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1.
Swiss Med Wkly ; 149: w20121, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31476243

RESUMO

OBJECTIVE: To characterise adherence and treat-to-target (T2T) strategy in gout patients within a Swiss tertiary hospital. METHODS: Consecutive presenting patients with proven gout were prospectively included in this cohort. Symptoms, comorbidities, medication and laboratory values were assessed (during hospitalisation and at planned 3- and 12-month follow-up assessments). RESULTS: 116 patients (98 men) with a mean age of 67 (range 23–94 years) were included, 74% of whom had active arthritis. Comorbidities were frequent: hypertension, renal impairment, and obesity were present in 72, 55 and 35% of patients, respectively. Thirty-five percent of patients received urate-lowering treatment at inclusion. Only 62 and 50% attended the 3- and 12-month follow-up. The target serum uric acid level of <360 μmol/l was achieved in 22 and 57% of patients by the 3- and 12-month follow-up visits, respectively. Patients followed up by rheumatologists reached the target serum uric acid at follow-up more often than those that were not (p = 0.033). Median daily allopurinol dose at 12-month follow-up was 300 mg in those achieving T2T and 100 mg in the others (p = 0.033). Flares occurred during the first 3 months in 52% and during the subsequent 9 months in 47% of patients. CONCLUSION: Only half of patients attended the planned follow-up visits, indicating low awareness for gout. Of those attending follow-up, only approximately 50% had achieved the serum urate target at 12 months. Although new treatments are available, care for gout patients remains insufficient, notably in difficult-to-treat multimorbid patient subsets as described in this cohort.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31436837

RESUMO

OBJECTIVES: [18F]Fluorodeoxyglucose (FDG)-PET/CT and US are both well established for diagnosing GCA. The present study investigates their accuracy and whether they provide overlapping or complementary information in a cohort of patients presenting with suspicion of GCA. METHODS: We selected consecutive patients from our cohort of suspected GCA cases that underwent both extended vascular US and PET/CT for diagnostic work-up between December 2006 and August 2012. RESULTS: A total of 102 patients were included. Diagnosis of GCA was confirmed in 68 patients and excluded in 34 patients (controls). Vasculitic changes in US were most often found in the temporal artery with 32 positive findings on each side, followed by the popliteal artery (10 right, 9 left) and the subclavian/axillary artery (7 right, 8 left). By contrast, PET/CT showed vasculitis most frequently in the vertebral (23 right, 33 left) and common carotid arteries (32 right, 24 left), followed by the subclavian arteries (16 right, 18 left), and the thoracic (17) and abdominal aorta (23). In 37/68 GCA patients PET/CT and US both revealed vasculitic findings, 11/68 had positive findings in US only and 14/68 in PET/CT only. Specificity of US was higher (one false-positive vs five false-positive in PET/CT). On a single segment level, only 20 of 136 positive segments were positive in both imaging modalities. CONCLUSION: PET/CT measuring vessel wall metabolism and US vessel wall morphology showed a comparable diagnostic accuracy for GCA. However PET/CT and US were often discrepant within single vascular regions. Thus PET/CT and US should be considered as complementary methods, with a second imaging modality increasing the diagnostic yield by 16-20%.

5.
Rheumatology (Oxford) ; 58(5): 792-797, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30544199

RESUMO

OBJECTIVES: To assess changes of arterial vessel wall morphology in large vessel GCA patients (LV-GCA) by repeated US. METHODS: Patients with LV-GCA on US examination were followed up 6, 12 and 24 months after diagnosis by US of the temporal, vertebral, carotid (common, internal, external), subclavian, axillary, femoral (deep, superficial and common) and popliteal arteries. Clinical and laboratory data were assessed at each visit. Vessel wall thickening was classified as moderate, marked or arteriosclerotic. RESULTS: A total of 42 patients (26 female) with a median age of 75 years at diagnosis had in median 2 (range 1-3) US follow-up exams. Twenty-eight had both LV and temporal artery involvement and 14 had LV-GCA only. The common carotid, subclavian, axillary, popliteal and/or superficial femoral artery were most commonly involved. Reduction of LV wall thickening occurred in 45% of patients during follow-up, corresponding to 71 of the 284 (25%) initially 'vasculitic' LV segments. In contrast, a reduction of vessel wall thickening in the temporal artery was found in 85% of patients. Of the LVs, the vertebral, axillary, subclavian and deep femoral arteries were most likely to improve. There was no difference in relapses or the received cumulative steroid dose between patients with or without a reduction of vessel wall thickening (temporal artery or LV) during follow-up. CONCLUSION: Regression of wall thickening within the LV is significantly less common than in the temporal artery and irrespective of clinical remission. Morphological regression does not seem to be a useful predictor for relapses.

