Association between IL-18 gene polymorphisms and biopsy-proven giant cell arteritis

7 pages, 1 figure, 1 table.-- Research article.[Introduction] The objective was to investigate the potential implication of the IL18 gene promoter polymorphisms in the susceptibility to giant-cell arteritis (GCA).[Methods] In total, 212 patients diagnosed with biopsy-proven GCA were included in this study. DNA from patients and matched controls was obtained from peripheral blood. Samples were genotyped for the IL18-137 G>C (rs187238), the IL18-607 C>A (rs1946518), and the IL18-1297 T>C (rs360719) gene polymorphisms with polymerase chain reaction, by using a predesigned TaqMan allele discrimination assay.[Results] No significant association between the IL18-137 G>C polymorphism and GCA was found. However, the IL18 -607 allele A was significantly increased in GCA patients compared with controls (47.8% versus 40.9% in patients and controls respectively; P = 0.02; OR, 1.32; 95% CI, 1.04 to 1.69). It was due to an increased frequency of homozygosity for the IL18 -607 A/A genotype in patients with GCA (20.4%) compared with controls (13.4%) (IL18 -607 A/A versus IL18 -607 A/C plus IL18 -607 C/C genotypes: P = 0.04; OR, 1.59; 95% CI, 1.02 to 2.46). Also, the IL18-1297 allele C was significantly increased in GCA patients (30.7%) compared with controls (23.0%) (P = 0.003; OR, 1.48; 95% CI, 1.13 to 1.95). In this regard, an increased susceptibility to GCA was observed in individuals carrying the IL18-1297 C/C or the IL18-1297 C/T genotypes compared with those carrying the IL18-1297 T/T genotype (IL18-1297 C/C plus IL18-1297 T/C versus IL18-1297 T/T genotype in GCA patients compared with controls: P = 0.005; OR, 1.61; 95% CI, 1.15 to 2.25). We also found an additive effect of the IL18 -1297 and -607 polymorphisms with TLR4 Asp299Gly polymorphism. The OR for GCA was 1.95 for combinations of genotypes with one or two risk alleles, whereas carriers of three or more risk alleles have an OR of 3.7.[Conclusions] Our results show for the first time an implication of IL18 gene-promoter polymorphisms in the susceptibility to biopsy-proven GCA. In addition, an additive effect between the associated IL18 and TLR4 genetic variants was observed.This study was supported by a grant from Fondo de Investigaciones Sanitarias PI06-0024 (Spain) and in part by Junta de Andalucía, grupo CTS-180 (Spain). This work was partially supported by the RETICS Program, RD08/0075 (RIER), from Instituto de Salud Carlos III (ISCIII).Peer reviewe

Autoantibodies against the immunodominant sCha epitope discriminate the risk of sudden death in chronic Chagas cardiomyopathy

In Chagas disease (ChD) caused by Trypanosoma cruzi, new biomarkers to predict chronic cardiac pathology are urgently needed. Previous studies in chagasic patients with mild symptomatology showed that antibodies against the immunodominant R3 epitope of sCha, a fragment of the human basic helix-loop-helix transcription factor like 5, correlated with cardiac pathology. To validate sCha as a biomarker and to understand the origin of anti-sCha antibodies, we conducted a multicenter study with several cohorts of chagasic patients with severe cardiac symptomatology. We found that levels of antibodies against sCha discriminated the high risk of sudden death, indicating they could be useful for ChD prognosis. We investigated the origin of the antibodies and performed an alanine scan of the R3 epitope. We identified a minimal epitope MRQLD, and a BLAST search retrieved several T. cruzi antigens. Five of the hits had known or putative functions, of which phosphonopyruvate decarboxylase showed the highest cross-reactivity with sCha, confirming the role of molecular mimicry in the development of anti-sCha antibodies. Altogether, we demonstrate that the development of antibodies against sCha, which originated by molecular mimicry with T. cruzi antigens, could discriminate electrocardiographic alterations associated with a high risk of sudden death.Ministerio de Economía y competitividad and Fondo Europeo de Desarrollo Regional (SAF2015-63868-R (MINECO/FEDER) to N.G., and SAF2016-75988-R (MINECO/FEDER) to M.F.); Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación and Fondo Europeo de Desarrollo Regional (PGC2018-096132-BI00 (MICINN/FEDER) to N.G.); Universidad Autónoma de Madrid-Banco de Santander Inter-University Cooperation Grant with Latin América (CEAL-AL/2015-12 to N.G.); Red de Investigación de Centros de Enfermedades Tropicales (RICET RD12/0018/0004 to M.F.); and Comunidad de Madrid (S-2010/BMD-2332 to M.F.). CBMSO institutional grants from Fundación Ramón Areces and Banco de Santande

A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Introduction: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.<p></p> Methods: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. Results: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.<p></p> Conclusion: Our results suggest a role of PPARG gene in the development of SSc

