in vitro. This study examines the in vivo relation between these two cytokines with assays of plasma IL-6 and TNF levels in subjects with chronic hepatitis B undergoing immunomodulatory therapy with recombinant TNF (rTNF). Plasma IL-6 was detected from 20 min after rTNF infusion with levels peaking after 2-3 h and levels correlated with the dose of rTNF administered (r = 0.67, P = 0.004). Peak levels of IL-6 (mean 295, range 266-297 ng/l) were lower than those seen in certain disease states despite the very high peak levels of rTNF (mean 11,750, range 5623-18,620 ng/l). These findings suggest that the very high levels of IL-6 found in certain disease states are not purely the result of circulating TNF. Other factors such as endotoxin or other cytokines may also play a role in determining levels of plasma IL-6.

Effect of recombinant alpha 2 interferon with or without prednisone in Chinese HBsAg carrier children.

Ninety Chinese hepatitis B surface antigen (HBsAg) carrier children, aged 2-17 years, positive for hepatitis B e antigen (HBeAg) and hepatitis B virus DNA on at least three occasions in 6 months, were randomized into 3 groups. Thirty children received syrup vitamin B complex as control, 29 received 6 weeks of placebo syrup followed by 16 weeks of recombinant alpha 2b-interferon [intron A (rIFN2b)], 5 x 10(6) u/m2 subcutaneously thrice weekly; and 31 received 6 weeks of syrup prednisone (0.6 mg/kg tailed to 0.2 mg/kg) followed by 16 weeks of recombinant alpha 2b-interferon as above. The placebo/prednisone syrup was given on a double-blind basis. At 24 months of follow-up, persistent loss of hepatitis B virus DNA occurred in none of the children in the control group, in one child receiving recombinant alpha 2b-interferon alone, who also seroconverted to anti-HBe and anti-HBs and in five children receiving interferon with steroid priming (p = 0.0571 compared with controls), with four seroconverting to anti-HBe and one also seroconverting to anti-HBs. A rise of transaminases to above twice the upper limit of normal levels during the first 7 months of follow-up occurred in one subject in the control group, four in the group receiving alpha 2b-interferon alone and nine in the group receiving recombinant alpha 2b-interferon with steroid priming (p = 0.0144 compared with controls). Side effects of the steroid were negligible; those of recombinant alpha 2b-interferon were transient and acceptable. We conclude that 6 weeks of prednisone followed by 16 weeks of recombinant alpha 2b-interferon is of use in inducing persistent loss of hepatitis B virus DNA (16.1 per cent) and e-seroconversion (12.9 per cent) in a proportion of Chinese HBsAg carrier children: the prednisone probably enhances the immunomodulatory effect of recombinant alpha 2b-interferon.