6.
Swiss Med Wkly ; 148: w14661, 2018 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-30141518

RESUMO

Historically, giant cell arteritis (GCA) was considered to be synonymous with temporal arteritis. However, the disease spectrum of GCA extends much further, and includes vasculitis of the aorta and its branches with or without involvement of the temporal arteries. Imaging is crucial for the diagnosis and follow-up of GCA patients. Large vessel GCA (LV-GCA) often presents as an inflammatory syndrome and is only detected by imaging modalities such as: colour duplex sonography (CDS), computed tomography (CT) / CT angiography (CTA), magnetic resonance imaging (MRI) or 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) / CT. Deciding which imaging modality to use in different clinical situations remains a matter of debate. CDS and MRI enable assessment of the temporal arteries with a presumably higher sensitivity than histology. In the context of a typical presentation, CDS can replace a biopsy. In about a third of patients, the temporal arteries are not involved, thus PET/CT, MRI, CT, or CDS of larger arteries is needed to diagnose GCA. The sensitivity of all modalities is affected by glucocorticoid therapy. Therefore, without delaying therapy, imaging should be performed within a few days of treatment initiation. The use of PET/CT for the work-up of inflammatory syndromes in the elderly reveals vasculitis in approximately 20% of examined patients and uncover relevant diagnoses in the majority of remaining patients. The aorta should be routinely assessed in all GCA patients at diagnosis and during follow-up. MRA or CTA are best suited to characterise structural damage of larger arteries. The role of imaging in monitoring GCA disease activity still needs to be further defined.

7.
PLoS One ; 13(6): e0198330, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29879160

RESUMO

Directed migration of cells relies on their ability to sense directional guidance cues and to interact with pericellular structures in order to transduce contractile cytoskeletal- into mechanical forces. These biomechanical processes depend highly on microenvironmental factors such as exposure to 2D surfaces or 3D matrices. In vivo, the majority of cells are exposed to 3D environments. Data on 3D cell migration are mostly derived from intravital microscopy or collagen-based in vitro assays. Both approaches offer only limited controllability of experimental conditions. Here, we developed an automated microfluidic system that allows positioning of cells in 3D microenvironments containing highly controlled diffusion-based chemokine gradients. Tracking migration in such gradients was feasible in real time at the single cell level. Moreover, the setup allowed on-chip immunocytochemistry and thus linking of functional with phenotypical properties in individual cells. Spatially defined retrieval of cells from the device allows down-stream off-chip analysis. Using dendritic cells as a model, our setup specifically allowed us for the first time to quantitate key migration characteristics of cells exposed to identical gradients of the chemokine CCL19 yet placed on 2D vs in 3D environments. Migration properties between 2D and 3D migration were distinct. Morphological features of cells migrating in an in vitro 3D environment were similar to those of cells migrating in animal tissues, but different from cells migrating on a surface. Our system thus offers a highly controllable in vitro-mimic of a 3D environment that cells traffic in vivo.

8.
NPJ Vaccines ; 3: 17, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29796310

RESUMO

Pneumococcal conjugate vaccine (PCV) is recommended for adults with chronic disease. Extensive limb swelling (ELS) is an acute vigorous local inflammatory reaction following vaccination. Predisposing immune system correlates and the influence of ELS on vaccine responses are not known. Here, we report a case of a 67-year-old woman with a history of multiple pneumonias who had a detailed immunological work-up pre-vaccination because of suspected immunodeficiency. Four days following a first vaccination with PCV13 she developed ELS-mimicking erysipelas. Treatment with 20 mg cortisone completely alleviated symptoms within 2 days. Skin biopsy showed a dense dermal and subdermal infiltration dominated by CD4+ T cells and macrophages. In a multiplexed serotype-specific measurement of the anti-pneumococcal IgG response, the patient showed very broad and strong vaccine responses. Pre-vaccination titers were low for the vaccine serotypes. We did not find in vivo nor in vitro evidence of an excessive T cell response to the diphtheria-derived PCV carrier protein. However, we could demonstrate a high antibody titer to a non-vaccine serotype, indicating in vivo pre-exposure to pneumococcus bacteria. Thus, traces of pneumococcal proteins included in PCV13 may have boosted pre-existing pneumococcus-specific T helper cells, which subsequently orchestrated ELS. Our case raises awareness for the risk of vaccine-induced ELS, especially in patients with a history of recurrent pneumococcal disease and thus partial immunity.