Biologic Therapy in Refractory Non-Multiple Sclerosis Optic Neuritis Isolated or Associated to Immune Mediated Inflammatory Diseases. A Multicenter Study

We aimed to assess the e cacy of biologic therapy in refractory non-Multiple Sclerosis (MS) Optic Neuritis (ON), a condition more infrequent, chronic and severe than MS ON. This was an open-label multicenter study of patients with non-MS ON refractory to systemic corticosteroids and at least one conventional immunosuppressive drug. The main outcomes were Best Corrected Visual Acuity (BCVA) and both Macular Thickness (MT) and Retinal Nerve Fiber Layer (RNFL) using Optical Coherence Tomography (OCT). These outcome variables were assessed at baseline, 1 week, and 1, 3, 6 and 12 months after biologic therapy initiation. Remission was defined as the absence of ON symptoms and signs that lasted longer than 24 h, with or without an associated new lesion on magnetic resonance imaging with gadolinium contrast agents for at least 3 months. We studied 19 patients (11 women/8 men; mean age, 34.8 13.9 years). The underlying diseases were Bechet?s disease (n = 5), neuromyelitis optica (n = 3), systemic lupus erythematosus (n = 2), sarcoidosis (n = 1), relapsing polychondritis (n = 1) and anti-neutrophil cytoplasmic antibody -associated vasculitis (n = 1). It was idiopathic in 6 patients. The first biologic agent used in each patient was: adalimumab (n = 6), rituximab (n = 6), infliximab (n = 5) and tocilizumab (n = 2). A second immunosuppressive drug was simultaneously used in 11 patients: methotrexate (n = 11), azathioprine (n = 2), mycophenolate mofetil (n = 1) and hydroxychloroquine (n = 1). Improvement of the main outcomes was observed after 1 year of therapy when compared with baseline data: mean SD BCVA (0.8 0.3 LogMAR vs. 0.6 0.3 LogMAR; p = 0.03), mean SD RNFL (190.5 175.4 m vs. 183.4 139.5 m; p = 0.02), mean SD MT (270.7 23.2 m vs. 369.6 137.4 m; p = 0.03). Besides, the median (IQR) prednisone-dose was also reduced from 40 (10?61.5) mg/day at baseline to. 2.5 (0?5) mg/day after one year of follow-up; p = 0.001. After a mean SD follow-up of 35 months, 15 patients (78.9%) achieved ocular remission, and 2 (10.5%) experienced severe adverse events. Biologic therapy is e ective in patients with refractory non-MS ON

Clinical characteristics and outcome of Spanish patients with ANCA-associated vasculitides Impact of the vasculitis type, ANCA specificity, and treatment on mortality and morbidity

The aim of this study was to describe the clinical characteristics of ANCA-associated vasculitides (AAV) at presentation, in a wide cohort of Spanish patients, and to analyze the impact of the vasculitis type, ANCA specificity, prognostic factors, and treatments administered at diagnosis, in the outcome. A total of 450 patients diagnosed between January 1990 and January 2014 in 20 Hospitals from Spain were included. Altogether, 40.9% had granulomatosis with polyangiitis (GPA), 37.1% microscopic polyangiitis (MPA), and 22% eosinophilic granulomatosis with polyangiitis (EGPA). The mean age at diagnosis was 55.6±17.3 years, patients with MPA being significantly older (P<0.001). Fever, arthralgia, weight loss, respiratory, and ear-nose-throat (ENT) symptoms, were the most common at disease onset. ANCAs tested positive in 86.4% of cases: 36.2% C-ANCA-PR3 and 50.2% P-ANCA-MPO. P-ANCA-MPO was significantly associated with an increased risk for renal disease (OR 2.6, P<0.001) and alveolar hemorrhage (OR 2, P=0.010), while C-ANCA-PR3 was significantly associated with an increased risk for ENT (OR 3.4, P<0.001) and ocular involvement (OR 2.3, P=0.002). All patients received corticosteroids (CS) and 74.9% cyclophosphamide (CYC). The median follow-up was 82 months (IQR 100.4). Over this period 39.9% of patients suffered bacterial infections and 14.6% opportunistic infections, both being most prevalent in patients with highcumulated doses of CYC and CS (P<0.001). Relapses were recorded in 36.4% of cases with a mean rate of 2.5±2.3, and were more frequent in patients with C-ANCA-PR3 (P=0.012). The initial disease severity was significantly associated with mortality but not with the occurrence of relapses. One hundred twenty-nine (28.7%) patients (74 MPA, 41 GPA, 14 EGPA) died. The mean survival was 58 months (IQR 105) and was significantly lower for patients with MPA (P<0.001). Factors independently related to death were renal involvement (P=0.010), cardiac failure (P=0.029) and age over 65 years old (P<0.001) at disease onset, and bacterial infections (P<0.001). An improved outcome with significant decrease in mortality and treatment-related morbidity was observed in patients diagnosed after 2000, and was related to the implementation of less toxic regimens adapted to the disease activity and stage, and a drastic reduction in the cumulated CYC and CS dose

