Pityriasis lichenoides: Long-term follow-up study.

BACKGROUND/OBJECTIVES: Pityriasis lichenoides is an uncommon papulosquamous disorder of unknown etiology. The objective of this study was to review the clinical features and treatment responses of individuals with pityriasis lichenoides seen at a tertiary referral center. METHODS: Seventy-five patients diagnosed with pityriasis lichenoides between 1997 and 2013 were reviewed, and 46 had long-term follow-up via telephone interviews. RESULTS: Fifty (67%) patients were diagnosed with pityriasis lichenoides chronica, 22 (29%) with pityriasis lichenoides et varioliformis acuta, and 3 (4%) with mixed pityriasis lichenoides chronica and pityriasis lichenoides et varioliformis acuta features. Mean ± standard deviation age at onset was 12 ± 13 years (median 8 years). Disease duration was significantly shorter for patients with pityriasis lichenoides et varioliformis acuta (35 ± 35 months) than for those with pityriasis lichenoides chronica (at least 78 ± 48 months). At long-term follow-up, 23 of 28 (82%) patients with pityriasis lichenoides chronica and 3 of 16 (19%) with pityriasis lichenoides et varioliformis acuta had active disease. None progressed to lymphomatoid papulosis or cutaneous T-cell lymphoma. Ten of 23 active pityriasis lichenoides chronica cases had residual pigmentary change independent of race and lasted at least 35 ± 20 months. The most effective treatments were phototherapy (47% response rate), heliotherapy (33%), topical corticosteroids (27%), and antibiotics (25%). CONCLUSION: Pityriasis lichenoides is a predominantly pediatric disorder. The time course of pityriasis lichenoides chronica is significantly longer than that of pityriasis lichenoides et varioliformis acuta. Pityriasis lichenoides chronica may persist with pigmentary alterations in the absence of other signs of active inflammation. Treatment response is often limited, particularly for patients with pityriasis lichenoides chronica.

Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps.

MicroRNAs (miRNAs) have critical roles in the regulation of gene expression; however, as miRNA activity requires base pairing with only 6-8 nucleotides of messenger RNA, predicting target mRNAs is a major challenge. Recently, high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP) has identified functional protein-RNA interaction sites. Here we use HITS-CLIP to covalently crosslink native argonaute (Ago, also called Eif2c) protein-RNA complexes in mouse brain. This produced two simultaneous data sets-Ago-miRNA and Ago-mRNA binding sites-that were combined with bioinformatic analysis to identify interaction sites between miRNA and target mRNA. We validated genome-wide interaction maps for miR-124, and generated additional maps for the 20 most abundant miRNAs present in P13 mouse brain. Ago HITS-CLIP provides a general platform for exploring the specificity and range of miRNA action in vivo, and identifies precise sequences for targeting clinically relevant miRNA-mRNA interactions.

Norepinephrine and adenosine-5'-triphosphate synergize in inducing IL-6 production by human dermal microvascular endothelial cells.

Endothelial cells (ECs) play important roles in cutaneous inflammation, in part, by release of inflammatory chemokines/cytokines. Because dermal blood vessels are innervated by sympathetic nerves, the sympathetic neurotransmitter norepinephrine (NE) and the co-transmitter adenosine-5'-triphosphate (ATP) may regulate expression of EC inflammatory factors. We focused on IL-6 regulation because it has many inflammatory and immune functions, including participation in Th17 cell differentiation. Strikingly, NE and ATP synergistically induced release of IL-6 by a human dermal microvascular endothelial cell line (HMEC-1). Adrenergic antagonist and agonist studies indicated that the effect of NE on induced IL-6 release is primarily mediated by ß2-adrenergic receptors (ARs). By real-time PCR IL-6 mRNA was also synergistically induced in HMEC-1 cells. This synergistic effect of NE and ATP was reproduced in primary human dermal endothelial cells (pHDMECs) and is also primarily mediated by ß2-ARs. Under conditions of stress, activation of the symphathetic nervous system may lead to release of ATP and NE by sympathetic nerves surrounding dermal blood vessels with induction of IL-6 production by ECs. IL-6 may then participate in immune and inflammatory processes including generation of Th17 cells. Production of IL-6 in this manner might explain stress-induced exacerbation of psoriasis, and perhaps, other skin disorders involving Th17-type immunity.

A mouse model of the human Fragile X syndrome I304N mutation.

The mental retardation, autistic features, and behavioral abnormalities characteristic of the Fragile X mental retardation syndrome result from the loss of function of the RNA-binding protein FMRP. The disease is usually caused by a triplet repeat expansion in the 5'UTR of the FMR1 gene. This leads to loss of function through transcriptional gene silencing, pointing to a key function for FMRP, but precluding genetic identification of critical activities within the protein. Moreover, antisense transcripts (FMR4, ASFMR1) in the same locus have been reported to be silenced by the repeat expansion. Missense mutations offer one means of confirming a central role for FMRP in the disease, but to date, only a single such patient has been described. This patient harbors an isoleucine to asparagine mutation (I304N) in the second FMRP KH-type RNA-binding domain, however, this single case report was complicated because the patient harbored a superimposed familial liver disease. To address these issues, we have generated a new Fragile X Syndrome mouse model in which the endogenous Fmr1 gene harbors the I304N mutation. These mice phenocopy the symptoms of Fragile X Syndrome in the existing Fmr1-null mouse, as assessed by testicular size, behavioral phenotyping, and electrophysiological assays of synaptic plasticity. I304N FMRP retains some functions, but has specifically lost RNA binding and polyribosome association; moreover, levels of the mutant protein are markedly reduced in the brain specifically at a time when synapses are forming postnatally. These data suggest that loss of FMRP function, particularly in KH2-mediated RNA binding and in synaptic plasticity, play critical roles in pathogenesis of the Fragile X Syndrome and establish a new model for studying the disorder.