ABSTRACT
INTRODUCTION: Increased levels of genes in the type I interferon (IFN) pathway have been observed in patients with systemic sclerosis (SSc), or scleroderma. How type I IFN regulates the dermal fibroblast and its participation in the development of dermal fibrosis is not known. We hypothesized that one mechanism by which type I IFN may contribute to dermal fibrosis is through upregulation of specific Toll-like receptors (TLRs) on dermal fibroblasts. Therefore, we investigated the regulation of TLR expression on dermal fibroblasts by IFN. METHODS: The expression of TLRs was assessed in cultured dermal fibroblasts from control and SSc patients stimulated with IFNα2. The ability of IFNα2 to regulate TLR-induced interleukin (IL)-6 and CC chemokine ligand 2 production was also assessed. Immunohistochemical analyses were performed to determine whether TLR3 was expressed in skin biopsies in the bleomycin-induced skin fibrosis model and in patients with SSc. RESULTS: IFNα2 increased TLR3 expression on human dermal fibroblasts, which resulted in enhanced TLR3-induced IL-6 production. SSc fibroblasts have an augmented TLR3 response to IFNα2 relative to control fibroblasts. Pretreatment of fibroblasts with transforming growth factor (TGF)-ß increased TLR3 induction by IFNα2, but coincubation of TGF-ß did not alter TLR3 induction by IFN. Furthermore, IFNα2 inhibits but does not completely block the induction of connective tissue growth factor and collagen expression by TGF-ßin fibroblasts. TLR3 expression was observed in dermal fibroblasts and inflammatory cells from skin biopsies from patients with SSc as well as in the bleomycin-induced skin fibrosis model. CONCLUSIONS: Type I IFNs can increase the inflammatory potential of dermal fibroblasts through the upregulation of TLR3.
Subject(s)
Fibroblasts/immunology , Interferon-alpha/immunology , Scleroderma, Systemic/immunology , Skin/immunology , Toll-Like Receptor 3/immunology , Animals , Cells, Cultured , Fibroblasts/metabolism , Fibrosis , Humans , Immunohistochemistry , Interferon-alpha/metabolism , Mice , Mice, Inbred C57BL , Real-Time Polymerase Chain Reaction , Scleroderma, Systemic/metabolism , Scleroderma, Systemic/pathology , Skin/metabolism , Skin/pathology , Toll-Like Receptor 3/biosynthesis , Up-RegulationABSTRACT
Daptomycin pharmacokinetics were evaluated for burn patients. Burn patients had decreases in the maximum concentration of the drug in serum (44%) and the area under the concentration-time curve (47%) and increases in the volume of distribution (64%) and total clearance (77%) compared to healthy volunteers. In burn patients, daptomycin at 10 to 12 mg/kg of body weight/day would be required to achieve drug exposures similar to those for healthy volunteers receiving 6 mg/kg.
Subject(s)
Burns/drug therapy , Daptomycin/pharmacokinetics , Adult , Anti-Bacterial Agents/blood , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/urine , Area Under Curve , Burns/metabolism , Chromatography, High Pressure Liquid , Daptomycin/blood , Daptomycin/urine , Female , Humans , Male , Metabolic Clearance Rate , Middle AgedABSTRACT
BACKGROUND: Gigantomastia is a rare and dangerous condition in pregnancy. Although improvement after delivery is likely, postpartum aggravation is possible. To date, various pharmacological approaches have been tried, with only marginal effectiveness. Surgical intervention is often necessary. CASE: A young woman presented at 32 weeks' gestation with mirror syndrome and gigantomastia. Two years earlier she had had reduction mammoplasty by free nipple transplant. She delivered by cesarean. Rapid postpartum progression of gigantomastia led to breast necrosis and sepsis. The clinical course was complicated by acute respiratory distress syndrome and renal failure. Emergent bilateral simple mastectomy was performed, with subsequent clinical improvement. CONCLUSION: When this devastating condition occurs in pregnancy or postpartum, urgent surgical intervention may prevent potentially fatal complications.
