Definition of remission and relapse in polymyalgia rheumatica: data from a literature search compared with a Delphi-based expert consensus

OBJECTIVE: To compare current definitions of remission and relapse in polymyalgia rheumatica (PMR) with items resulting from a Delphi-based expert consensus. METHODS: Relevant studies including definitions of PMR remission and relapse were identified by literature search in PubMed. The questionnaire used for the Delphi survey included clinical (n=33), laboratory (n=54) and imaging (n=7) parameters retrieved from a literature search. Each item was assessed for importance and availability/practicability, and limits were considered for metric parameters. Consensus was defined by an agreement rate of ≥80%. RESULTS: Out of 6031 articles screened, definitions of PMR remission and relapse were available in 18 and 34 studies, respectively. Parameters used to define remission and/or relapse included history and clinical assessment of pain and synovitis, constitutional symptoms, morning stiffness (MS), physician's global assessment, headache, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), blood count, fibrinogen and/or corticosteroid therapy. In the Delphi exercise a consensus was obtained on the following parameters deemed essential for definitions of remission and relapse: patient's pain assessment, MS, ESR, CRP, shoulder and hip pain on clinical examination, limitation of upper limb elevation, and assessment of corticosteroid dose required to control symptoms. CONCLUSIONS: Assessment of patient's pain, MS, ESR, CRP, shoulder pain/limitation on clinical examination and corticosteroid dose are considered to be important in current available definitions of PMR remission and relapse and the present expert consensus. The high relevance of clinical assessment of hips was unique to this study and may improve specificity and sensitivity of definitions for remission and relapse in PMR

Hsp90β inhibition modulates nitric oxide production and nitric oxide-induced apoptosis in human chondrocytes

<p>Abstract</p> <p>Background</p> <p>Hsp90β is a member of the Hsp90 family of protein chaperones. This family plays essential roles in the folding, maturation and activity of many proteins that are involved in signal transduction and transcriptional regulation. The role of this protein in chondrocytes is not well understood, although its increase in osteoarthritic cells has been reported. The present study aimed to explore the role of Hsp90β in key aspects of OA pathogenesis.</p> <p>Methods</p> <p>Human OA chondrocytes were isolated from cartilage obtained from patients undergoing joint replacement surgery, and primary cultured. Cells were stimulated with proinflammatory cytokines (IL-1β or TNF-α) and nitric oxide donors (NOC-12 or SNP). For Hsp90β inhibition, two different chemical inhibitors (Geldanamycin and Novobiocin) were employed, or siRNA transfection procedures were carried out. Gene expression was determined by real-time PCR, apoptosis was quantified by flow cytometry and ELISA, and nitric oxide (NO) production was evaluated by the Griess method. Indirect immunofluorescence assays were performed to evaluate the presence of Hsp90β in stimulated cells.</p> <p>Results</p> <p>Hsp90β was found to be increased by proinflammatory cytokines. Inhibition of Hsp90β by the chemicals Geldanamycin (GA) and Novobiocin (NB) caused a dose-dependent decrease of the NO production induced by IL-1β in chondrocytes, up to basal levels. Immunofluorescence analyses demonstrate that the NO donors NOC-12 and SNP also increased Hsp90β. Chemical inhibition or specific gene silencing of this chaperone reduced the DNA condensation and fragmentation, typical of death by apoptosis, that is induced by NO donors in chondrocytes.</p> <p>Conclusions</p> <p>The present results show how Hsp90β modulates NO production and NO-mediated cellular death in human OA chondrocytes.</p

Abstracts from the 23rd Italian congress of Cystic Fibrosis and the 13th National congress of Cystic Fibrosis Italian Society

Cystic Fibrosis (CF) occurs most frequently in caucasian populations. Although less common, this disorder have been reported in all the ethnicities. Currently, there are more than 2000 described sequence variations in CFTR gene, uniformly distributed and including variants pathogenic and benign (CFTR1:www.genet.sickkids.on.ca/). To date,only a subset have been firmily established as variants annotated as disease-causing (CFTR2: www.cftr2.org). The spectrum and the frequency of individual CFTR variants, however, vary among specific ethnic groups and geographic areas. Genetic screening for CF with standard panels of CFTR mutations is widely used for the diagnosis of CF in newborns and symptomatic patients, and to diagnose CF carrier status. These screening panels have an high diagnostic sensitivity (around 85%) for CFTR mutations in caucasians populations but very low for non caucasians. Developed in the last decade, Next-Generation Sequencing (NGS) has been the last breakthrough technology in genetic studies with a substantial reduction in cost per sequenced base and a considerable enhancement of the sequence generation capabilities. Extended CFTR gene sequencing in NGS includes all the coding regions, the splicing sites and their flankig intronic regions, deep intronic regions where are localized known mutations,the promoter and the 5'-3' UTR regions. NGS allows the analysis of many samples concurrently in a shorter period of time compared to Sanger method . Moreover, NGS platforms are able to identify CFTR copy number variation (CNVs), not detected by Sanger sequencing. This technology has provided new and reliable approaches to molecular diagnosis of CF and CFTR-Related Disorders. It also allows to improve the diagnostic sensitivity of newborn and carrier screeningmolecular tests. In fact, bioinformatics tools suitable for all the NGS platforms can filter data generated from the gene sequencing, and analyze only mutations with well-established disease liability. This approach allows the development of targeted mutations panels with a higher number of frequent CF mutations for the target populationcompared to the standard panels and a consequent enhancement of the diagnostic sensitivity. Moreover, in the emerging challenge of diagnosing CF in non caucasians patients, the possibility of customize a NGS targeted mutations panel should increase the diagnostic sensitivity when the target population has different ethnicities

Non-Standard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants