Enumeration and phenotypical analysis of distinct dendritic cell subsets in psoriatic arthritis and rheumatoid arthritis

Dendritic cells (DCs) comprise heterogeneous subsets of professional antigen-presenting cells, linking innate and adaptive immunity. Analysis of DC subsets has been hampered by a lack of specific DC markers and reliable quantitation assays. We characterised the immunophenotype and functional characteristics of psoriatic arthritis (PsA)-derived and rheumatoid arthritis (RA)-derived myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) to evaluate their potential role in arthritis. Circulating peripheral blood (PB) pDC numbers were significantly reduced in PsA patients (P = 0.0098) and RA patients (P = 0.0194), and mDCs were significantly reduced in RA patients (P = 0.0086) compared with healthy controls. The number of circulating mDCs in RA PB was significantly inversely correlated to C-reactive protein (P = 0.021). The phenotype of both DC subsets in PsA PB and RA PB was immature as compared with healthy controls. Moreover, CD62L expression was significantly decreased on both mDCs (PsA, P = 0.0122; RA, P = 0.0371) and pDCs (PsA, P = 0.0373; RA, P = 0.0367) in PB. Both mDCs and pDCs were present in PsA synovial fluid (SF) and RA SF, with the mDC:pDC ratio significantly exceeding that in matched PB (PsA SF, P = 0.0453; RA SF, P = 0.0082). pDCs isolated from RA SF and PsA SF displayed an immature phenotype comparable with PB pDCs. RA and PsA SF mDCs, however, displayed a more mature phenotype (increased expression of CD80, CD83 and CD86) compared with PB mDCs. Functional analysis revealed that both SF DC subsets matured following toll-like receptor stimulation. pDCs from PB and SF produced interferon alpha and tumour necrosis factor alpha on TLR9 stimulation, but only SF pDCs produced IL-10. Similarly, mDCs from PB and SF produced similar tumour necrosis factor alpha levels to TLR2 agonism, whereas SF mDCs produced more IL-10 than PB controls. Circulating DC subset numbers are reduced in RA PB and PsA PB with reduced CD62L expression. Maturation is incomplete in the inflamed synovial compartment. Immature DCs in SF may contribute to the perpetuation of inflammation via sampling of the inflamed synovial environment, and in situ presentation of arthritogenic antigen

Experiences and recommendations of veterinarians for the Dutch disciplinary system-a survey-based study

INTRODUCTION: In the Netherlands, the veterinary disciplinary system is governmentally executed and was originally designed to provide an educational effect on veterinarians as part of maintaining quality standards. METHODS: Over 900 veterinarians were questioned (20% of the total number of veterinarians working in veterinary medicine in the Netherlands). It was ascertained whether or not they were aware of the disciplinary system, if it affected their way of working and what impact it had on their way of working after having faced a disciplinary case. Respondents were given the opportunity to express their opinions about the system and possible improvements. RESULTS: The risk of complaints was found to be significantly greater when a veterinarian owned a practice compared to veterinarians who were employees. Veterinarians with their own practice were generally older (male) veterinarians. Whether this was a direct effect or just the effect of having a longer career could not be answered. Multiple disciplinary procedures appeared to have no influence. In 13%, veterinarians indicated that the disciplinary system had led to a more defensive way of practicing medicine to avoid complaints. DISCUSSION AND CONCLUSIONS: Most veterinarians supported a disciplinary system as a tool for maintaining and improving the integrity and reputation of the profession as a whole. Recommendations to improve were (1) shortening the length of the procedure, (2) screening for validity, (3) using online systems for communication with the disciplinary council, (4) the option of mediation before getting involved in a full procedure and (5) instituting a complaint fee

Cluster analysis of higher-education competitiveness in selected European countries

The subject of research in this paper is higher-education competitiveness on account of its impact on the enhancement of social and economic competitiveness, as well as on the growth of human capital and creation of social knowledge. The purpose of this paper is to group the selected European countries according to higher-education competitiveness, by means of the hierarchical cluster analysis method, with a special focus on the position of Serbia. Higher-education competitiveness in the chosen countries is analysed by means of three indicators of competitiveness: the ratio of the number of students per number of inhabitants, the number of students per number of employed, as well as the amount of budgetary funds allocated per student. The research results indicate different higher-education competitiveness in the analysed countries and also the fact that, according to this analysis, Serbia is in the group of countries with low competitiveness of higher education

