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The Hungarian National Institute for Sports Medicine (NISM) was founded in 1952 to provide medical coverage for national teams, screening and periodic health evaluation (PHE) for all Hungarian athletes. The system of 'all in one and ASAP' evolved by now to a specific state-funded healthcare provider with complex sports medical and sport-related services available for athletes. The NISM created a countrywide network to make health clearance available for all athletes close to their place of residency. This centralised system guarantees the uniformity and financial independence of the network, as it is directly financed by the government and free for every competitive athlete. Thus, it leaves no chance for conflict of interest in evaluating athletes' eligibility. In 2013, NISM established an online registry for preparticipation screening and PHE. This made the registry available for sports physicians and certain data for both sports physicians and athletes themselves. Furthermore, NISM created a nationwide, centrally coordinated, out of turn care with central coordination for elite athletes nationwide. Outpatient and inpatient clinics of NISM provide sports-specific care. Most of the minimally invasive techniques used at the Department of Sports Surgery are applied only here in the country. The medical staff of NISM has special experience in Sports Medicine and sport-related conditions. All tasks are managed within the same system, within institutional frames by professionals at Sports Medicine, which guarantees institutional expertise, competence and responsibility. Our aim is to introduce the complex system, the services and the recent achievements of the Hungarian NISM., Competing Interests: Competing interests: None declared.

In this paper, I take a look at certain forms of contemporary art as practices that allow meanings within biomedical science and medical practice to emerge in novel ways. I claim that conceptual art and biological art are two unique spaces within which the understanding of embodiment and disease comes to be shaped actively and reflexively, sometimes on the very level of the materiality of the body, sometimes through the articulation and representation of medical images and technologies. I link these developments to Paul Rabinow's notion of biosociality and argue that the molecularization and geneticization of the medical gaze, conjoined with certain social and cultural shifts, results in the formation of an experimental public of artists, scientists and lay people, all invested in actively shaping the conceptualization of bodies and diseases. This will take me to a consideration of the intertwining of art and medicine beyond the domain of the visual.

The "Bermuda triangle" of genetics, environment and autoimmunity is involved in the pathogenesis of rheumatoid arthritis (RA). Various aspects of genetic contribution to the etiology, pathogenesis and outcome of RA are discussed in this review. The heritability of RA has been estimated to be about 60 %, while the contribution of HLA to heritability has been estimated to be 11-37 %. Apart from known shared epitope (SE) alleles, such as HLA-DRB1*01 and DRB1*04, other HLA alleles, such as HLA-DRB1*13 and DRB1*15 have been linked to RA susceptibility. A novel SE classification divides SE alleles into S1, S2, S3P and S3D groups, where primarily S2 and S3P groups have been associated with predisposition to seropositive RA. The most relevant non-HLA gene single nucleotide polymorphisms (SNPs) associated with RA include PTPN22, IL23R, TRAF1, CTLA4, IRF5, STAT4, CCR6, PADI4. Large genome-wide association studies (GWAS) have identified more than 30 loci involved in RA pathogenesis. HLA and some non-HLA genes may differentiate between anti-citrullinated protein antibody (ACPA) seropositive and seronegative RA. Genetic susceptibility has also been associated with environmental factors, primarily smoking. Some GWAS studies carried out in rodent models of arthritis have confirmed the role of human genes. For example, in the collagen-induced (CIA) and proteoglycan-induced arthritis (PgIA) models, two important loci - Pgia26/Cia5 and Pgia2/Cia2/Cia3, corresponding the human PTPN22/CD2 and TRAF1/C5 loci, respectively - have been identified. Finally, pharmacogenomics identified SNPs or multiple genetic signatures that may be associated with responses to traditional disease-modifying drugs and biologics.

Pharmacogenetics and pharmacogenomics deal with possible associations of a single genetic polymorphism or those of multiple gene profiles with responses to drugs. In rheumatology, genes and gene signatures may be associated with altered efficacy and/or safety of anti-inflammatory drugs, disease-modifying antirheumatic drugs (DMARDs) and biologics. In brief, genes of cytochrome P450, other enzymes involved in drug metabolism, transporters and some cytokines have been associated with responses to and toxicity of non-steroidal anti-inflammatory drugs, corticosteroids and DMARDs. The efficacy of biologics may be related to alterations in cytokine, chemokine and FcγR genes. Numerous studies reported multiple genetic signatures in association with responses to biologics; however, data are inconclusive. More, focused studies carried out in larger patient cohorts, using pre-selected genes, may be needed in order to determine the future of pharmacogenetics and pharmacogenomics as tools for personalized medicine in rheumatology.

