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1.
Trials ; 19(1): 67, 2018 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-29370811

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting 1% of the world population. It has major impact on patients through disability and associated comorbidities. Current treatment strategies have considerably improved the prognosis, but recent innovations (especially biologic drugs and the new class of so-called "JAK/STAT inhibitors") have important safety issues and are very costly. Glucocorticoids (GCs) are highly effective in RA, and could reduce the need for expensive treatment with biologic agents. However, despite more than 65 years of clinical experience, there is a lack of studies large enough to adequately document the benefit/harm balance. The result is inappropriate treatment strategies, i.e. both under-use and over-use of GCs, and consequently suboptimal treatment of RA. METHODS: The GLORIA study is a pragmatic multicentre, 2-year, randomised, double-blind, clinical trial to assess the safety and effectiveness of a daily dose of 5 mg prednisolone or matching placebo added to standard of care in elderly patients with RA. Eligible participants are diagnosed with RA, have inadequate disease control (disease activity score, DAS28 ≥ 2.6), and are ≥ 65 years. The primary outcome measures are the time-averaged mean value of the DAS28 and the occurrence of serious adverse events or adverse events of special interest. During the trial, change in antirheumatic therapy is permitted as clinically indicated, except for GCs. Cost-effectiveness and cost-utility are secondary outcomes. The main challenge is the interpretation of the trial result with two primary endpoints and the pragmatic trial design that allows co-interventions. Another challenge is the definition of safety and the relative lack of power to detect differences between treatment groups. We have chosen to define safety as the number of patients experiencing at least one serious adverse event. We also specify a decision tree to guide our conclusion on the balance of benefit and harm, and our methodology to combat potential confounding caused by co-interventions. DISCUSSION: Pragmatic trials minimise impact on daily practice and maximise clinical relevance of the results, but analysis and interpretation of the results is challenging. We expect that the results of this trial are of importance for all rheumatologists who treat elderly patients with RA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02585258 . Registered on 20 October 2015.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Glucocorticoides/administração & dosagem , Prednisolona/administração & dosagem , Fatores Etários , Idoso , Antirreumáticos/efeitos adversos , Antirreumáticos/economia , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/economia , Artrite Reumatoide/fisiopatologia , Ensaios Clínicos Fase IV como Assunto , Análise Custo-Benefício , Método Duplo-Cego , Custos de Medicamentos , Quimioterapia Combinada , Europa (Continente) , Feminino , Glucocorticoides/efeitos adversos , Glucocorticoides/economia , Humanos , Masculino , Adesão à Medicação , Estudos Multicêntricos como Assunto , Ensaios Clínicos Pragmáticos como Assunto , Prednisolona/efeitos adversos , Prednisolona/economia , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
2.
Cell Mol Neurobiol ; 38(1): 379-383, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28712091

RESUMO

OBJECTIVE: Lower production of adrenal androgens has been confirmed in females with rheumatoid arthritis (RA); however, the mechanisms of this finding are not completely understood. The aim of our study was to assess the contribution of genetic factors associated with variability of dehydroepiandrosterone sulfate (DHEAS) levels to lower DHEAS in female RA patients. METHODS: 448 RA and 648 healthy controls were genotyped for single-nucleotide polymorphisms (SNPs) in genes ZKSCAN5 (rs11761528), SULT2A1 (rs2637125), HHEX (rs2497306), and ARPC1A (rs740160). Serum DHEAS concentrations were measured in 112 RA patients and 91 healthy women. RESULTS: The allele frequencies in DHEAS-related loci were similar in RA and controls. RA patients had significantly lower serum DHEAS concentrations compared to healthy women. The cumulative number of alleles associated with lower DHEAS within genes ZKSCAN5, SULT2A1, HHEX, and ARPC1A present in each individual negatively correlated with DHEAS levels in RA patients, but not in controls. Linear regression analysis showed significant effect of polymorphisms in genes ZKSCAN5 and ARPC1A on serum DHEAS levels in female RA patients but not in the control group. CONCLUSION: Our findings suggest that complex interactions exist between genotype and adrenal androgen hypofunction in RA.


Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Sulfato de Desidroepiandrosterona/sangue , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Feminino , Frequência do Gene/genética , Humanos , Pessoa de Meia-Idade
3.
Arthritis Res Ther ; 19(1): 196, 2017 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-28870258

RESUMO

The Central European Congress of Rheumatology (CECR) has been organized by seven Central European countries: Austria, Croatia, Czech Republic, Hungary, Poland, Slovakia, and Slovenia. These countries have lots of similarities, but also differences, with respect to rheumatology research. In this paper, based on questionnaires, we wish to demonstrate achievements and difficulties in rheumatology research performed in our region.


Assuntos
Pesquisa Biomédica/tendências , Reumatologia/tendências , Áustria , Pesquisa Biomédica/métodos , Croácia , República Tcheca , Europa (Continente) , Humanos , Hungria , Polônia , Reumatologia/métodos , Eslováquia , Eslovênia
4.
BMC Musculoskelet Disord ; 18(1): 2, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-28056936

RESUMO

BACKGROUND: The aim of this study was to assess the efficacy of choline-stabilized orthosilicic acid (ch-OSA) in patients with symptomatic knee osteoarthritis (OA). METHODS: In a multicenter, double-blind, placebo-controlled study, 211 patients with knee OA (Kellgren and Lawrence grade II or III) and moderate to moderately severe pain were randomly allocated to ch-OSA or placebo for 12 weeks. The primary outcome was the change in the WOMAC pain subscale from baseline to week 12. Secondary outcomes were changes from baseline to week 12 in WOMAC total, WOMAC stiffness, WOMAC physical function, Subject Global Assessment and levels of cartilage degradation biomarkers C-terminal telopeptide of collagen type II (CTX-II) and cartilage oligomeric matrix protein (COMP). Pre-specified subgroup analyses included the effect of gender. RESULTS: A total of 166 (120 women, 46 men) patients were included in the analysis (87 and 79 in the ch-OSA and placebo group, respectively). In the total study population, no differences were observed between the two treatment groups for the different outcomes but significant treatment x gender interactions were found. In men taking ch-OSA, a significant improvement in WOMAC total, WOMAC stiffness and WOMAC physical function as well as a lower increase in biomarker levels of cartilage degradation was observed, but not in women. The change in WOMAC pain showed a similar positive trend in men taking ch-OSA. CONCLUSION: After 12 weeks of treatment, no effect was found of ch-OSA in the total study population on clinical parameters and biomarkers, but a gender interaction was observed. In men, ch-OSA was found effective in reducing symptoms of knee OA, which was associated with a slight but significant reduction of biomarkers that are related to cartilage degradation. TRIAL REGISTRATION: The study was registered retrospectively: ISRCTN88583133 . Registration date: 2015-10-07.


Assuntos
Proteína de Matriz Oligomérica de Cartilagem/análise , Colina/uso terapêutico , Colágeno Tipo II/análise , Osteoartrite do Joelho/tratamento farmacológico , Manejo da Dor/métodos , Ácido Silícico/uso terapêutico , Administração Oral , Idoso , Biomarcadores/análise , Cartilagem/patologia , Colina/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Fatores Sexuais , Ácido Silícico/administração & dosagem , Resultado do Tratamento
5.
Ann Rheum Dis ; 76(3): 554-561, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27884822

RESUMO

OBJECTIVES: Treat-to-target recommendations have identified 'remission' as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE. METHODS: An international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%. RESULTS: The task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by …………………. (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life. CONCLUSIONS: The work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.


Assuntos
Lúpus Eritematoso Sistêmico/tratamento farmacológico , Corticosteroides/uso terapêutico , Anticorpos Antinucleares/sangue , Antimaláricos/uso terapêutico , Proteínas do Sistema Complemento/metabolismo , Consenso , DNA/imunologia , Humanos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/sangue , Quimioterapia de Manutenção , Indução de Remissão , Índice de Gravidade de Doença , Exacerbação dos Sintomas
6.
PLoS One ; 11(4): e0153316, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27092776