International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework

Background - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by ventricular arrhythmias and progressive ventricular dysfunction. Genetic testing is recommended and a pathogenic variant in an ARVC-associated gene is a major criterion for diagnosis according to the 2010 Task Force Criteria (TFC). As incorrect attribution of a gene to ARVC can contribute to misdiagnosis, we assembled an international multidisciplinary ARVC ClinGen Gene Curation Expert Panel to reappraise all reported ARVC genes. / Methods - Following a comprehensive literature search, six two-member teams conducted blinded independent curation of reported ARVC genes using the semi-quantitative ClinGen framework. /Results - Of 26 reported ARVC genes, only six (PKP2, DSP, DSG2, DSC2, JUP, TMEM43) had strong evidence and were classified as definitive for ARVC causation. There was moderate evidence for two genes, DES and PLN. The remaining 18 genes had limited or no evidence. RYR2 was refuted as an ARVC gene since clinical data and model systems exhibited a catecholaminergic polymorphic ventricular tachycardia (CPVT) phenotype. In ClinVar, only 5 pathogenic / likely pathogenic (P/LP) variants (1.1%) in limited evidence genes had been reported in ARVC cases in contrast to 450 desmosome gene variants (97.4%). / Conclusions - Using the ClinGen approach to gene-disease curation, only eight genes, (PKP2, DSP, DSG2, DSC2, JUP, TMEM43, PLN, DES) had definitive or moderate evidence for ARVC and these genes accounted for nearly all P/LP ARVC variants in ClinVar. Therefore, only P/LP variants in these eight genes should yield a major criterion for ARVC diagnosis. P/LP variants identified in other genes in a patient should prompt further phenotyping as variants in many of these genes are associated with other cardiovascular conditions

The dynamics of university units as a multi-level process. Credibility cycles and resource dependencies

This paper presents an analysis of resource acquisition and profile development of institutional units within universities. We conceptualize resource acquisition as a two level nested process, where units compete for external resources based on their credibility, but at the same time are granted faculty positions from the larger units (department) to which they belong. Our model implies that the growth of university units is constrained by the decisions of their parent department on the allocation of professorial positions, which represent the critical resource for most units’ activities. In our field of study this allocation is largely based on educational activities, and therefore, units with high scientific credibility are not necessarily able to grow, despite an increasing reliance on external funds. Our paper therefore sheds light on the implications that the dual funding system of European universities has for the development of units, while taking into account the interaction between institutional funding and third-party funding

Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome

Background: Leigh syndrome is an early onset, progressive, neurodegenerative disorder with developmental and motor skills regression. Characteristic magnetic resonance imaging abnormalities consist of focal bilateral lesions in the basal ganglia and/or the brainstem. The main cause is a deficiency in oxidative phosphorylation due to mutations in an mtDNA or nuclear oxidative phosphorylation gene. Methods and results: A consanguineous Moroccan family with Leigh syndrome comprise 11 children, three of which are affected. Marker analysis revealed a homozygous region of 11.5 Mb on chromosome 20, containing 111 genes. Eight possible mitochondrial candidate genes were sequenced. Patients were homozygous for an unclassified variant (p.P193L) in the cardiolipin synthase gene (CRLS1). As this variant was present in 20% of a Moroccan control population and enzyme activity was only reduced to 50%, this could not explain the rare clinical phenotype in our family. Patients were also homozygous for an amino acid substitution (p.L159F) in C20orf7, a new complex I assembly factor. Parents were heterozygous and unaffected sibs heterozygous or homozygous wild type. The mutation affects the predicted S-adenosylmethionine (SAM) dependent methyltransferase domain of C20orf7, possibly involved in methylation of NDUFB3 during the assembly process. Blue native gel electrophoresis showed an altered complex I assembly with only 30-40% of mature complex I present in patients and 70-90% in carriers. Conclusions: A new cause of Leigh syndrome can be a defect in early complex I assembly due to C20orf7 mutations

15 years of facts and figures on veterinary disciplinary measures in the Netherlands

In most countries, a veterinary disciplinary system is in force to ensure the quality of the veterinary profession and to offer an objective platform for complaints. We present an analysis of 15 years of veterinary disciplinary verdicts (2001-2016) to compare facts and figures and identify which factors are of major influence on the outcome of the verdicts. Rulings were collected from both paper files and the digital database of the veterinary disciplinary council (VDC), categorized, and used to create a database that enabled a statistical analysis. The results showed that complaints pertaining to companion animals are filed predominantly by owners, whereas complaints about livestock are mostly filed by the governmental civil servant (CS). CS complaints mostly address compliance issues. For the complaints made by owners (client complaints, CCs), reporting, communication, and veterinary mistakes appeared to be of statistical significance. Further studies are needed to investigate the impact of the complaints on veterinarians in general and how we can improve the veterinary disciplinary system

Correction to: The genetic architecture of Plakophilin 2 cardiomyopathy

PURPOSE: The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function. METHODS: We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort. RESULTS: The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 × 10-16), increases for ARVC specifically (EF = 0.96 [0.94,0.97], p < 2 × 10-16), and is highest in definite ARVC versus non-ACM individuals (EF = 1.00 [1.00,1.00], p < 2 × 10-16). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants. CONCLUSION: This multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position