Large-scale serum analysis identifies unique systemic biomarkers in psoriasis and hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is now recognized as a systemic inflammatory disease, sharing molecular similarities with psoriasis. Direct comparison of the systemic inflammation in HS with psoriasis is lacking. OBJECTIVES: To evaluate the serum proteome of HS and psoriasis, and to identify biomarkers associated with disease severity. METHODS: In this cross-sectional study, 1536 serum proteins were assessed using the Olink Explore (Proximity Extension Assay) high-throughput panel in patients with moderate-to-severe HS (n = 11), patients with psoriasis (n = 10) and age- and body mass index-matched healthy controls (n = 10). RESULTS: HS displayed an overall greater dysregulation of circulating proteins, with 434 differentially expressed proteins (absolute fold change ≥ 1·2; P ≤ 0·05) in patients with HS vs. controls, 138 in patients with psoriasis vs. controls and 503 between patients with HS and patients with psoriasis. Interleukin (IL)-17A levels and T helper (Th)1/Th17 pathway enrichment were comparable between diseases, while HS presented greater tumour necrosis factor- and IL-1ß-related signalling. The Th17-associated markers peptidase inhibitor 3 (PI3) and lipocalin 2 (LCN2) were able to differentiate psoriasis from HS accurately. Both diseases presented increases of atherosclerosis-related proteins. Robust correlations between clinical severity scores and immune and atherosclerosis-related proteins were observed across both diseases. CONCLUSIONS: HS and psoriasis share significant Th1/Th17 enrichment and upregulation of atherosclerosis-related proteins. Despite the greater body surface area involved in psoriasis, HS presents a greater serum inflammatory burden.

Bimekizumab for the treatment of moderate-to-severe plaque psoriasis: efficacy, safety, pharmacokinetics, pharmacodynamics and transcriptomics from a phase IIa, randomized, double-blind multicentre study.

BACKGROUND: Bimekizumab is a monoclonal antibody that selectively inhibits both interleukin (IL)-17A and IL-17F, which is currently under investigation for treatment of moderate-to-severe plaque psoriasis. Maintenance dosing every 4 weeks is well established with IL-17 inhibitors for psoriasis. OBJECTIVES: To investigate the possible dosing interval during bimekizumab maintenance therapy to maintain clear skin, to inform phase III studies. METHODS: Forty-nine patients with moderate-to-severe plaque psoriasis received bimekizumab 320 mg at weeks 0/4, followed at week 16 by bimekizumab 320 mg (n = 17) or placebo (n = 32). Efficacy, safety, pharmacokinetics, immunogenicity and biopsy transcriptomic analyses were assessed to week 28. RESULTS: At week 8, 47% of patients achieved a 100% improvement from baseline in Psoriasis Area and Severity Index (PASI 100), increasing to 57% at week 12 (8 weeks after the second dose) before decreasing. In those who received bimekizumab at week 16, PASI 100 rate increased to comparable peak levels at week 20, but reduced by week 28 to 41% (12 weeks after the third dose). The week 8 transcriptional signature observed in lesional psoriatic skin rapidly normalized to levels consistent with nonlesional skin, resulting in molecular remission. Keratinocyte-related gene products such as CXCL1 (C-X-C motif chemokine ligand 1), IL-8 (encoded by the CXCL8 gene), CCL20 (C-C motif chemokine 20), IL-36γ and IL-17C were profoundly normalized to levels associated with nonlesional skin. CONCLUSIONS: Here, inhibition of IL-17F in addition to IL-17A resulted in rapid, deep clinical responses. Additionally, profound normalization of keratinocyte biology and the psoriatic transcriptome was observed, including normalization of both IL17 and IL23 gene expression by week 8. These data provide evidence to support evaluation of bimekizumab maintenance dosing both every 8 and every 4 weeks in phase III clinical trials.

Signalling of multiple interleukin (IL)-17 family cytokines via IL-17 receptor A drives psoriasis-related inflammatory pathways.