9.
Pathog Immun ; 3(1): 2-18, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29541698

RESUMO

Background: Hepatitis B virus (HBV) affects up to 400 million people worldwide and accounts for approximately one million deaths per year from liver pathologies. Current treatment regimens are effective in suppressing viremia but usually have to be taken indefinitely, warranting research into new therapeutic approaches. Acute HBV infection in adults almost universally results in resolution of viremia, with the exception of immunocompromised persons, suggesting that the immune response can functionally cure or even eradicate HBV infection. Methods: Because immunophenotypic and functional studies have implicated a role for Natural Killer (NK) cells in HBV clearance during acute infection, we hypothesized that a distinct NK-cell profile exists in acute HBV infection that could provide information for the mechanism of HBV clearance. Using multivariate flow cytometry, we evaluated the expression of key activating and inhibitory receptors on NK cells, and their ability to respond to classic target cell lines. Results: Multivariate analysis revealed selective perturbation of the CD56dim NK-cell subset during acute infection, displaying low levels of NKp46+, NKp30+, CD160+ and CD161+ cells. Intriguingly, the CD56dim NK-cell profile predicted time to HBV surface antigen (HBsAg) clearance from the blood, and distinct NK-cell profiles predicted early (NKp30, CD94, CD161) and late clearance (KIR3DL1, CD158a, perforin, NKp46). Finally, functional analysis demonstrated that early and late clearance tracked with elevated degranulation (CD107a) or IFNγ production, respectively, in response to ADCC-mediated activation. Conclusion: The cytolytic CD56dim NK-cell subset is selectively activated in acute HBV infection and displays distinct phenotypic and functional profiles associated with efficient and early control of HBV, implicating antibody-mediated cytolytic NK-cell responses in the early control and functional cure of HBV infection.

10.
Front Immunol ; 9: 224, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29515569

RESUMO

The adaptive immune system recognizes antigens via an immense array of antigen-binding antibodies and T-cell receptors, the immune repertoire. The interrogation of immune repertoires is of high relevance for understanding the adaptive immune response in disease and infection (e.g., autoimmunity, cancer, HIV). Adaptive immune receptor repertoire sequencing (AIRR-seq) has driven the quantitative and molecular-level profiling of immune repertoires, thereby revealing the high-dimensional complexity of the immune receptor sequence landscape. Several methods for the computational and statistical analysis of large-scale AIRR-seq data have been developed to resolve immune repertoire complexity and to understand the dynamics of adaptive immunity. Here, we review the current research on (i) diversity, (ii) clustering and network, (iii) phylogenetic, and (iv) machine learning methods applied to dissect, quantify, and compare the architecture, evolution, and specificity of immune repertoires. We summarize outstanding questions in computational immunology and propose future directions for systems immunology toward coupling AIRR-seq with the computational discovery of immunotherapeutics, vaccines, and immunodiagnostics.

11.
Eur Heart J Cardiovasc Imaging ; 19(8): 933-940, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29126277

RESUMO

Aims: The usefulness of [18F] fluorodeoxyglucose-positron emission tomography/computed tomography ([18F]FDG-PET/CT) for diagnosing giant cell arteritis (GCA) has been previously reported. Yet, the interpretation of PET scans is not clear-cut. The present study aimed at determining the best method to analyse PET/CT in a large, real-life cohort of patients presenting with suspicion of GCA. Methods and results: One hundred and three patients with clinical suspicion of GCA undergoing PET/CT between 2006 and 2012 were included. Clinical data were retrieved from patients' charts. PET/CT was categorized by visual scoring of the uptake and by the artery/liver standardized uptake values (SUV) ratios. Diagnosis of GCA was confirmed in 68 patients and excluded in 35 patients, which served as the controls. GCA patients were older (median age 75 vs. 68 years), and presented more often with ischaemic symptoms. The best discrimination between GCA patients and controls was achieved for PET/CT findings within the supra-aortic arteries (sensitivity 0.71, specificity 0.91 for a SUV/LE cut-off value of 1.0). Specificity of PET/CT for the aorta and the iliofemoral arteries was lower (<0.34). Visual scoring correlated poorly to SUV measurements (Kendall Tau-b 0.13-0.55) and had a lower diagnostic accuracy (sensitivity 0.77, specificity 0.75). Prednisone treatment for ≥10 days significantly reduced PET/CT sensitivity (P = 0.009). Conclusion: SUV based analysis of PET/CT enhances diagnostic accuracy with best discrimination in the supra-aortic region, particularly in steroid naïve patients. For discrimination based on the aorta and the iliofemoral region, higher cut-off values have to be applied, resulting in lower sensitivities for diagnosing GCA.