RESUMO

INTRODUCTION: The aim of the study was to analyse genetic architecture of RA by utilizing multiparametric statistical methods such as linear discriminant analysis (LDA) and redundancy analysis (RDA). METHODS: A total of 1393 volunteers, 499 patients with RA and 894 healthy controls were included in the study. The presence of shared epitope (SE) in HLA-DRB1 and 11 SNPs (PTPN22 C/T (rs2476601), STAT4 G/T (rs7574865), CTLA4 A/G (rs3087243), TRAF1/C5 A/G (rs3761847), IRF5 T/C (rs10488631), TNFAIP3 C/T (rs5029937), AFF3 A/T (rs11676922), PADI4 C/T (rs2240340), CD28 T/C (rs1980422), CSK G/A (rs34933034) and FCGR3A A/C (rs396991), rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA) and clinical status was analysed using the LDA and RDA. RESULTS: HLA-DRB1, PTPN22, STAT4, IRF5 and PADI4 significantly discriminated between RA patients and healthy controls in LDA. The correlation between RA diagnosis and the explanatory variables in the model was 0.328 (Trace = 0.107; F = 13.715; P = 0.0002). The risk variants of IRF5 and CD28 genes were found to be common determinants for seropositivity in RDA, while positivity of RF alone was associated with the CTLA4 risk variant in heterozygous form. The correlation between serologic status and genetic determinants on the 1st ordinal axis was 0.468, and 0.145 on the 2nd one (Trace = 0.179; F = 6.135; P = 0.001). The risk alleles in AFF3 gene together with the presence of ACPA were associated with higher clinical severity of RA. CONCLUSIONS: The association among multiple risk variants related to T cell receptor signalling with seropositivity may play an important role in distinct clinical phenotypes of RA. Our study demonstrates that multiparametric analyses represent a powerful tool for investigation of mutual relationships of potential risk factors in complex diseases such as RA.


Assuntos
Artrite Reumatoide/genética , Antígenos CD28/genética , Predisposição Genética para Doença/genética , Fatores Reguladores de Interferon/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Autoanticorpos/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fator Reumatoide/genética , Fatores de Risco
7.
Eur J Hum Genet ; 24(1): 66-72, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25804398

RESUMO

Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650-85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.


Assuntos
Alcaptonúria/genética , Doenças Ósseas Metabólicas/genética , Osso e Ossos/enzimologia , Homogentisato 1,2-Dioxigenase/genética , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Alcaptonúria/diagnóstico , Alcaptonúria/enzimologia , Alcaptonúria/patologia , Sequência de Bases , Doenças Ósseas Metabólicas/diagnóstico , Doenças Ósseas Metabólicas/enzimologia , Doenças Ósseas Metabólicas/patologia , Osso e Ossos/patologia , Domínio Catalítico , Bases de Dados Genéticas , Éxons , Feminino , Expressão Gênica , Heterogeneidade Genética , Homogentisato 1,2-Dioxigenase/química , Humanos , Íntrons , Itália , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Linhagem , Fenótipo , Estrutura Secundária de Proteína , Análise de Sequência de DNA
8.
Ann Rheum Dis ; 75(2): 362-7, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25475116

RESUMO

BACKGROUND: Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied. METHODS: Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone. FINDINGS: A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8 mg doses, respectively. For the most efficacious dose, 8 mg daily, this corresponds to a mean reduction of u-HGA24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA. Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4 weeks of nitisinone therapy. CONCLUSIONS: In this study in patients with AKU, nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range. TRIAL REGISTRATION NUMBER: EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463.


Assuntos
Alcaptonúria/tratamento farmacológico , Cicloexanonas/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Ácido Homogentísico/urina , Nitrobenzoatos/administração & dosagem , Adulto , Alcaptonúria/sangue , Alcaptonúria/urina , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Ácido Homogentísico/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Projetos de Pesquisa , Tirosina/sangue
9.
Langmuir ; 31(25): 7148-57, 2015 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-26048139

RESUMO

Impedimetric lectin biosensors capable of recognizing two different carbohydrates (galactose and sialic acid) in glycans attached to antibodies isolated from human serum were prepared. The first step entailed the modification of a gold surface by a self-assembled monolayer (SAM) deposited from a solution containing a carboxybetaine-terminated thiol applied to the subsequent covalent immobilization of lectins and to resist nonspecific protein adsorption. In the next step, Sambucus nigra agglutinin (SNA) or Ricinus communis agglutinin (RCA) was covalently attached to the SAM, and the whole process of building a bioreceptive layer was optimized and characterized using a diverse range of techniques including electrochemical impedance spectroscopy, cyclic voltammetry, quartz crystal microbalance, contact angle measurements, zeta-potential assays, X-ray photoelectron spectroscopy, and atomic force microscopy. In addition, the application of the SNA-based lectin biosensor in the glycoprofiling of antibodies isolated from the human sera of healthy individuals and of patients suffering from rheumatoid arthritis (RA) was successfully validated using an SNA-based lectin microarray. The results showed that the SNA lectin, in particular, is capable of discriminating between the antibodies isolated from healthy individuals and those from RA patients based on changes in the amount of sialic acid present in the antibodies. In addition, the results obtained by the application of RCA and SNA biosensors indicate that the abundance of galactose and sialic acid in antibodies isolated from healthy individuals is age-related.


