A feed-forward relay integrates the regulatory activities of Bicoid and Orthodenticle via sequential binding to suboptimal sites.

The K50 (lysine at amino acid position 50) homeodomain (HD) protein Orthodenticle (Otd) is critical for anterior patterning and brain and eye development in most metazoans. In Drosophila melanogaster, another K50HD protein, Bicoid (Bcd), has evolved to replace Otd's ancestral function in embryo patterning. Bcd is distributed as a long-range maternal gradient and activates transcription of a large number of target genes, including otd Otd and Bcd bind similar DNA sequences in vitro, but how their transcriptional activities are integrated to pattern anterior regions of the embryo is unknown. Here we define three major classes of enhancers that are differentially sensitive to binding and transcriptional activation by Bcd and Otd. Class 1 enhancers are initially activated by Bcd, and activation is transferred to Otd via a feed-forward relay (FFR) that involves sequential binding of the two proteins to the same DNA motif. Class 2 enhancers are activated by Bcd and maintained by an Otd-independent mechanism. Class 3 enhancers are never bound by Bcd, but Otd binds and activates them in a second wave of zygotic transcription. The specific activities of enhancers in each class are mediated by DNA motif variants preferentially bound by Bcd or Otd and the presence or absence of sites for cofactors that interact with these proteins. Our results define specific patterning roles for Bcd and Otd and provide mechanisms for coordinating the precise timing of gene expression patterns during embryonic development.

Severe hypercalcemia after transition from calcium carbonate to calcium citrate in an elderly woman treated with ergocalciferol 50,000 IU per day.

BACKGROUND: Absorption of calcium carbonate in the fasting state has been reported to be significantly compromised in subjects with achlorhydria. Although calcium carbonate malabsorption in the fasting state cannot be predicted, it might be corrected if the compound is administered with meals. However, administering calcium carbonate with meals is logistically challenging in long-term care facilities. OBJECTIVE: The aim of this study was to report the case of a woman who was transitioned to calcium citrate and subsequently experienced symptomatic severe hypercalcemia. METHODS: An 89-year-old female resident of the Wisconsin Veterans Home, a skilled nursing facility in King, Wisconsin, was receiving long-term treatment with ergocalciferol (vitamin D2) 50,000 IU/d. The patient also was receiving calcium carbonate supplements in the morning, and she rarely ate breakfast (fasting state). The patient was transitioned from 2000 mg/d of elemental calcium as carbonate to 1230 mg/d as citrate. RESULTS: After being switched from calcium carbonate to calcium citrate, the patient developed severe symptomatic hypercalcemia (16.8 mg/dL), the primary cause of which was the administration of an inappropriately high dose of vitamin D. CONCLUSIONS: We report a case of symptomatic severe hypercalcemia in a skilled nursing facility resident treated with an inappropriately high daily dose of vitamin D. Hypercalcemia manifested when calcium carbonate was replaced with calcium citrate.