A modular system of DNA enhancer elements mediates tissue-specific activation of transcription by high dietary zinc in C. elegans.

Zinc is essential for biological systems, and aberrant zinc metabolism is implicated in a broad range of human diseases. To maintain homeostasis in response to fluctuating levels of dietary zinc, animals regulate gene expression; however, mechanisms that mediate the transcriptional response to fluctuating levels of zinc have not been fully defined. Here, we identified DNA enhancer elements that mediate intestine-specific transcriptional activation in response to high levels of dietary zinc in C. elegans. Using bioinformatics, we characterized an evolutionarily conserved enhancer element present in multiple zinc-inducible genes, the high zinc activation (HZA) element. The HZA was consistently adjacent to a GATA element that mediates expression in intestinal cells. Functional studies using transgenic animals demonstrated that this modular system of DNA enhancers mediates tissue-specific transcriptional activation in response to high levels of dietary zinc. We used this information to search the genome and successfully identified novel zinc-inducible genes. To characterize the mechanism of enhancer function, we demonstrated that the GATA transcription factor ELT-2 and the mediator subunit MDT-15 are necessary for zinc-responsive transcriptional activation. These findings define new mechanisms of zinc homeostasis and tissue-specific regulation of transcription.

Outpatient follow-up for patients with rheumatoid arthritis in relation to New Zealand Rheumatology Association guidelines at Dunedin Hospital.

AIM: Current treatment for rheumatoid arthritis (RA) involves the use of various disease-modifying anti-rheumatic drugs (DMARDs) and biologic response agents which require ongoing medical supervision. An audit was undertaken to assess the adequacy of outpatient specialist follow-up for supervision of treatment in patients with RA in the Otago region. METHODS: The Rheumatology Service database was used to assess time between follow-up for the penultimate and last visit to rheumatology outpatient clinic for all patients who made at least two visits between 1 October 2001 and 30 September 2006. Other recorded data included demographic information and clinician expectations for the timing of the next outpatient visit. Comparisons were made between actual follow-up intervals, those indicated by specialists and the follow-up intervals recommended by the New Zealand Rheumatology Association Guidelines. Patients were characterised according to four groups specified in the guidelines: Group A: patients newly started on DMARDs; Group B: patients with some change in disease management: Group C: patient stable on potent medications: Group D: patients stable on less severe medication. RESULTS: According to the guidelines only 40% of patients were followed up within the recommended intervals. Groups A and B (76.9% and 70.6% respectively) had a significantly greater proportion of patients with follow-up at variance to guideline recommendations compared to groups C and D (50% and 45.3% respectively) (p<0.001). There were marked discrepancies between the guideline recommended follow-up intervals and those suggested by the clinicians. Compared with guideline recommendations clinicians advised less frequent follow-up for groups A and B but more frequent for patients in Groups C and D. However, an assessment of the quality of life scores amongst the patients suggested that follow-up was still appropriately targeted to those patients with lower quality of life. CONCLUSION: Discrepancies in follow-up were most marked in the patient groups potentially most at risk of medication-related problems in whom guidelines suggested more intensive monitoring. Additional strategies to promote guideline-based follow-up arrangements may be indicated. Further work should examine the relationships between guideline recommended, physician intended and actual follow-up among rheumatology patients in other regions in order to assess whether modifications should occur to clinician behaviour or guideline content.

Early-stage biotech companies: strategies for survival and growth.

The promise of start-up biotechnology companies is enormous. So are the risks and the uncertainty of product development. The authors present a checklist for young biotech companies, covering environmental factors, alliances, and strategic planning.