Enrico V. Avvedimento

This account of the mechanisms of scleroderma highlights the genetic and molecular changes that cause the vascular changes and fibrosis in the disease. The role of autoantibodies, of which there are several in scleroderma, is unclear. The authors outline a stepwise process that begins with inflammation, reaches its zenith in fibrosis, and ends in atrophy.

BACKGROUND: Systemic sclerosis (scleroderma) is characterized by immunologic abnormalities, injury of endothelial cells, and tissue fibrosis. Abnormal oxidative stress has been documented in scleroderma and linked to fibroblast activation. Since platelet-derived growth factor (PDGF) stimulates the production of reactive oxygen species (ROS) and since IgG from patients with scleroderma reacts with human fibroblasts, we tested the hypothesis that patients with scleroderma have serum autoantibodies that stimulate the PDGF receptor (PDGFR), activating collagen-gene expression. METHODS: We analyzed serum from 46 patients with scleroderma and 75 controls, including patients with other autoimmune diseases, for stimulatory autoantibodies to PDGFR by measuring the production of ROS produced by the incubation of purified IgG with mouse-embryo fibroblasts carrying inactive copies of PDGFR alpha or beta chains or the same cells expressing PDGFR alpha or beta. Generation of ROS was assayed with and without specific PDGFR inhibitors. Antibodies were characterized by immunoprecipitation, immunoblotting, and absorption experiments. RESULTS: Stimulatory antibodies to the PDGFR were found in all the patients with scleroderma. The antibodies recognized native PDGFR, inducing tyrosine phosphorylation and ROS accumulation. Autoantibody activity was abolished by preincubation with cells expressing the PDGFR alpha chain or with recombinant PDGFR or by PDGFR tyrosine kinase inhibitors. Stimulatory PDGFR antibodies selectively induced the Ha-Ras-ERK1/2 and ROS cascades and stimulated type I collagen-gene expression and myofibroblast phenotype conversion in normal human primary fibroblasts. CONCLUSIONS: Stimulatory autoantibodies against PDGFR appear to be a specific hallmark of scleroderma. Their biologic activity on fibroblasts strongly suggests that they have a causal role in the pathogenesis of the disease.

Modifications at the N-terminal tails of nucleosomal histones are required for efficient transcription in vivo. We analyzed how H3 histone methylation and demethylation control expression of estrogen-responsive genes and show that a DNA-bound estrogen receptor directs transcription by participating in bending chromatin to contact the RNA polymerase II recruited to the promoter. This process is driven by receptor-targeted demethylation of H3 lysine 9 at both enhancer and promoter sites and is achieved by activation of resident LSD1 demethylase. Localized demethylation produces hydrogen peroxide, which modifies the surrounding DNA and recruits 8-oxoguanine-DNA glycosylase 1 and topoisomeraseIIbeta, triggering chromatin and DNA conformational changes that are essential for estrogen-induced transcription. Our data show a strategy that uses controlled DNA damage and repair to guide productive transcription.

We report on the case of a healthy 2-year-old boy weighing 13 kg, with a history of snoring and sleep-study–confirmed sleep apnea, who under -went elective adenotonsillectomy. The outpatient surgery was uncomplicated, and 6 hours after sur -gery the boy received 10 mg of meperidine and 12.5 mg of dimenhydrinate intramuscularly and was sent home with instructions for 10 to 12.5 mg of codeine and 120 mg of acetaminophen syrup to be administered orally every 4 to 6 hours as needed. On the second evening after surgery, fever and wheezing developed in the child. At 9 a.m. the next day, the child’s vital signs were absent, and resuscitation efforts failed.Postmortem examination showed evidence of chronic tracheitis, aspiration of food particles, and bilateral consolidation in the lungs that was con-sistent with bronchopneumonia. Codeine (0.70 mg per liter) and morphine (32 ng per milliliter) were detected in the femoral blood by means of gas chromatography–mass spectrometry; there was no evidence of other drugs or metabolites. Cyto -chrome P-450 2D6 (CYP2D6) genotyping revealed functional duplication of the