Absence of Scleroderma pattern at nail fold capillaroscopy valuable in the exclusion of Scleroderma in unselected patients with Raynaud's Phenomenon

Background: To report the predictive value of nail-fold capillaroscopy (NFC) patterns of vasculopathy for systemic sclerosis (Scleroderma; SSc) in an unselected cohort of patients with Raynaud's phenomenon (RP). Methods: Patients referred to a tertiary SSc clinic with RP were evaluated by light/video-NFC. Clinical diagnosis, details and serology were recorded. Primary RP was defined as RP with no features of connective tissue disease (CTD)/antibody. NFC patterns were determined: normal, non-specific, 'early', 'active' or 'late' SSc patterns. Fulfilment of the VEDOSS or 2013 ACR/EULAR criteria for SSc was determined following NFC assessment. Results: Three hundred forty-seven patients were referred: mean (SD) age 47 (15.2) years. On clinical review, 54 (16 %) did not have RP, 69 (20 %) had primary RP, 52 (15 %) had SSc and 172 (50 %) had secondary RP. NFC SSc pattern was detected in 80 (23 %) patients; 37/52 with SSc, 30/172 with secondary RP, 9/69 with primary RP and 4/54 with no RP. For identifying patients who met either the VEDOSS or 2013 ACR/EULAR criteria for SSc, detection of a SSc NFC pattern had a sensitivity of 71 %, specificity 95 %, positive predictive value 84 % and negative predictive value 90 %. Conclusions: The absence of SSc NFC pattern in patients with RP or suspected CTD is very valuable in the exclusion of SSc

Biomarkers as an opportunity to stratify for outcome in systemic sclerosis

Systemic sclerosis (SSc) is a highly complex disease whose heterogeneity includes multiple aspects of the condition, such as clinical presentation, progression, extent and type of organ involvement, and clinical outcomes. Thus far, these features remain not easily predictable both at the patient group level and in a given patient with regard to age at onset and clinical course. The unpredictable clinical course represents an obstacle to focusing potentially effective treatment in patients that need it the most. At the time of organ involvement and clinical diagnosis, most of the clinical manifestations are irreversible; therefore, predicting outcomes becomes crucial. This can explain the multiple attempts to identify prognostic, predictive, and monitoring—both soluble and imaging—biomarkers over the past years. They range from the currently most used biomarkers, the autoantibodies associated with disease-specific clinical features and course, to the single recently proposed skin, lung, cardiac involvement biomarkers and to the composite scores capturing multiple aspects of the disease. This review will focus on soluble and imaging biomarkers that recently showed promising evidence for outcome stratification in patients with SSc

Affective picture modulation: Valence, arousal, attention allocation and motivational significance

The present study analyses the modulatory effects of affective pictures in the early posterior negativity (EPN), the late positive potential (LPP) and the human startle response on both the peripheral (eye blink EMG) and central neurophysiological levels (Probe P3), during passive affective pictures viewing. The affective pictures categories were balanced in terms of valence (pleasant; unpleasant) and arousal (high; low). The data shows that EPN may be sensitive to specific stimulus characteristics (affective relevant pictures versus neutral pictures) associated with early stages of attentional processing. In later stages, the heightened attentional resource allocation aswell as themotivated significance of the affective stimuliwas found to elicit enhancedamplitudes of slow wave processes thought to be related to enhanced encoding, namely LPP,. Although pleasant low arousing pictureswere effective in engaging the resources involved in the slowwave processes, the highly arousing affective stimuli (pleasant and unpleasant) were found to produce the largest enhancement of the LPP, suggesting that high arousing stimulimay are associatedwith increasedmotivational significance. Additionally the response to high arousing stimulimay be suggestive of increasedmotivational attention, given the heightened attentional allocation, as expressed in the P3 probe, especially for the pleasant pictures. The hedonic valencemay then serve as amediator of the attentional inhibition to the affective priming, potentiating or inhibiting a shift towards defensive activation, as measured by the startle reflex.Portuguese Foundation for Science and Technology with individual grants (SFRH/BD/41484/2007 and SFRH/BD/64355/2009) and by the Spanish Xunta de Galicia – with FEDER funds – (DOG 233 — Resolution date: 2009 November 18t