Introduction: There has been a burst in the use of biological therapies in the past decade resulting in increasing costs. In 2006 - 2010 the following biological agents were available in Hungary: adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, tocilizumab, and ustekinumab. All biological agents except rituximab were first line therapies; rituximab was a second line option in rheumatoid arthritis., Areas Covered: Data of the financing system related to health care services from the data warehouse of the Hungarian National Health Insurance Fund were in inflammatory conditions. Our analysis showed a constant increase in number of patients and overall cost of biological therapy as well as annual cost of biological agents. Distribution of first choice of biological therapy was compared in different diseases. Time from diagnosis to start of biological therapy showed relatively high deviations., Expert Opinion: In order to achieve both health benefit and cost-effectiveness it is crucial that biological therapy is initiated early enough in the course of the disease, after the failure of non-biological therapies. Health authorities in close collaboration with clinical decision-makers should ensure that early detection of the disease and early initiation of appropriate therapies-including non-biological and biological therapies-are carried out in the health care systems.

Objective: Production of anti-citrullinated protein antibodies (ACPAs) is an important biomarker for rheumatoid arthritis (RA). We undertook this study to determine whether genetic factors (HLA-DRB1 alleles) are associated with extreme ACPA levels in individuals with ACPA-positive RA, and to ascertain whether there are any phenotypic characteristics associated with these subgroups of RA., Methods: HLA-DRB1 allelic groups were genotyped in 1,073 ACPA-positive RA patients from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. We found that 283 patients (26.4%) had high ACPA levels (defined as >1,500 units/ml using the Euro-Diagnostica anti-CCP2 test), while the rest of the patients had moderate ACPA levels and served as the comparison group. A replication group consisted of 235 RA patients., Results: No significant differences in baseline disease activity were observed between patients with high and those with moderate ACPA levels. However, the HLA-DRB1*15 allele was associated with high ACPA levels (P=0.0002). A similar trend was detected in HLA-DRB1*15-positive patients in the replication cohort, with meta-analysis of the discovery and replication cohorts demonstrating an overall effect of HLA-DRB1*15 on development of high ACPA levels in both the discovery and replication cohorts (P<0.0001 by Mantel-Haenszel test with a fixed-effects model)., Conclusion: Our data indicate that HLA-DRB1*15 may promote the production of high ACPA levels. Due to the high value of ACPA level scores in the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA, the presence of HLA-DRB1*15 may, at least in part, contribute to fulfilling the criteria for RA. This illustrates the complex nature of the genetic regulation of ACPA levels. Additional mechanistic studies of the regulation of ACPAs and ACPA-positive RA are pending., (Copyright © 2012 by the American College of Rheumatology.)

Background: The clinical course of cystic fibrosis (CF) lung disease varies between patients bearing identical CFTR mutations. This suggests that additional genetic modifiers may contribute to the pulmonary phenotype. The highly conserved ancestral haplotype 8.1 (8.1AH), carried by up to one quarter of Caucasians, comprises linked gene polymorphisms on chromosome 6 that play a key role in the inflammatory response: LTA +252A/G; TNF -308G/A, HSP70-2 +1267A/G and RAGE -429T/C. As inflammation is a key component inducing CF lung damage, we investigated whether the 8.1AH represents a lung function modifier in CF., Methods: We analyzed the lung function of 404 European CF patients from France (n=230), Germany (n=95) and UK (n=79). FEV(1) differences between 8.1AH carriers and non-carriers were calculated in each country and pooled using a random effects model., Results: The frequency of 8.1AH carriers was similar between French (22%), German (29%) and UK (27%) patients. We found that 8.1AH carriers had significantly lower FEV(1), adjusted for age classes and countries (P<0.04, mean FEV(1) difference -6.4% CI95% [-12.4%, -0.5%]). No difference was observed with respect to BMI Z-scores and chronic colonization with P. aeruginosa., Conclusions: These findings support the concept that 8.1AH is an important genetic modifier of lung disease in CF. To conclude, multiple linked genes outside the CF locus might explain some of the variability in lung phenotype., (Copyright © 2011 European Cystic Fibrosis Society. All rights reserved.)