BACKGROUND: The interleukin (IL)-23/IL-17 immune axis is of central importance in psoriasis. However, the impact of IL-17 family cytokines other than IL-17A in psoriasis has not been fully established. OBJECTIVES: To elucidate the contribution of IL-17 family cytokines in psoriasis. METHODS: To address the expression and localization of IL-17 family cytokines, lesional and nonlesional skin samples from patients with psoriasis were analysed by several complementary methods, including quantitative polymerase chain reaction, immunoassays, in situ hybridization and immunohistochemistry. Mechanistic studies assessing the functional activity of IL-17 family cytokines were performed using ex vivo cultured human skin biopsies and primary human keratinocytes. RESULTS: We demonstrated that IL-17A, IL-17F, IL-17A/F and IL-17C are expressed at increased levels in psoriasis lesional skin and induce overlapping gene expression responses in ex vivo cultured human skin that correlate with the transcriptomic signature of psoriasis skin. Furthermore, we showed that brodalumab, in contrast to ixekizumab, normalizes gene expression responses induced by the combination of IL-17A, IL-17F, IL-17A/F and IL-17C in human keratinocytes. CONCLUSIONS: Several IL-17 ligands signalling through IL-17RA are overexpressed in psoriasis skin and induce similar psoriasis-related inflammatory pathways demonstrating their relevance in relation to therapeutic intervention in psoriasis.

A phase I, randomized, double-blind study to assess the safety, tolerability and efficacy of the topical RORC2 inverse agonist PF-06763809 in participants with mild-to-moderate plaque psoriasis.

BACKGROUND: Transcription factor retinoic acid-related orphan receptor 2 (RORC2/RORγT) mediates interleukin (IL)-17A and IL-17F expression. IL-17A plays a central role in the pathogenesis of several inflammatory disorders, including psoriasis. The RORC2 inhibitor PF-06763809 has been hypothesized to inhibit IL-17A production in T-helper 17 (Th17) cells, thereby reducing psoriasis symptoms. AIM: To assess the safety, tolerability and effect on skin infiltrate thickness of PF-06763809 in participants with mild/moderate chronic plaque psoriasis. METHODS: This was a randomized, double-blind, first-in-human study (trial registration: ClinicalTrials.gov NCT03469336). Participants received each of the following six treatments once daily for 18 days: three topical doses (2.3%, 0.8%, 0.23%) of PF-06763809, a vehicle and two active comparators (betamethasone and calcipotriol). Primary endpoints included change from baseline in psoriatic skin infiltrate thickness [echo-poor band (EPB) on ultrasonography] at Day 19, and safety. Change in psoriasis-associated gene expression (Day 19), evaluated by real-time reverse transcription PCR of skin biopsies, was an exploratory endpoint. RESULTS: In total, 17 participants completed the study. Change from baseline in the EPB on Day 19 for all three doses of PF-06763809 was not significantly different from that of vehicle (P > 0.05). A significant reduction in EPB from baseline was observed with betamethasone on Day 19 relative to all other treatments (P < 0.0001). Treatment-related adverse events were mild/moderate. There were no significant differences in gene expression on Day 19 between vehicle and PF-06763809-treated skin lesions. CONCLUSION: Using a psoriasis plaque test design, PF-06763809 was found to be well tolerated with an acceptable safety profile in participants with psoriasis, but without reduction in skin infiltrate thickness or disease biomarkers.

[Forensic analysis of the socio-economic profile of women victims of domestic violence in the region of Liège according to the seriousness of the injuries suffered]. / Analyse médico-légale du profil socio-économique de femmes victimes de violences conjugales en région liégeoise selon la gravité des blessures subies.

The aim of this study was to analyse retrospectively the profile of female victims of intimate partner violence (IPV) within the population of victims of assault and battery seen in expertise at the Forensic Institute of Liège. Overall, 678 files were analysed. The proportion, nature and type of IPV were determined, as well as the profile of the victims. The link between the socio-economic profile and the seriousness of the sequelae was analysed on the basis of the Chi-square test. 8,4 % of the files concerned IPV, of which 93,0 % were female victims. All the victims had suffered physical domestic violence and 55,5 % of the victims cumulated at least two forms of violence. According to Johnson's typology, 56,6 % of IPV cases may be considered as «Situational Couple Violence¼ and 43,4 % as «Intimate Terrorism¼. There are differences between the profile of victims of IPV according to the literature and the profile of victims seen at the IML. Subject to these differences, we have not found a link between the socio-economic status and the severity of the sequelae of IPV victims.

