Severely Photosensitive Psoriasis: A Phenotypically Defined Patient Subset

A subset of patients with chronic plaque psoriasis exhibits severely photosensitive psoriasis (PP) with a pronounced seasonal pattern, but the pathomechanism is not understood. We performed two related studies; first, a detailed clinical characterization of PP, and second, a controlled investigation exploring the underlying pathomechanisms through the assessment of disease onset after photoprovocation. Patients with PP (n=20) showed striking female predominance (19F:1M), very low mean age of psoriasis onset (11 years, range 2–24), family history of psoriasis (13/20), a strong HLA–Cw*0602 association (16/17), and a rapid abnormal clinical response to broadband UVA, comprising erythema±scaling plaques (17/20). Subsequently, patients with PP (n=10), non-PP (n=9), and healthy volunteers (n=11) were challenged with low-dose broadband UVA on 3 consecutive days, and serial biopsies were taken after 6hours to 7 days and from unchallenged skin. Histological changes consistent with early psoriasis occurred in 4 of 10 PP patients, but in neither of the control groups, with significant dermal infiltration by neutrophils, CD4+, CD8+, and CD45RO+ cells at 24h, accompanied by acanthosis. Thus, a phenotypically distinct subset of psoriasis has been characterized. In contrast with earlier assumptions, UV can provoke psoriasiform features rapidly de novo; a role for memory effector T cells is supported in the early phase

Multi-exon deletions of the FBN1 gene in Marfan syndrome

BACKGROUND: Mutations in the fibrillin -1 gene (FBN1) cause Marfan syndrome (MFS), an autosomal dominant multi-system connective tissue disorder. The 200 different mutations reported in the 235 kb, 65 exon-containing gene include only one family with a genomic multi-exon deletion. METHODS: We used long-range RT-PCR for mutation detection and long-range genomic PCR and DNA sequencing for identification of deletion breakpoints, allele-specific transcript analyses to determine stability of the mutant RNA, and pulse-chase studies to quantitate fibrillin synthesis and extracellular matrix deposition in cultured fibroblasts. Southern blots of genomic DNA were probed with three overlapping fragments covering the FBN1 coding exons RESULTS: Two novel multi-exon FBN1 deletions were discovered. Identical nucleotide pentamers were found at or near the intronic breakpoints. In a Case with classic MFS, an in-frame deletion of exons 42 and 43 removed the C-terminal 24 amino acids of the 5(th) LTBP (8-cysteine) domain and the adjacent 25(th) calcium-binding EGF-like (6-cysteine) domain. The mutant mRNA was stable, but fibrillin synthesis and matrix deposition were significantly reduced. A Case with severe childhood-onset MFS has a de novo deletion of exons 44–46 that removed three EGF-like domains. Fibrillin protein synthesis was normal, but matrix deposition was strikingly reduced. No genomic rearrangements were detected by Southern analysis of 18 unrelated MFS samples negative for FBN1 mutation screening. CONCLUSIONS: Two novel deletion cases expand knowledge of mutational mechanisms and genotype/phenotype correlations of fibrillinopathies. Deletions or mutations affecting an LTBP domain may result in unstable mutant protein cleavage products that interfere with microfibril assembly

Increased function of pronociceptive TRPV1 at the level of the joint in a rat model of osteoarthritis pain

Objectives Blockade of transient receptor potential vanilloid 1 (TRPV1) with systemic antagonists attenuates osteoarthritis (OA) pain behaviour in rat models, but on-target-mediated hyperthermia has halted clinical trials. The present study investigated the potential for targeting TRPV1 receptors within the OA joint in order to produce analgesia. Methods The presence of TRPV1 receptors in human synovium was detected using western blotting and immunohistochemistry. In a rat model of OA, joint levels of an endogenous ligand for TRPV1, 12- ydroxyeicosatetraenoic acid (12-HETE), were quantified using liquid chromatography-tandem mass spectrometry (LCMS/MS). Effects of peripheral administration of the TRPV1 receptor antagonist JNJ-17203212 on afferent fibre activity, pain behaviour and core body temperature were investigated. Effects of a spinal administration of JNJ-17203212 on dorsal horn neuronal responses were studied. Results We demonstrate increased TRPV1 immunoreactivity in human OA synovium, confirming the diseased joint as a potential therapeutic target for TRPV1-mediated analgesia. In a model of OA pain, we report increased joint levels of 12-HETE, and the sensitisation of joint afferent neurones to mechanical stimulation of the knee. Local administration of JNJ- 17203212 reversed this sensitisation of joint afferents and inhibited pain behaviour (weight-bearing asymmetry), to a comparable extent as systemic JNJ- 17203212, in this model of OA pain, but did not alter core body temperature. There was no evidence for increased TRPV1 function in the spinal cord in this model of OA pain. Conclusions Our data provide a clinical and mechanistic rationale for the future investigation of the therapeutic benefits of intra-articular administration of TRPV1 antagonists for the treatment of OA pain

Interleukin-6 promoter polymorphism interacts with pain and life stress influencing depression phenotypes

Interleukin-6 (IL-6) has emerged as a potent biomarker for depression as its elevated plasma levels in patients with clinical depression have been confirmed by meta-analyses. Increased plasma IL-6 concentration was associated with various psychological stress factors and physical disorders accompanied by pain. Another modulator of the IL-6 level is rs1800795, a promoter polymorphism in the IL-6 gene which is able to influence its expression rate. Therefore, we examined in a Hungarian population sample of 1053 volunteers with European origins if rs1800795 polymorphism can affect depression symptoms measured by Zung Self-rating Depression Scale (ZSDS), and Brief Symptom Inventory (BSI). We also investigated the interactions of the polymorphism with reported painful physical conditions and Recent Negative Life Events (RLE) measured by the List of Life Threatening Experiences. Rs1800795 significantly interacted with both RLE and painful condition on depressive symptoms measured by ZSDS and BSI using different heritability models, while no main effects of the polymorphism were identified. After correction for multiple testing only the rs1800795 x RLE interaction effect (recessive model) remained significant on the BSI score, while both RLE and painful conditions significantly interacted on the ZSDS. In conclusion, the functional IL-6 rs1800795 polymorphism in interaction with various stress factors increases the risk of depression and has a greater impact on symptoms measured by the ZSDS. Thus, IL-6 and other cytokines may be more relevant in the development of somatic symptoms compared to affective signs of depression, delineating a specific genotype-phenotype relationship in this heterogeneous disorder

Descending controls modulate inflammatory joint pain and regulate CXC chemokine and iNOS expression in the dorsal horn.

Descending control of nociceptive processing, by pathways originating in the rostral ventromedial medulla (RVM) and terminating in the dorsal horn, contributes to behavioural hypersensitivity in a number of pain models. Two facilitatory pathways have been identified and are characterized by serotonin (5-HT) content or expression of the mu opiate receptor. Here we investigated the contribution of these pathways to inflammatory joint pain behaviour and gene expression changes in the dorsal horn

Reptation and interdiffusion in polystyrene networks

We have used helium-3 nuclear reaction analysis to measure the interdiffusion of linear polystyrene into a film of crosslinked polystyrene and the intradiffusion of polystyrene in polystyrene networks. The interdiffusion is compared with that predicted from the Kramer-Sillescu theory, and is found to be considerably faster. This is attributed to the relaxation of inhomogeneities in the network. The molecular weight and crosslinking dependence of the intradiffusion coefficients of free polystyrene chains trapped inside networks is discussed in terms of the simple tube model and provides reasonably good agreement with that predicted from reptation theory