Perspectivas de la empresa y la economía mexicana frente a la reestructuración productiva

1 archivo PDF (404 páginas)Este texto se presenta una reflexión de investigadores de la UAM, así como de otras Instituciones de Educación Superior respecto al marco en el que se han desenvuelto las empresas mexicanas en los últimos años, así como del desarrollo en algunos de sus sistemas organizacionales. PALABRAS CLAVE: Mexico Economic policy 1970-1994

Tocilizumab in refractory Caucasian Takayasu's arteritis: a multicenter study of 54 patients and literature review

Objective: To assess the efficacy and safety of tocilizumab (TCZ) in Caucasian patients with refractory Takayasu's arteritis (TAK) in clinical practice. Methods: A multicenter study of Caucasian patients with refractory TAK who received TCZ. The outcome variables were remission, glucocorticoid-sparing effect, improvement in imaging techniques, and adverse events. A comparative study between patients who received TCZ as monotherapy (TCZMONO) and combined with conventional disease modifying anti-rheumatic drugs (cDMARDs) (TCZCOMBO) was performed. Results: The study comprised 54 patients (46 women/8 men) with a median [interquartile range (IQR)] age of 42.0 (32.5-50.5) years. TCZ was started after a median (IQR) of 12.0 (3.0-31.5) months since TAK diagnosis. Remission was achieved in 12/54 (22.2%), 19/49 (38.8%), 23/44 (52.3%), and 27/36 (75%) patients at 1, 3, 6, and 12 months, respectively. The prednisone dose was reduced from 30.0 mg/day (12.5-50.0) to 5.0 (0.0-5.6) mg/day at 12 months. An improvement in imaging findings was reported in 28 (73.7%) patients after a median (IQR) of 9.0 (6.0-14.0) months. Twenty-three (42.6%) patients were on TCZMONO and 31 (57.4%) on TCZCOMBO: MTX (n = 28), cyclosporine A (n = 2), azathioprine (n = 1). Patients on TCZCOMBO were younger [38.0 (27.0-46.0) versus 45.0 (38.0-57.0)] years; difference (diff) [95% confidence interval (CI) = -7.0 (-17.9, -0.56] with a trend to longer TAK duration [21.0 (6.0-38.0) versus 6.0 (1.0-23.0)] months; diff 95% CI = 15 (-8.9, 35.5), and higher c-reactive protein [2.4 (0.7-5.6) versus 1.3 (0.3-3.3)] mg/dl; diff 95% CI = 1.1 (-0.26, 2.99). Despite these differences, similar outcomes were observed in both groups (log rank p = 0.862). Relevant adverse events were reported in six (11.1%) patients, but only three developed severe events that required TCZ withdrawal. Conclusion: TCZ in monotherapy, or combined with cDMARDs, is effective and safe in patients with refractory TAK of Caucasian origin.Funding: This work was partially supported by RETICS Programs, RD08/0075 (RIER), RD12/0009/0013 and RD16/0012 from “Instituto de Salud Carlos III” (ISCIII) (Spain)

Measurement of Upper Limb Range of Motion Using Wearable Sensors: A Systematic Review.

Background: Wearable sensors are portable measurement tools that are becoming increasingly popular for the measurement of joint angle in the upper limb. With many brands emerging on the market, each with variations in hardware and protocols, evidence to inform selection and application is needed. Therefore, the objectives of this review were related to the use of wearable sensors to calculate upper limb joint angle. We aimed to describe (i) the characteristics of commercial and custom wearable sensors, (ii) the populations for whom researchers have adopted wearable sensors, and (iii) their established psychometric properties. Methods: A systematic review of literature was undertaken using the following data bases: MEDLINE, EMBASE, CINAHL, Web of Science, SPORTDiscus, IEEE, and Scopus. Studies were eligible if they met the following criteria: (i) involved humans and/or robotic devices, (ii) involved the application or simulation of wearable sensors on the upper limb, and (iii) calculated a joint angle. Results: Of 2191 records identified, 66 met the inclusion criteria. Eight studies compared wearable sensors to a robotic device and 22 studies compared to a motion analysis system. Commercial (n = 13) and custom (n = 7) wearable sensors were identified, each with variations in placement, calibration methods, and fusion algorithms, which were demonstrated to influence accuracy. Conclusion: Wearable sensors have potential as viable instruments for measurement of joint angle in the upper limb during active movement. Currently, customised application (i.e. calibration and angle calculation methods) is required to achieve sufficient accuracy (error < 5°). Additional research and standardisation is required to guide clinical application

Las unidades de deshabituación tabáquica como oportunidad para el diagnóstico de EPOC: el proyecto 1000-200

This study received an unconditional grant from GlaxoSmithKline Laboratories Spain