Treatments for chronic pruritus outside of the box

Patients with chronic pruritus are in desperate need of novel treatment options, as current therapeutic possibilities are often not effective, have a poor level of evidence and are mostly off-label. In recent years, much effort has been put into the identification of potential targets for the treatment of chronic pruritus. More importantly, a number of promising new drugs that are aimed at treating pruritus in different conditions are currently in advanced stages of clinical trials. Here, current pharmacological developments leading to potential new drugs for the treatment of chronic pruritus within various conditions are summarized. Hopefully, these new approaches will result in effective and safe therapies for our patients with chronic pruritus associated with dermatological or non-dermatological diseases in the near future

Genotype-phenotype correlation of 2q37 deletions including NPPC gene associated with skeletal malformations

Coordinated bone growth is controlled by numerous mechanisms which are only partially understood because of the involvement of many hormones and local regulators. The C-type Natriuretic Peptide (CNP), encoded by NPPC gene located on chromosome 2q37.1, is a molecule that regulates endochondral ossification of the cartilaginous growth plate and influences longitudinal bone growth. Two independent studies have described three patients with a Marfan-like phenotype presenting a de novo balanced translocation involving the same chromosomal region 2q37.1 and overexpression of NPPC. We report on two partially overlapping interstitial 2q37 deletions identified by array CGH. The two patients showed opposite phenotypes characterized by short stature and skeletal overgrowth, respectively. The patient with short stature presented a 2q37 deletion causing the loss of one copy of the NPPC gene and the truncation of the DIS3L2 gene with normal CNP plasma concentration. The deletion identified in the patient with a Marfan-like phenotype interrupted the DIS3L2 gene without involving the NPPC gene. In addition, a strongly elevated CNP plasma concentration was found in this patient. A possible role of NPPC as causative of the two opposite phenotypes is discussed in this study

Increased periodontal attachment loss in patients with systemic sclerosis

Background: Patients with inflammatory rheumatic diseases and periodontitis share common pathogenetic characteristics, such as pro-inflammatory traits causative for tissue degradation and loss of function. Aim of the present case control study was to investigate the association between systemic sclerosis (SSc) and periodontitis. Methods: The association between SSc and periodontitis was examined in 58 SSc patients and 52 control patients, matched for age and gender. Periodontal examination included periodontal attachment loss, probing pocket depth, bleeding on probing, plaque index and gingival index. Potential risk factors of periodontitis were assessed through patients' questionnaires. Results: In unadjusted analyses, patients with SSc had a significant 0.61 mm higher periodontal attachment loss (95 % confidence interval (CI), 0.24 - 0.97; p = 0.002) when compared to controls. In a stepwise logistic regression, including SSc status, age, gender, education, smoking, alcohol consumption and BMI, only SSc status, age, and gender remained significantly associated with periodontitis. Adjusted for age and gender, patients with SSc had 0.52 mm higher periodontal attachment loss compared to controls (95 % CI, 0.16 - 0.88; p = 0.005). The strength of the association of SSc with periodontal attachment loss remained statistically significant after further adjustment for plaque index (0.44 mm; 95 % CI 0.02 - 0.86; p = 0.038) or gingival index (0.61 mm; 95 % CI, 0.24 - 0.97 p = 0.001). Conclusions: The study demonstrates higher periodontal clinical attachment loss in SSc patients, which remained significant following adjustment. The study indicates a possible relationship between SSc and periodontitis

A phenomenological approach to the simulation of metabolism and proliferation dynamics of large tumour cell populations

A major goal of modern computational biology is to simulate the collective behaviour of large cell populations starting from the intricate web of molecular interactions occurring at the microscopic level. In this paper we describe a simplified model of cell metabolism, growth and proliferation, suitable for inclusion in a multicell simulator, now under development (Chignola R and Milotti E 2004 Physica A 338 261-6). Nutrients regulate the proliferation dynamics of tumor cells which adapt their behaviour to respond to changes in the biochemical composition of the environment. This modeling of nutrient metabolism and cell cycle at a mesoscopic scale level leads to a continuous flow of information between the two disparate spatiotemporal scales of molecular and cellular dynamics that can be simulated with modern computers and tested experimentally.Comment: 58 pages, 7 figures, 3 tables, pdf onl

Stiffness is more than just duration and severity: A qualitative exploration in people with rheumatoid arthritis

Objective. Stiffness is internationally recognized as an important indicator of inflammatory activity in RA but is poorly understood and difficult to measure. The aim of this study was to explore the experience of stiffness from the patient perspective. Methods. Semi-structured interviews conducted with 16 RA patients were analysed independently by researchers and pat.ient partners using inductive thematic analysis. Results. Six themes were identified. Part of having RA identified stiffness as a normal consequence of RA, perceived as associated with disease-related aspects such as fluctuating disease activity, other RA symptoms and disease duration. Local and widespread highlighted stiffness occurring not only in joints, but also over the whole body, being more widespread during the morning or flare. Linked to behaviour and environment illustrated factors that influence stiffness, including movement, medications and weather. Highly variable captured the fluctuating nature of stiffness within and between patients and in relation to temporality, duration and intensity. Impacts on daily life emphasized the effect of stiffness on a range of domains, including physical function, quality of life, psychological well-being, activities of daily living and participation in work and leisure activities. Requires self-management detailed self-management strategies targeting both the symptom and its consequences. Conclusion. Patients’ experiences of stiffness were varied, complex and not exclusive to the morning period. Importantly, stiffness was reported in terms of impact rather than the traditional measurement concepts of severity or duration. Based on these findings, further research is needed to develop a patient-centred measure that adequately reflects inflammatory activity