Aims: Immigrants are at increased risk of dying from external causes, particularly suicide. This study presents mortality data from a complete follow-up of a cohort of immigrants from the Former Soviet Union to Germany. Number of residential changes after migration and time period between residential change and death are analysed as predictors for suicide and other causes of mortality., Methods: A representative cohort of immigrants (n=34,393) was followed up until 31 December 2002. Residential changes were monitored through city registries. Standardized mortality ratios were calculated for all causes of death and external causes of death (suicides, accidents, other external causes) and deaths attributable to psychoactive substance use. Data on residential change were analysed using Poisson regression to examine differences in external-cause mortality among immigrants who changed residence after immigration. Mortality rates by time since changing residence were calculated, and linear regression analysis was performed to model the effect of cause of death on the time interval between residential change and death., Results: Male immigrants had a significantly higher risk of dying from external causes and suicide than Germans, and this increases with frequency of residential changes. Suicide mortality was significantly higher shortly after residential change. Linear regression showed that time to death after residential change was 2.5 times shorter for suicide than for any other cause., Conclusions: High risk of death from external causes and from deaths attributable to substance abuse in immigrants suggests integration problems. Preventive efforts at targeted integration programmes for immigrants, in particular shortly after residential change, are recommended.

Objective: Homozygotes for the normal (A) allele of mannose-binding lectin (MBL2) gene have higher risks to develop an early restenosis after eversion carotid endarterectomy (CEA). Activation of the lectin pathway is regulated by C1-inhibitor (C1-INH). The objective of the present study was to determine the predictive value of C1-INH in restenosis after CEA., Methods and Results: C1-INH and MBL-associated serine protease-2 (MASP-2) were determined in samples serially taken from 64 patients with CEA, who were followed-up with carotid duplex scan (CDS) examinations for 14 months. MBL2 genotypes were also determined. Patients with >50% restenosis had lower C1-INH levels at 6 weeks (P=0.0052) and at 4 days (P=0.0277) postsurgery. C1-INH levels at 6 weeks correlated inversely with the CDS values at 14 months (r=-0.3415, P=0.0058), but only in MBL2 A/A homozygotes (r=-0.5044, P=0.0015). Patients with low C1-INH levels (C1-INH <115%) had higher CDS values already at 7 months postsurgery. Patients with MBL2 A/A and low C1-INH levels at 6 weeks postsurgery had 13.97 (95% CI:1.95 to 100.21, P=0.0087) times higher risk to develop an early restenosis. Differences in the MASP-2 concentration were not associated with restenosis., Conclusions: Determining C1-INH levels at 6 weeks postsurgery-together with genotyping of MBL2-might be a useful marker in the identification of patients with high risk for early carotid restenosis.

Many recent data indicate that some alleles encoded in the central major histocompatibility complex (MHC) region (Class III) of short arm of chromosome 6 may modify the risk of cancer development. Therefore we determined 4 single nucleotide polymorphisms (SNPs) of this region (TNF-alpha -308 G > A, RAGE -429 T > C, HSP70-2 -1267 A > G, LTA 252 A > G) in genomic DNA samples from 183 Hungarian patients with colorectal cancer and 141 age matched control subjects representing the Hungarian population of the same age and gender. No significant differences were found in either SNP tested. When, however, three- or four-locus haplotypes consisting of known constituents of the so-called 8.1 ancestral haplotype (8.1AH) were considered, marked differences were observed. Frequency of TNF-alpha -308A, RAGE -429C, HSP70-2 -1267G, LTA 252G (8.1AH) haplotype was significantly (p = 0.006) more frequent (19.1%) among patients than in the controls (7.7%). Age- and gender-adjusted ratio of the 8.1AH carriers vs. non-carriers to have colorectal cancer was 2.514 (1.130-5.594). This risk was higher in