Assuntos
Betaína/química , Técnicas Biossensoriais/métodos , Galactose/análise , Imunoglobulina G/sangue , Imunoglobulina G/química , Ácido N-Acetilneuramínico/análise , Compostos de Sulfidrila/química , Artrite Reumatoide/sangue , Betaína/análogos & derivados , Eletroquímica , Humanos , Modelos Moleculares , Lectinas de Plantas/química , Conformação Proteica
10.
Arthritis Res Ther ; 17: 56, 2015 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-25890314

RESUMO

INTRODUCTION: Rheumatoid arthritis (RA) is characterized by decreased androgen levels, which was the first hormonal abnormality described. Several studies indicated that steroidogenesis is directed towards endogenous glucocorticoids at the expense of androgens. The decisive step governing androgen synthesis is the 17,20-lyase activity of the CYP17A1 gene-encoded enzyme cytochrome P450 17A1. Here, we focused on the role in RA of the critical cofactor for 17,20-lyase activity, cytochrome b5, encoded by the CYB5A gene. METHODS: Data sets of two genome wide RA association studies (GWAS) were screened for single nucleotide polymorphisms (SNP) in the CYB5A gene. Candidate SNPs in CYB5A were studied in a case-control study population of Slovakia. Expression analyses were done in synovial fibroblasts from RA patients by quantitative real-time polymerase chain reaction, and cytochrome b5-expression was detected by immunohistochemistry. Real-life androgen production after steroid conversion was measured using radiolabeled substrates. RESULTS: The study identified the RA-associated intronic SNP rs1790834 in the CYB5A gene in one GWAS and confirmed the same SNP in our study. The minor allele reduced RA risk selectively in women (P=4.1*10(-3); OR=0.63, 95% CI [0.46-0.86]). The protective effect was confined to rheumatoid factor-positive (OR=0.53, [0.37-0.75]) and anti-cyclic citrullinated peptide-positive (OR=0.58, [0.41-0.83]) cases, respectively. The protective allele doubles CYB5A mRNA-expression resulting in 2-3fold activation of steroid 17,20-lyase activity, and protective allele was accompanied by a higher density of cytochrome b5-positive cells in synovial tissue. CONCLUSIONS: CYB5A is the first RA susceptibility gene involved in androgen synthesis. Our functional analysis of SNP rs1790834 indicates that it contributes to the sex bias observed in RA.


Assuntos
Androgênios/sangue , Artrite Reumatoide/genética , Citocromos b5/genética , DNA/genética , Predisposição Genética para Doença , Polimorfismo Genético , Adolescente , Adulto , Idoso , Alelos , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/patologia , Células Cultivadas , Cromatografia em Camada Delgada , Citocromos b5/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Membrana Sinovial/metabolismo , Adulto Jovem
11.
JIMD Rep ; 24: 21-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25772318

RESUMO

BACKGROUND: Alkaptonuria (AKU) is a serious genetic disease due to a defect in tyrosine metabolism, leading to increased serum levels of homogentisic acid (HGA). Nitisinone decreases HGA in AKU, but the concentration-response relationship has not been previously reported. OBJECTIVES: To determine the relationship between serum concentrations of nitisinone and the effect on both HGA and tyrosine; secondly to determine steady-state pharmacokinetics of nitisinone in AKU patients. METHOD: Thirty-two patients with AKU received either 1, 2, 4, or 8 mg nitisinone daily. Urine and serum HGA and serum tyrosine and nitisinone were measured during 24 h at baseline (before first dose) and after 4 weeks of treatment. RESULTS: Nitisinone pharmacokinetics (area under the curve [AUC] and maximum concentrations [C max]) were dose proportional. The median oral clearance determined in all patients, irrespective of dose, was 3.18 mL/h·kg (range 1.6-6.7).Nitisinone decreased urinary excretion of HGA in a concentration-dependent manner, with a maximum effect seen at average nitisinone concentrations of 3 µmol/L. The association between nitisinone and tyrosine concentrations was less pronounced. Serum levels of HGA at Week 4 were below the limit of quantitation in 65% of samples, which prevented determination of the relationship with nitisinone concentrations. CONCLUSION: Nitisinone exhibits dose-proportional pharmacokinetics in the studied dosage interval. Urinary excretion of HGA decreases in a concentration-dependent manner, while the increase in tyrosine is less clearly related to nitisinone concentrations.