15.
J Clin Immunol ; 37(7): 707-714, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28825155

RESUMO

Mutations in Sp110 are the underlying cause of veno-occlusive disease with immunodeficiency (VODI), a combined immunodeficiency that is difficult to treat and often fatal. Because early treatment is critically important for patients with VODI, broadly usable diagnostic tools are needed to detect Sp110 protein deficiency. Several factors make establishing the diagnosis of VODI challenging: (1) Current screening strategies to identify severe combined immunodeficiency are based on measuring T cell receptor excision circles (TREC). This approach will fail to identify VODI patients because the disease is not associated with severe T cell lymphopenia at birth; (2) the SP110 gene contains 17 exons, making it a challenge for Sanger sequencing. The recently developed next-generation sequencing (NGS) platforms that can rapidly determine the sequence of all 17 exons are available in only a few laboratories; (3) there is no standard functional assay to test for the effects of novel mutations in Sp110; and (4) it has been difficult to use flow cytometry to identify patients who lack Sp110 because of the low level of Sp110 protein in peripheral blood lymphocytes. We report here a novel flow cytometric assay that is easily performed in diagnostic laboratories and might thus become a standard assay for the evaluation of patients who may have VODI. In addition, the assay will facilitate investigations directed at understanding the function of Sp110.


Assuntos
Citometria de Fluxo/métodos , Hepatopatia Veno-Oclusiva/diagnóstico , Síndromes de Imunodeficiência/diagnóstico , Antígenos de Histocompatibilidade Menor/metabolismo , Proteínas Nucleares/metabolismo , Linfócitos T/metabolismo , Adenoviridae/genética , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Hepatopatia Veno-Oclusiva/metabolismo , Humanos , Síndromes de Imunodeficiência/metabolismo , Leucócitos Mononucleares/citologia , Masculino , Antígenos de Histocompatibilidade Menor/genética , Proteínas Nucleares/genética
16.
Am J Hum Genet ; 100(1): 64-74, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28041642

RESUMO

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10-54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10-10, OR = 1.28; and rs128738, p = 4.60 × 10-9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.


Assuntos
Alelos , Predisposição Genética para Doença/genética , Variação Genética , Estudo de Associação Genômica Ampla , Arterite de Células Gigantes/genética , Plasminogênio/genética , Prolil Hidroxilases/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Europa (Continente)/etnologia , Feminino , Humanos , Masculino , Neovascularização Fisiológica , Polimorfismo de Nucleotídeo Único/genética , Risco
17.
Rheumatology (Oxford) ; 56(5): 829-834, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28064210

RESUMO

Objectives: Autoantibodies are useful biomarkers for diagnosing and monitoring treatment in some autoimmune diseases. Antibodies against isoforms of 14-3-3 protein have been proposed as biomarkers for the presence of aortic aneurysm in large-vessel vasculitis (LVV). Here, we aimed to evaluate the diagnostic role and potential immunopathological involvement of anti-14-3-3 antibodies in newly diagnosed LVV patients. Methods: Antibodies against three isoforms of 14-3-3 (γ, ɛ and ζ) were measured in 90 subjects: 48 GCA and 3 Takayasu's arteritis (TA) patients, and 39 controls (non-inflammatory and inflammatory diseases), using a multiplexed bead-based immunoassay and immunoprecipitation studies. The positive cut-off value was defined based on young healthy controls. Anti-14-3-3 IgG antibodies in LVV patients were compared with those in controls in order to assess their diagnostic performance, and the relationship of anti-14-3-3 IgG antibodies to the immunohistopathology of artery explants was assessed. Results: Antibodies against all three 14-3-3 isoforms were detected in LVV patients as well as in age-matched inflammatory and non-inflammatory controls. Among LVV patients, detection of antibodies targeting 14-3-3 ɛ and ζ was associated with more severe disease. Detection of antibodies against 14-3-3 γ was linked to latent Toxoplasma gondii infection, a parasite that secrets a 14-3-3 homologue, suggesting potential cross-reactivity. Conclusion: Detection of antibodies against 14-3-3 proteins at the time of LVV diagnosis is not disease-specific. Their presence at high levels in LVV patients with stroke, aortitis and-in a previous study-aneurysm formation may indicate an association with extensive tissue destruction. The relevance of 14-3-3 antibodies in non-LVV patients needs to be investigated in larger cohorts.