Cette étude avait pour but d'analyser rétrospectivement le profil des victimes féminines de violences conjugales (VC) au sein de la population des victimes de coups et blessures vues en expertise à l'Institut Médico-Légal (IML) de Liège. Un total de 678 dossiers ont été analysés. La proportion, la nature et le type de VC ont été déterminés, ainsi que le profil des victimes. La gravité des séquelles a été appréciée selon les définitions des articles 399 et 400 du code pénal belge. Le lien entre le profil socio-économique et la gravité des séquelles a été analysé sur base du test du Chi carré. 8,4 % des dossiers concernaient des VC, dont 93,0 % de victimes féminines. Toutes les victimes avaient subi des violences physiques et 55,5 % des victimes cumulaient au moins deux formes de violences. 56,6 % des cas de VC relevaient de «Situational Couple Violence¼ et 43,4 % d'«Intimate Terrorism¼ (typologie de Johnson). Il y a des différences entre les profils des victimes de VC identifiés par la littérature et ceux rencontrés à l'IML. Nous n'avons pas mis en évidence de lien entre le statut socio-économique et la gravité des séquelles des victimes de VC vues en médecine légale.

Canal shaping with a reciprocating system is easy to learn.

AIM: To assess progressive learning of root canal shaping in order to define the number of simulated canals in resin blocks needed to reach a level of learning beyond which no further improvement in performance is observed. METHODOLOGY: A total of 216 simulated canals in resin blocks were instrumented by 18 operators without experience in Endodontics and by 18 Endodontists. The R25 file of the Reciproc system (VDW, Munich, Germany) was used to prepare the canals. The blocks were photographed before and after instrumentation. An analysis was made of the variations in the dimensions of the canals at 6 locations and of the instrumentation time. A Student's t-test was used to analyse the data (P < 0.05). RESULTS: The group without experience were associated with significant differences in instrumentation time between the first canal and the subsequent canals (P < 0.05) but differences in canal dimensions were not significant (P > 0.05). In the group with experience, the instrumentation time did not differ significantly after the fifth canal, and no significant variations in canal dimensions were observed (P > 0.05). CONCLUSIONS: When conducting studies on root canal shaping or educating students with new instruments, a simulated canal sample size of 6 was appropriate to achieve competence.

Dust mite induces multiple polar T cell axes in human skin.

BACKGROUND: House dust mite/HDM atopy patch test/APT elicits positive reactions in a high fraction of atopic dermatitis/AD and healthy individuals. Experimental systems for new-onset/chronic AD are needed to support rapid therapeutic development, particularly since animal models representing human AD are lacking. While HDM APT has been considered to simulate AD, its suitability to model AD's emerging Th2/Th22 phenotype with Th1 and Th17 components is unknown. OBJECTIVE: To assess whether HDM APT reproduces AD. METHODS: Positive HDM APTs (n = 15) from patients with and without AD were evaluated, using genomic and immunohistochemistry studies, against intrapersonal control skin. RESULTS: APT lesions showed higher T cell and dendritic cell infiltrates vs. CONTROLS: Seven hundred and forty-three up- and 326 downregulated genes were differentially expressed in HDM APT (fold change >2 and false discovery rate < 0.05), with increased expression of Th2, Th9, Th17/Th22 polar cytokines (i.e. IL-5, IL-13, IL-9, IL-17, IL-22). CONCLUSION: While HDM caused significant Th2 skewing, it also illustrated differences in Th2 induction and barrier defects; thus, HDM APT does not fully simulate AD. Given its widespread availability and sensitization rates, HDM may potentially be a useful tool that represents select aspects of AD, psoriasis, or contact dermatitis.

Nonlesional atopic dermatitis skin shares similar T-cell clones with lesional tissues.