12.
Anal Chim Acta ; 853: 555-562, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25467503

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease seriously affecting patient's quality of life. The heterogeneity of the disease also means that identification and subsequent validation of biomarkers of the disease is quite challenging. A fully validated single biomarker for diagnosis, prognosis, disease activity and assessment of response to therapy is not yet available. The main aim of this study was to apply an alternative assay protocol to the immunoassay-based analysis of this disease by employment of sialic acid recognizing lectin Sambucus nigra agglutinin (SNA) to glycoprofile serum samples. To our best knowledge this is the first study describing direct lectin-based glycoprofiling of serum SSc samples. Three different analytical methods for glycoprofiling of serum samples relying on application of lectins are compared here from a bioanalytical point of view including traditional ELISA-like lectin-based method (ELLA), novel fluorescent lectin microarrays and ultrasensitive impedimetric lectin biosensors. Results obtained by all three bioanalytical methods consistently showed differences in the level of sialic acid present on glycoproteins, when serum from healthy people was compared to the one from patients having SSc. Thus, analysis of sialic acid content in human serum could be of a diagnostic value for future detection of SSc, but further work is needed to enhance selectivity of assays for example by glycoprofiling of a fraction of human serum enriched in antibodies for individual diagnostics.


Assuntos
Técnicas Biossensoriais , Glicoproteínas/sangue , Imunoensaio , Lectinas de Plantas/química , Análise Serial de Proteínas , Proteínas Inativadoras de Ribossomos/química , Escleroderma Sistêmico/metabolismo , Adulto , Espectroscopia Dielétrica , Eletrodos , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Ácido N-Acetilneuramínico/análise , Lectinas de Plantas/metabolismo , Ligação Proteica , Proteínas Inativadoras de Ribossomos/metabolismo , Sambucus nigra/metabolismo , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/patologia
13.
Ann Rheum Dis ; 73(6): 958-67, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24739325

RESUMO

The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012-2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that 'treating-to-target' can and will be applicable to the care of patients with SLE.


Assuntos
Comitês Consultivos , Lúpus Eritematoso Sistêmico/terapia , Planejamento de Assistência ao Paciente , Gerenciamento Clínico , Humanos , Indução de Remissão/métodos , Prevenção Secundária/métodos
14.
FASEB J ; 28(2): 683-91, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24148886

RESUMO

Osteoarthritis (OA) is the most common form of arthritis. It is characterized by cartilage destruction and bone remodeling, mediated in part by synovial fibroblasts (SFs). Given the functional significance of cadherins in these cells, we aimed at determining the role of genetic variants of N-cadherin (CDH2) in OA of the knee and hip. Six single-nucleotide polymorphisms in the genomic region of the CDH2 gene were genotyped in 312 patients with OA and 259 healthy control subjects. Gene expression of CDH2 was analyzed by qRT-PCR. Liquid chromatography-mass spectrometry was used to identify a transcription factor isolated by DNA pulldown. Its potential for binding to gene variants was examined by electrophoretic mobility shift assay, enzyme-linked immunosorbent assay, and chromatin immunoprecipitation. Genetic analysis identified a polymorphism located in the CDH2 promoter region to be associated with risk of OA. The minor allele of rs11564299 had a protective effect against OA. Compared to carriers of the major allele, carriers of the minor allele of rs11564299 displayed increased N-cadherin levels in SFs. Based on in silico analysis, the minor allele was predicted to generate a novel transcription factor binding site, Direct-binding assays and mass spectrometric analysis identified hnRNP K as binding selectively to the minor allele. In summary, a CDH2 promoter polymorphism influences the risk of OA, and hnRNP K was found to be involved in the regulation of elevated N-cadherin expression in patients with OA carrying the minor allele of rs11564299.