Background and Purpose: Recently we found that the incidence of restenosis after carotid endarterectomy was significantly higher in patients homozygous for the normal genotype of mannose-binding lectin (MBL2) than in with patients with MBL2 variant genotypes. Several growth factors are also known to contribute to restenosis. Therefore, we investigated whether early postoperative changes in serum vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF) concentrations and MBL2 genotypes interact in the development of restenosis., Methods: Eighty-two patients who underwent carotid eversion endarterectomy and were followed up by carotid duplex scan sonography for 14 months were studied. Growth factors were measured preoperatively and 4 days after surgery., Results: Pronounced significant increases in both VEGF and PDGF predicted restenosis but only in patients who were homozygous for the normal MBL2 genotype. In this group, the adjusted odds ratios of restenosis at 14 months in patients with high versus low early VEGF and PDGF increases were 27.73 (2.42 to 317.26) and 9.23 (1.45 to 58.70), respectively., Conclusions: These findings indicate that the development of restenosis depends on both complement activation regulated by the MBL2 gene and pathologic processes leading to enhanced production of VEGF and PDGF during the very early postoperative period.

Within the human MHC region larger stretches of conserved DNA, called conserved ancestral haplotypes exist. However, many MHC haplotypes contain only fragments of an ancestral haplotype. Little is known, however, on relative distribution of the ancestral haplotypes to their fragments. Therefore we determined the frequency of carriers of the whole ancestral haplotype 8.1 (AH8.1) and its fragments in 127 healthy Hungarian people, 101 healthy Ohioian females, and in nine Hungarian families. The HLA-DQ2, HLA-DR3(17), RAGE -429C allele, the mono-S-C4B genotype, the HSP70-2 1267G allele and the TNF -308A (TNF2) allele were used as markers of the AH8.1. Frequency of carriers of the whole AH8.1 and its fragments was similar in the both populations. 18% of the subjects carried the whole AH8.1 in at least one chromosome, while 17-20%, 36-39%, and 24-29%, respectively carried two or three constituents of the haplotype, only one constituent or none of them. Similar results were obtained in the family study. In addition, marked differences were found in the relationship of the constituents' alleles to the whole AH8.1. In both populations, 29%, 50-59%, 52-56% and 76-96%, respectively of the carriers of HSP70-2 1267G, RAGE-429C, TNF2, and mono-S carriers carried the whole 8.1 haplotype. These findings may have important implications for studies of the disease associations with different MHC ancestral haplotypes.

Previously we reported on strong linkage disequilibrium (LD) between the mono-S-C4B-RCCX module (mono-S) and the TNF2 allele (both known constituents of the 8.1 ancestral haplotype (8.1 AH)) in two Caucasian populations. The gene for the receptor of advanced glycation endproducts (RAGE) is encoded between the RCCX module and the HLA class II genes in the central MHC region. In order to assess the relationship between the promoter polymorphisms of the RAGE gene and the 8.1 AH, we performed a family study in eight informative families affected with type 1 diabetes mellitus; haplotypes of a RAGE promoter SNP (-429T>C) with the HLA-DQ2, -DR-3(17) and TNF2 alleles, as well as the mono-S genotype were determined. A similar analysis was performed in 82 unrelated patients with type 1 diabetes mellitus, and in unrelated healthy individuals of three different Caucasian populations (Hungarians, Ohioian females, Icelandics). In the diabetic patients clinical correlations were also investigated. Out of the 32 paternal and maternal chromosome 6 from the eight families, 15 different MHC haplotypes were found. Haplotypes containing at least three of the known constituents of the 8.1 AH (HLA-DQ2, -DR17, mono-S, TNF2) were always linked to the RAGE -429C allele. The RAGE -429C allele exhibited highly significant (p<0.0001) LD coefficients to known constituents of the 8.1 AH both in healthy persons and patients with type 1 diabetes. In the group of patients with diabetes we found significantly (p=0.013) higher maximal hemoglobinA1C concentration in the carriers of the RAGE -429C allele, this trait, however was not linked to the 8.1 AH. Our present findings indicate that the RAGE -429C allele can be considered as a candidate member of the 8.1 AH. The results also reveal a spectrum of recombinant MHC haplotypes in addition to the conserved ancestral haplotypes.

