The Self-Inactivating KamiCas9 System for the Editing of CNS Disease Genes.

Neurodegenerative disorders are a major public health problem because of the high frequency of these diseases. Genome editing with the CRISPR/Cas9 system is making it possible to modify the sequence of genes linked to these disorders. We designed the KamiCas9 self-inactivating editing system to achieve transient expression of the Cas9 protein and high editing efficiency. In the first application, the gene responsible for Huntington's disease (HD) was targeted in adult mouse neuronal and glial cells. Mutant huntingtin (HTT) was efficiently inactivated in mouse models of HD, leading to an improvement in key markers of the disease. Sequencing of potential off-targets with the constitutive Cas9 system in differentiated human iPSC revealed a very low incidence with only one site above background level. This off-target frequency was significantly reduced with the KamiCas9 system. These results demonstrate the potential of the self-inactivating CRISPR/Cas9 editing for applications in the context of neurodegenerative diseases

Effects and safety of rituximab in systemic sclerosis: An analysis from the European Scleroderma Trial and Research (EUSTAR) group

Objectives: To assess the effects of Rituximab (RTX) on skin and lung fibrosis in patients with systemic sclerosis (SSc) belonging to the European Scleroderma Trial and Research (EUSTAR) cohort and using a nested case-control design. Methods: Inclusion criteria were fulfilment of American College of Rheumatology classification criteria for SSc, treatment with RTX and availability of follow-up data. RTX-treated patients were matched with control patients from the EUSTAR database not treated with RTX. Matching parameters for skin/lung fibrosis were the modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), follow-up duration, scleroderma subtype, disease duration and immunosuppressive co-treatment. The primary analysis was mRSS change from baseline to follow-up in the RTX group compared with the control group. Secondary analyses included change of FVC and safety measures. Results: 63 patients treated with RTX were included in the analysis. The case-control analysis in patients with severe diffuse SSc showed that mRSS changes were larger in the RTX group versus matched controls (N=25; -24.0±5.2% vs-7.7±4.3%; p=0.03). Moreover, in RTX-treated patients, the mean mRSS was significantly reduced at follow-up compared with baseline (26.6±1.4 vs 20.3±1.8; p=0.0001). In addition, in patients with interstitial lung disease, RTX prevented significantly the further decline of FVC compared with matched controls (N=9; 0.4±4.4% vs-7.7±3.6%; p=0.02). Safety measures showed a good profile consistent with previous studies in autoimmune rheumatic diseases. Conclusions: The comparison of RTX treated versus untreated matched-control SSc patients from the EUSTAR cohort demonstrated improvement of skin fibrosis and prevention of worsening lung fibrosis, supporting the therapeutic concept of B cell inhibition in SSc

Update of EULAR recommendations for the treatment of systemic sclerosis

The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc

Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry

OBJECTIVES: The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc). METHODS: The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers. RESULTS: Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group. CONCLUSIONS: This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies

Pharmacotherapy of chronic back pain: Are there prospects?

Treatment for chronic back pain (CBP) is a complex therapeutic challenge. The heterogeneity of the disease, different phenotypes of pain, comorbidities, and individual sensitivity to drugs require the use of a broad-spectrum of analgesics with different mechanisms of action. The present review briefly considers the evidence base of basic pharmacological groups that are used for the treatment of CBP in real clinical practice or in clinical trials: nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, tumor necrosis factor-α (TNF-α) inhibitors, nerve growth factor inhibitors, opioids, antidepressants, and muscle relaxants, as well as antibiotic therapy. It is shown that at the moment there are no existing or promising drugs that are able to completely solve the problem of CBP. Treatment should be initiated with NSAIDs. Although their efficacy in CBP is relatively low; nevertheless, the use of NSAIDs makes it possible to achieve a certain reduction in pain and to create conditions for the successful use of other drug classes and non-drug methods. The benefits of nimesulide that may be deemed to be a first-line drug among NSAIDs are considered in terms of its efficacy, relative safety, and availability

Avaliação da rugosidade superficial de três resinas compostas submetidas a diferentes técnicas de polimento Evaluation of the superficial roughness of three composite resins submitted to different polishing techniques

Neste estudo, avaliou-se a rugosidade superficial de resinas classificadas como compactáveis e uma híbrida tradicional comparando-se diferentes técnicas de polimento. Confeccionaram-se corpos-de-prova, que foram armazenados em água destilada por 24 horas e posteriormente submetidos a duas técnicas de tratamento superficial, em que foram empregados dois sistemas de discos de acabamento e polimento e pontas siliconizadas. Os resultados revelaram maior rugosidade superficial da resina AlertTM em relação a Solitaire® e Degufill Mineral®, não havendo diferenças estatisticamente significantes entre as últimas citadas. A rugosidade superficial das restaurações cujo polimento foi executado com as pontas Enhance® foi maior que o polimento obtido com os sistemas de discos, não havendo diferenças estatisticamente significante entre esses.<br>In this study, the superficial roughness of two composite resins classified as condensable and of a traditional hybrid composite resin was analyzed after different polishing techniques. Test specimens were confected, immersed in distilled water for 24 hours and submitted to two different techniques of superficial treatment, in which disc systems (Sof-LexTM and Super Snap®) and silicon tips (Enhance®) were utilized. The results revealed the greater superficial roughness of AlertTM, when compared with Solitaire® and Degufill Mineral® - no statistically significant differences were observed between the last two materials. The superficial roughness of the specimens polished with Enhance® tips was greater than that of the specimens polished with discs and there were no statistically significant differences between both disc systems