TGFbeta signaling regulates central cellular processes such as proliferation and extracellular matrix production during development of the orofacial region. Extracellular TGFbeta binds to cell surface receptors to activate the nucleocytoplasmic Smad proteins that, along with other transcription factors and cofactors, bind specific DNA sequences in the promoters of target genes to regulate their expression. To determine the identity of Smad binding proteins that regulate TGFbeta signaling in developing murine orofacial tissue, a yeast two-hybrid screening approach was employed. The PR-domain containing protein, PRDM16/MEL1 was identified as a novel Smad binding protein. The interaction between PRDM16/MEL1 and Smad 3 was confirmed by GST pull-down assays. The expression of PRDM16/MEL1 was detected in developing orofacial tissue by both Northern blot and in situ hybridization. PRDM16/MEL1 was constitutively expressed in orofacial tissue on E12.5-E14.5 as well as other embryonic tissues such as heart, brain, liver, and limb buds. Taken together, these results demonstrate that PRDM16/MEL1 is a Smad binding protein that may be important for development of orofacial structures through modulation of the TGFbeta signaling pathway.

Summary:A patient with an allergy to a macrolide antibiotic was given tacrolimus and developed a sudden cutaneous reaction. Bone Marrow Transplantation (2000) 25, 907-908. Keywords: tacrolimus; macrolide; allergy Tacrolimus (FK506) is a macrolide immunosuppressant produced by the fungus Streptomyces tsukubaensis. The drug is indicated for liver transplant rejection prophylaxis and is under investigation for use in kidney, cardiac, pancreas, small bowel, and bone marrow transplantation. Tacrolimus inhibits T lymphocyte activation by binding to an intracellular protein (FKBP), which interacts with calcineurin and subsequently inhibits the phosphatase activity of calcineurin. Without this phosphatase activity, it is thought that the generation of gene transcription for the interleukins (IL-2, ␥-interferon) is inhibited and thus results in decreased T lymphocyte activation.Cutaneous reactions to tacrolimus occur in 10-24% of patients and are described as simply 'a rash'. Cutaneous reactions to macrolide antibiotics such as clarithromycin range from mild skin eruptions to Stevens-Johnson syndrome. The mild symptoms resolve when the drug is stopped. Case reportA 45-year-old woman, was referred to our institution for a haploidentical allogeneic bone marrow transplant for treatment of acute myelogenous leukemia (FAB M4) in second remission. She received a preparative regimen containing thiotepa (5 mg/kg × 1, day −6), cyclophosphamide (60 mg/kg/day × 2, days −5, −4), antithymocyte globulin (equine) (15 mg/kg/day × 2, days −4, −2 and 10 mg/kg/day × 6, days +5 to +10), and total body irradiation (200 cGy × 5 fractions, days −2, −1, 0). For graft-versus-host disease prophylaxis, tacrolimus (FK506) at 0.03 mg/kg/day as continuous infusion was started on day −1.The patient had a history of allergies to ciprofloxacin, clarithromycin, vancomycin, and allopurinol, all of which caused a rash, apart from vancomycin which caused itching. Upon admission, skin examination was normal, with normal turgor and tone, without presence of petechiae, echymoses, or lesions. With the patient's stated macrolide allergy, we were concerned at starting tacrolimus, so a review of the medical literature was undertaken to look for any reports of cross-reactivity between tacrolimus and clarithromycin. In a thorough review as well as conversations with the manufacturer of tacrolimus, Fujisawa (Deerfield, IL, USA), no such reports had been made during clinical trials or within the post-marketing period. The decision was made to initiate therapy and monitor the patient closely. Tacrolimus was started as described in the above regimen. The patient also received cytomegalovirus immune globulin, sulfamethoxazole and trimethoprim, fluconazole, methylprednisolone, radiation, ursodeoxycholic acid, famotidine, conjugated estrogen, and alprazolam on the same day. After 3 days she developed an erythematous, follicular rash and the next day, she had diffuse, generalized erythema. Because of the escalating skin problems, the tacrolimus was stopped and replaced with...

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