OP0137 GENOME-WIDE WHOLE-BLOOD TRANSCRIPTOME PROFILING IN A LARGE EUROPEAN COHORT OF SYSTEMIC SCLEROSIS PATIENTS

Background:The analysis of annotated transcripts from genome-wide expression studies data is of paramount importance to understand the molecular phenomena underlying the occurrence of complex diseases, such as systemic sclerosis (SSc).Objectives:To perform whole-blood transcriptome and pathway analysis on whole-blood (WB) RNA collected in two cohorts of European SSc patients. Via a discovery and validation strategy we aimed at characterizing the molecular pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations.Methods:WB samples from 252 controls and 162 SSc patients were collected in RNA stabilizers. Patients were divided into a discovery (n=79; Southern Europe) and validation cohort (n=83; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the FAIME algorithm. In parallel, a immunophenotyping analysis on 28 circulating cell populations was assessed. We then tested: the presence of differentially expressed genes or pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated.Results:A total of 15224 genes and 1277 related functional pathways were available for analysis. Among these, 99 genes and 225 pathways were significant in both sets. The heatmap in figure shows the relative expression of replicated pathways and the distribution of cases and controls (red and green bars). Among the significant pathways we found a deregulation in: type-I IFN, TLR-cascade and signalling, function of the tumor suppressor p53 protein, platelet degranulation and activation. Correlation analysis showed that the count of several cell subtypes is jointly associated with RNA transcripts or FAIME scores with strong differences in relation to the geographical origin of samples; neutrophils emerged as the major determinant of gene expression in SSc-whole-blood samples.Conclusion:We discovered a set of differentially expressed genes and pathways that could be validated in two independent sets of SSc patients highlighting a number of deregulated molecular processes that have relevance for the pathogenesis of autoimmunity and SSc.Acknowledgments:This work was supported by EU/EFPIA/Innovative Medicines Initiative Joint Undertaking PRECISESADS grant No. 115565.Disclosure of Interests:Lorenzo Beretta Grant/research support from: Pfizer, Guillermo Barturen: None declared, Barbara Vigone: None declared, Chiara Bellocchi: None declared, Nicolas Hunzelmann: None declared, Ellen Delanghe: None declared, László Kovács: None declared, Ricard Cervera: None declared, Maria Gerosa: None declared, Rafaela Ortega Castro: None declared, Isabel Almeida: None declared, Divi Cornec: None declared, Carlo Chizzolini Consultant of: Boehringer Ingelheim, Roche, Jacques-Olivier Pers: None declared, Zuzanna Makowska Employee of: Bayer AG, Anne buttgereit Employee of: Bayer AG, Ralf Lesche Employee of: Bayer, Martin Kerick: None declared, Marta Alarcon-Riquelme: None declared, Javier Martin Ibanez: None declare

Cold non-ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig-to-baboon xenotransplantation

Background Successful preclinical transplantations of porcine hearts into baboon recipients are required before commencing clinical trials. Despite years of research, over half of the orthotopic cardiac xenografts were lost during the first 48 hours after transplantation, primarily caused by perioperative cardiac xenograft dysfunction (PCXD). To decrease the rate of PCXD, we adopted a preservation technique of cold non-ischemic perfusion for our ongoing pig-to-baboon cardiac xenotransplantation project. Methods Fourteen orthotopic cardiac xenotransplantation experiments were carried out with genetically modified juvenile pigs (GGTA1- KO/hCD46/hTBM) as donors and captive-bred baboons as recipients. Organ preservation was compared according to the two techniques applied: cold static ischemic cardioplegia (IC; n = 5) and cold non-ischemic continuous perfusion (CP; n = 9) with an oxygenated albumin-containing hyperoncotic cardioplegic solution containing nutrients, erythrocytes and hormones. Prior to surgery, we measured serum levels of preformed anti-non-Gal-antibodies. During surgery, hemodynamic parameters were monitored with transpulmonary thermodilution. Central venous blood gas analyses were taken at regular intervals to estimate oxygen extraction, as well as lactate production. After surgery, we measured troponine T and serum parameters of the recipient's kidney, liver and coagulation functions. Results In porcine grafts preserved with IC, we found significantly depressed systolic cardiac function after transplantation which did not recover despite increasing inotropic support. Postoperative oxygen extraction and lactate production were significantly increased. Troponin T, creatinine, aspartate aminotransferase levels were pathologically high, whereas prothrombin ratios were abnormally low. In three of five IC experiments, PCXD developed within 24 hours. By contrast, all nine hearts preserved with CP retained fully preserved systolic function, none showed any signs of PCXD. Oxygen extraction was within normal ranges; serum lactate as well as parameters of organ functions were only mildly elevated. Preformed anti-non-Gal-antibodies were similar in recipients receiving grafts from either IC or CP preservation. Conclusions While standard ischemic cardioplegia solutions have been used with great success in human allotransplantation over many years, our data indicate that they are insufficient for preservation of porcine hearts transplanted into baboons: Ischemic storage caused severe impairment of cardiac function and decreased tissue oxygen supply, leading to multi-organ failure in more than half of the xenotransplantation experiments. In contrast, cold non-ischemic heart preservation with continuous perfusion reliably prevented early graft failure. Consistent survival in the perioperative phase is a prerequisite for preclinical long-term results after cardiac xenotransplantation