Assuntos
Caderinas/genética , Osteoartrite/genética , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sítios de Ligação/genética , Sítios de Ligação/fisiologia , Células Cultivadas , Imunoprecipitação da Cromatina , Ensaio de Desvio de Mobilidade Eletroforética , Ensaio de Imunoadsorção Enzimática , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem
15.
Gen Physiol Biophys ; 32(3): 395-404, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23817641

RESUMO

TLR4-mediated inflammatory responses are important for innate immune functions, thus their alterations may participate in the pathogenesis of rheumatoid arthritis (RA). Cortisol is one of the most potent immunomodulatory hormones involved in control of inflammation. In this study, we analyzed TLR4-mediated responses and cortisol effects on the process in peripheral blood mononuclear cells (PBMC) from RA patients. Lipopolysaccharide-stimulated PBMC from 23 female patients and 15 healthy controls were cultured in the presence or absence of cortisol (1 µM) for 24 h. A panel of 17 inflammatory cytokines was analyzed in the cell culture supernatants. Higher (p < 0.05) concentrations of IL-6, IL-17 and MCP-1 were found in lipopolysaccharide-stimulated PBMC from RA patients compared to controls. After normalization of stimulated cytokine secretion to unstimulated cells, a significantly higher (p < 0.05) IL-6 and G-CSF production was found in RA PBMC. Cortisol induced stronger (p < 0.05) suppression of lipopolysaccharide-stimulated secretion of IL-1ß, IL-6, IL-17 and G-CSF in RA group compared to controls. The observed higher production of the key inflammatory cytokines by RA PBMC to lipopolysaccharide stimulation supports involvement of TLR4-mediated processes in RA pathogenesis. The higher sensitivity of LPS-stimulated RA PBMC to immunosuppressive effects of cortisol may reflect adaptive processes to chronic inflammation.


Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/metabolismo , Interleucina-17/biossíntese , Interleucina-6/biossíntese , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Receptor 4 Toll-Like/metabolismo , Adulto , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Feminino , Glucocorticoides/farmacologia , Humanos , Hidrocortisona/farmacologia , Imunomodulação/efeitos dos fármacos , Interleucina-17/sangue , Interleucina-6/sangue , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia
16.
Ann Rheum Dis ; 71(11): 1868-71, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22833373

RESUMO

BACKGROUND/OBJECTIVE: Current therapies for psoriatic arthritis (PsA) comprise synthetic drugs and tumour necrosis factor inhibitors. In contrast, other biologicals including rituximab (RTX) are available for treating rheumatoid arthritis (RA). RTX is effective in autoantibody positive RA patients, although some efficacy has been reported in seronegative individuals. RTX has not yet been assessed in PsA. Therefore, an open label study of RTX in PsA was performed. PATIENTS AND METHODS: Nine patients with PsA and 14 with RA received RTX at 1000 mg twice within 14 days and were evaluated over 6 months. RESULTS: A PsA response criteria response was attained in 56% of patients. DAS28 improved from 6.2 to 4.9 (medians) in PsA and 6.4 to 5.2 in RA, and Health Assessment Questionnaire from 1.5 to 1.0 and from 2.1 to 1.4, respectively (all p≤0.05). Disease Activity index for PSoriatic Arthritis changed from 52.0 to 32.5 (p<0.05); C reactive protein and Psoriasis Area and Severity Index did not change significantly. RTX was tolerated well. CONCLUSIONS: In this exploratory open study, RTX exhibited significant efficacy in PsA patients with long-standing disease. Thus, RTX may have efficacy in PsA warranting a randomised controlled clinical trial.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/patologia , Artrite Psoriásica/fisiopatologia , Feminino , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/patologia , Hiperalgesia/fisiopatologia , Articulações/efeitos dos fármacos , Articulações/patologia , Articulações/fisiopatologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Rituximab , Resultado do Tratamento
17.
Cas Lek Cesk ; 151(2): 64-8, 2012.
Artigo em Eslovaco | MEDLINE | ID: mdl-22515011