BACKGROUND: Atopic dermatitis (AD) is characterized by robust immune activation. Various T-cell subsets, including Th2/Th22 cells, are increased in lesional and nonlesional skin. However, there is conflicting literature on the diversity of the T-cell receptor (TCR) repertoire in lesional AD, and its relation to nonlesional skin remains unclear. METHODS: We performed high-throughput deep sequencing of the ß-TCR repertoire in 29 lesional and 19 nonlesional AD biopsies, compared to six healthy control and six cutaneous T-cell lymphoma (CTCL) samples from previously published cohorts. RESULTS: While greater T-cell infiltrates were observed in lesional vs nonlesional AD, TCR repertoire diversity was similar in lesional and nonlesional tissues, and absolute numbers of unique T-cell clones correlated with respective T-cell counts. Most (87%) top expanded lesional T-cell clones were shared with nonlesional tissues, and they were largely maintained after 16 weeks of successful treatment with topical triamcinolone. Nevertheless, both lesional and nonlesional AD showed a highly polyclonal TCR pattern, without evidence of oligoclonal expansion, or a preferred usage of certain V-ß genes in AD skin. Size of the overall T-cell infiltrate, but not the level of clonality, correlated with mRNA levels of key inflammatory mediators (e.g., IL-13, CCL17, IL23p19, CXCL10). CONCLUSION: While AD harbors a highly polyclonal T-cell receptor repertoire, and despite the lack of information on TCR antigen specificity, the sharing of top abundant clones between lesional and nonlesional skin, and their persistence after months of therapy, points to the continuous presence of potentially pathogenic skin resident memory T cells well beyond clinically inflamed lesions.

Association between the number of early carious lesions and diet in children with a high prevalence of caries.

AIM: An investigation was conducted in a population of paediatric patients with a high risk of caries in order to assess the association between caries history (CH) and the number of early carious lesions (ECLs) and the frequency and timing of cariogenic food and beverage intake, sugar-containing medication, the frequency and efficacy of tooth brushing, and the use of topical fluorides. MATERIALS AND METHODS: Study design: descriptive study. One hundred children aged 6-15 years with≥ ECL of a permanent tooth and not enrolled in any dental health educational or preventive programme were selected. For diagnosis it was used an explorer according to the ICDAS II criteria. The participants completed a closed-list questionnaire on the frequency and timing of cariogenic food intake. RESULTS: There was a nonsignificant tendency to present more ECLs and a greater CH among patients who consumed cariogenic foods and beverages. A significant relationship (p<0.05) was observed between cariogenic beverages and the number of ECL or CH. Using the number of ECLs as dependent variable, regular fluoridated rinses (p=0.003), frequent sugar-containing medication (p=0.007), and cariogenic beverage consumption (p=0.024) were identified as explanatory parameters in the linear regression model. STATISTICS: The Student t-test was used to compare ECL and CH with dietetic factors, fluoridated rinses, sugar- containing medicines, and the frequency and efficacy of tooth brushing. Linear regression analysis correlated the number of ECLs to the mentioned explanatory variables. CONCLUSION: The frequent consumption of sugary beverages and medications, and failure to regularly use fluoridated rinses, were positively correlated to an increased number of ECLs in patients with a high prevalence of caries.

[FROM THE LAW "RELATED TO ABNORMAL AND HABITUAL OFFENDERS" TO THE LAW OF INTERNMENT OF PERSONS WITH MENTAL DISORDERS"]. / TRIBULATIONS D'UNE VIEILLE DAME. De la "loi relative aux anormaux et délinquants d'habitude" à la "loi relative à l'internement des personees atteintes d'un trouble mental".

The Belgian forensic system for offenders with mental disorders is organized according to a principle of social defense. It is characterized, on the one hand, by the protection of the society and neutralization of risks and, on the other hand, by the requirements of mental care for the internee. The evolution of the legal framework from the 1930 law related to "abnormal and habitual offenders" to the law about "internment of persons with mental disorder" voted in 2014 reflects the vicissitudes born of the tension between these two pillars. In this difficult balance between medical and judicial issues, although published, but not yet effective, the 2014 version of the law is, in many ways, a positive development in the integration of internees and their needs.

[Intraoperative endoscopic surveillance in laparoscopic surgical treatment of achalasia]. / Endoscopía Transoperatoria en la Cirugía Laparoscópica de la Acalasia.

We study the utility of intraoperative endoscopic control, in laparoscopic surgical treatment of the typical Achalasia of Esophagus. 81 patients were intervened surgically in Centro de Cirugia Endoscopica. Hospital Universitario Calixto Garcia in a five year-old period. All patients received intraoperative endoscopic evaluation to guarantee the effectiveness and integrity of the esophago-cardiomyotomy. The average time of surgical procedure was of 144,7 minutes. The transendoscopic complication in relation with endoscopic procedure was seen in one case but it didn't modify the morbi-mortality of the study. According to Vantrappen classification, 79 patients were considered with a evolution between excellent and good. The use of endoscopic intraoperative control is recommended in the surgical interventions of the patients with achalasia.