Early restenosis following carotid endarterectomy (CEA) is an inflammatory process leading to myointimal hyperplasia of smooth muscle cells. The risk for restenosis is increased in homozygous carriers of the normal (A) allele of mannose-binding lectin (MBL2) gene. Our objective was to study the associations of C3 and as control three non-complement acute-phase reactants (APRs) (C-reactive protein, haptoglobin and alpha2HSglycoprotein) with early restenosis following CEA. We also considered, whether MBL2 genotype relates to C3 levels and to the risk of restenosis. Concentrations of the APRs were determined by radial immunodiffusion or immunoturbidimetric methods in 64 patients who underwent eversion CEA and were followed up with carotid duplex scan (CDS) examinations for at least one year. MBL2 genotypes were determined by a PCR-SSP method. C3 levels increased during the follow-up and correlated with the percentage of restenosis detected by CDS at 14 months postsurgery, in MBL2 A/A allele carriers. Patients with high C3 levels had nearly five-fold higher odds for the presence of significant restenosis (>50% reduction in diameter) even after adjusting for MBL2 genotype, age and gender. By contrast, no such associations were detected between the non-complement APRs and early restenosis. C3 is associated with and might have a direct role in the development of an early restenosis following CEA, which is partially related to an intact MBL lectin pathway, thus determining C3 levels might have clinical importance. On the other hand, our results indicate that the regulation of C3 differs from non-complement APRs.

Background and Purpose: Enhanced release of proinflammatory cytokines may contribute to the pathogenesis of stroke. It was examined whether G to A promoter polymorphism in the tumor necrosis factor-alpha gene at position -308 affects the risk of stroke., Methods: We genotyped 336 patients with ischemic stroke and 333 healthy controls for this polymorphism. Patients were divided into different groups based on the Oxfordshire Community Stroke Project (OCSP) or a modified TOAST classification. Distribution of the alleles at -308 G>A promoter polymorphism was determined by PCR-RLFP method., Results: Patients with ischemic stroke had a significantly (p<0.001) decreased (0.115) frequency of the -308 A (TNF2) allele compared to the healthy controls (0.196). When patients were categorized according to the OCSP classification, it turned out that significant (p=0.002) decrease in TNF2 allele frequency (0.065) was restricted to the patients with lacunar infarct (LACI) whereas the frequency of the TNF2 alleles in patients with the other three subtypes (TACI, PACI, and POCI) did not significantly differ from that in healthy controls. Similar results were obtained when the patients were divided according to the modified TOAST classification: the frequencies of the TNF2 allele were 0.068 and 0.140 (p=0.010) in the patients with small-vessel and non-small vessel (large vessel infarction or ischemic stroke of other origin) infarction, respectively. The age-adjusted odds ratio of the patients carrying the TNF2 allele to develop lacunar infarct was 0.33 (0.16-0.68) (p=0.002) compared to the non-carriers. This difference was also restricted to the male patients., Conclusions: Our results suggest that male carriers of TNF2 allele are less susceptible for the development of lacunar subtype of ischemic stroke than the non-carriers.

Background and Purpose: Mannose-binding lectin (MBL) is thought to influence the pathophysiology of cardiovascular disease by decreasing the risk of advanced atherosclerosis and by contributing to enhanced ischemia reperfusion injury. Thus, we investigated the role of MBL in restenosis after eversion endarterectomy in patients with severe carotid atherosclerosis., Methods: In a prospective study, 123 patients who underwent carotid endarterectomy were followed-up by carotid duplex scan (CDS) sonography for 14 months. In a retrospective study, we examined 17 patients and 29 patients, respectively, who had or had not at least 50% restenosis 29 months after carotid eversion endarterectomy. MBL genotypes were analyzed by a polymerase chain reaction-based method, and MBL serum concentrations were measured., Results: In the prospective study in the patients homozygous for the normal MBL genotype, CDS values were significantly higher after 14 months of follow-up compared with the values measured 6 weeks after surgery (P<0.001). In contrast, only a slight increase was registered in patients carrying MBL variant alleles. The differences were much more pronounced in female than in male patients. Similar differences were observed when patients with high and low MBL serum concentrations were compared. In the retrospective study, a significant increase in the frequency of MBL variant genotypes was observed in patients not experiencing restenosis compared with the patients with restenosis (P=0.007)., Conclusions: These results indicate that reoccurrence of stenosis after carotid endarterectomy is partially genetically determined and imply that MBL contributes significantly to the pathophysiology of this condition.