RESUMO

Relapsing polychondritis (RP) is an unusually rare disease involving multiple organs. It has an episodic course, occasionally also progressing. Typically, inflammation of cartilaginous tissues and tissues rich in glycosaminoglycans is present. Clinical symptoms are concentrated in auricula, nose, larynx, upper respiratory tract, joints, heart, blood vessels, inner ear, cornea and sclera. Manifestations include: (1) chondritis of auricular, nasal, laryngotracheal, costal and joint cartilages, (2) inflammation of the eyes and inner ear, (3) collapse of laryngotracheal structures and structures in the subglottic area resulting in increased susceptibility to upper respiratory tract infections, (4) diversity of clinical manifestations, of the disease course and also of the treatment response. Concurrent systemic vasculitis or glomerulonephritis may contribute to higher morbidity and premature mortality. In about 30% of cases the RP is secondary, accompanied by other systemic connective tissue disorders as RA, SLE, Sjögren's syndrome, thyroiditis, ulcerative colitis, psoriasis and Behcet's syndrome. Diagnosis is based on 1986 diagnostic criteria from Minnesota and RP has to be suspected when the inflammatory bouts involve at least two of the typical sites - auricular, nasal, laryngotracheal or one of the typical sites and two other--ocular, statoacoustic disturbances (hearing loss and/or vertigo) and arthritis. In the treatment are, apart from corticoids and nonsteroidal anti-inflammatory drugs, also corticoids combined with immunosuppressive therapy (cyclophosphamide, azathioprine, chlorambucil, cyclosporine) used. More recently, also biologic therapy is used in RP (infliximab, adalimumab, ethanercept, tocilizumab, rituximab). It is necessary to underscore that biologic therapy for RP is only a research modality used in very severe refractory forms of RP. Preliminary results suggest that biologic therapy will have its place in severe refractory relapsing forms of RP.


Assuntos
Policondrite Recidivante , Humanos , Policondrite Recidivante/complicações , Policondrite Recidivante/diagnóstico , Policondrite Recidivante/tratamento farmacológico
18.
Cell Mol Neurobiol ; 32(5): 897-901, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22311280

RESUMO

The sympathoneural and the adrenomedullary systems are involved in regulation of immune processes. Their impairment has been suggested in patients with rheumatoid arthritis (RA). In this study, sympathetic response to orthostasis was evaluated in 22 RA females with <40 years of age and in 15 matched healthy controls. The testing consisted of stabilization period in supine position, legs-up position, 10 min of orthostasis and again supine position. In each of the body position blood samples were drawn, blood pressure and electrocardiogram was recorded. Plasma levels of epinephrine (EPI) and norepinephrine (NE) were measured and sympathoneural activity was evaluated by analysis of heart rate variability (HRV). During the testing, RA patients had similar EPI and NE concentrations compared to controls. Baseline diastolic blood pressure tended to be higher in RA patients compared to controls; however, blood pressure response to orthostasis was comparable between the groups. The RA and control groups did not differ in heart rate and HRV parameters. This study showed normal reactivity of the sympathoneural and the adrenomedullary systems during orthostatic challenge in RA patients younger than 40 years.


Assuntos
Artrite Reumatoide/fisiopatologia , Sistema Nervoso Autônomo/fisiopatologia , Adulto , Artrite Reumatoide/sangue , Artrite Reumatoide/complicações , Pressão Sanguínea/fisiologia , Estudos de Casos e Controles , Diástole/fisiologia , Tontura/complicações , Tontura/fisiopatologia , Epinefrina/sangue , Feminino , Frequência Cardíaca/fisiologia , Humanos , Norepinefrina/sangue , Sístole/fisiologia
20.
Cas Lek Cesk ; 151(11): 520-2, 2012.
Artigo em Eslovaco | MEDLINE | ID: mdl-23301586

RESUMO

The review article focuses on the structure and function of lymphatic capillaries in connective tissues of skin, muscles and synovial membrane. Lymphatic capillaries (initial lymphatics) are formed from endothelial cells mutually arranged so that their intercellular junctions have different structure. In one of the different types of intercellular junctions the distal ends of endothelial cells overlap one another in the form of projections. Desmosomes are missing between the cell membranes of the internal and external projection without presence of any other junctional complexes. The external projection of the endothelial cell is tightly attached to the surrounding connective tissue with the help of anchoring filaments. The internal projection of the neighbouring endothelial cell may tilt over to the lumen of the lymphatic capillary and this may result in a several micrometers wide communication between the interstitium and the lumen with efflux of tissue fluid and leukocytes from the interstitium in to the lumen of the capillary. Lymphologists call the above mentioned openable intercellular junctions in their works also endothelial microvalves or primary valves. These primary valves in cooperation with classical (secondary) intralymphatic valves enable one way lymph flow during spontaneous contractions of the initial lymphatics. It is supposed that primary valves in lymphatic capillaries have an important role in the drainage of the connective tissues affected by inflammation also in the synovial joint.


Assuntos
Vasos Linfáticos/fisiologia , Membrana Sinovial/fisiologia , Humanos , Vasos Linfáticos/ultraestrutura
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