Assuntos
Proteínas 14-3-3/imunologia , Autoanticorpos/metabolismo , Arterite de Células Gigantes/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aortite/imunologia , Biomarcadores/metabolismo , Feminino , Arterite de Células Gigantes/diagnóstico , Humanos , Imunoglobulina G/metabolismo , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/imunologia , Arterite de Takayasu/imunologia , Toxoplasma/imunologia , Toxoplasmose/imunologia , Remodelação Vascular/imunologia , Adulto Jovem
18.
Blood ; 129(7): 879-882, 2017 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-27940476

RESUMO

Major advances have been made in understanding the pathogenesis of Erdheim-Chester disease (ECD) leading to novel treatment strategies. Targeted therapies such as BRAF inhibition have shown a significant impact on disease management, emphasizing the importance of the activated mitogen-associated protein kinase pathway in this disease. However, incomplete responsiveness, potentially limiting adverse effects, and the occurrence of treatment resistance to BRAF inhibition observed in other BRAF-mutant malignancies imply the importance of therapeutic strategies beyond BRAF inhibition. We report a patient with ECD who carried the BRAFV600E mutation and developed treatment resistance under BRAF inhibition despite initial treatment response. Genetic analyses of a newly developing ECD lesion revealed a somatic KRASQ61H mutation without the presence of BRAFV600E Accordingly, the addition of MEK-inhibiting trametinib to BRAF-inhibiting dabrafenib was able to overcome acquired partial treatment resistance. This is the first report of treatment resistance as a result of a secondary MAPK pathway-activating mutation during BRAF inhibition in ECD. This case contributes to the ongoing efforts of simultaneous BRAF/MEK inhibition as a promising strategy in ECD.


Assuntos
Doença de Erdheim-Chester/tratamento farmacológico , Imidazóis/uso terapêutico , Oximas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Doença de Erdheim-Chester/genética , Doença de Erdheim-Chester/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação Puntual , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores
20.
Hum Immunol ; 77(12): 1147-1153, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27521484

RESUMO

Differences in HLA-C expression are inversely correlated with HIV viral load set-point and slower progression to AIDS, linked to enhanced cytotoxic T cell immunity. Yet, beyond T cells, HLA-C serves as a dominant ligand for natural killer (NK) cell killer immunoglobulin-like receptors (KIR). Thus, we speculated that HLA-C expression levels may also impact NK activity, thereby modulating HIV antiviral control. Phenotypic and functional profiling was performed on freshly isolated PBMCs. HLA-C expression was linked to changes in NK subset distribution and licensing, particularly in HLA-C1/C1, KIR2DL3+2DL2-individuals. Moreover, high levels of HLA-C, were associated with reduced frequencies of anergic CD56neg NKs and lower frequencies of KIR2DL1/2/3+ NK cells, pointing to an HLA-C induced influence on the NK cell development in the absence of disease. In HIV infection, several spontaneous controllers, that expressed higher levels of HLA-C demonstrated robust NK-IFN-γ secretion in response to target cells, highlighting a second disease induced licensing phenotype. Thus this population study points to a potential role for HLA-C levels both in NK cell education and development.


Assuntos
Infecções por HIV/imunologia , HIV-1/fisiologia , Antígenos HLA-C/metabolismo , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos/imunologia , Adolescente , Adulto , Doenças Assintomáticas , Estudos de Coortes , Citotoxicidade Imunológica , Feminino , Frequência do Gene , Infecções por HIV/genética , Antígenos HLA-C/genética , Haplótipos , Humanos , Imunofenotipagem , Interferon gama/metabolismo , Células Matadoras Naturais/virologia , Ativação Linfocitária , Subpopulações de Linfócitos/virologia , Masculino , Pessoa de Meia-Idade , Receptores KIR/genética , Receptores KIR/metabolismo , Carga Viral , Adulto Jovem
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