Abnormal processing of emotional prosody in Williams syndrome: an event-related potentials study

Williams syndrome (WS), a neurodevelopmental genetic disorder due to a microdeletion in chromosome 7, is described as displaying an intriguing socio-cognitive phenotype. Deficits in prosody production and comprehension have been consistently reported in behavioral studies. It remains, however, to be clarified the neurobiological processes underlying prosody processing in WS. This study aimed at characterizing the electrophysiological response to neutral, happy, and angry prosody in WS, and examining if this response was dependent on the semantic content of the utterance. A group of 12 participants (5 female and 7male), diagnosed with WS, with age range between 9 and 31 years, was compared with a group of typically developing participants, individually matched for chronological age, gender and laterality. After inspection of EEG artifacts, data from 9 participants with WS and 10 controls were included in ERP analyses. Participants were presented with neutral, positive and negative sentences, in two conditions: (1) with intelligible semantic and syntactic information; (2) with unintelligible semantic and syntactic information (‘pure prosody’ condition). They were asked to decide which emotion was underlying the auditory sentence. Atypical event-related potentials (ERP) components were related with prosodic processing (N100, P200, N300) in WS. In particular, reduced N100 was observed for prosody sentences with semantic content; more positive P200 for sentences with semantic content, in particular for happy and angry intonations; and reduced N300 for both types of sentence conditions. These findings suggest abnormalities in early auditory processing, indicating a bottomup contribution to the impairment in emotional prosody processing and comprehension. Also, at least for N100 and P200, they suggest the top-down contributions of semantic processes in the sensory processing of speech. This study showed, for the first time, that abnormalities in ERP measures of early auditory processing in WS are also present during the processing of emotional vocal information. This may represent a physiological signature of underlying impaired on-line language and socio-emotional processing.This work was supported by a Doctoral Grant (SFRH/BD/35882/2007) awarded to APP, as well as by the grant PIC/IC/83290/2007Fundação para a Ciência e a Tecnologia (FCT

Long non-coding RNA HOTAIR induces GLI2 expression through Notch signalling in systemic sclerosis dermal fibroblasts

Objectives Systemic sclerosis (SSc) is characterised by tissue fibrosis of the major organs of the body including the skin, lungs and heart. We have previously reported that the lncRNA HOTAIR plays a central role in the activation of SSc myofibroblasts, the key cellular elements of fibrosis. HOTAIR induces fibroblast activation through H3K27me3-mediated activation of the Notch signalling pathway. Here we aimed to identify the signalling events downstream of Notch that drive SSc myofibroblast activation. Methods Patient fibroblasts were obtained from full-thickness forearm skin biopsies of 3 adult patients with SSc of recent onset. The lncRNA HOTAIR was expressed in healthy dermal fibroblasts by lentiviral transduction. Hedgehog signalling pathway was inhibited with GANT61 and GLI2 siRNA. Gamma secretase inhibitors RO4929097 and DAPT were used to block Notch signalling. GSK126 was used to inhibit Enhancer of Zeste 2 (EZH2). Results Overexpression of HOTAIR in dermal fibroblasts induced the expression of the Hedgehog pathway transcription factor GLI2. This is mediated by activation of Notch signalling following epigenetic downregulation of miRNA-34a expression. Inhibition of H3K27 methylation and Notch signalling reduced expression of GLI2 in HOTAIR-expressing fibroblasts as well as in SSc dermal fibroblasts. Importantly, the inhibition of GLI2 function using GANT61 or siRNA mitigates the pro-fibrotic phenotype induced by HOTAIR. Conclusions Our data indicates that GLI2 expression is stably upregulated in SSc myofibroblasts through HOTAIR and that GLI2 mediates the expression of pro-fibrotic markers downstream of Notch