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Paul Hasler

Publications and source records attributed to Paul Hasler.

12 recordsLinked to original sources
PubMed2006

Protein microarray platform for the multiplex analysis of biomarkers in human sera.

Many biomarkers are currently used to monitor patients in clinical studies. Technologies which evaluate, validate and monitor biomarkers in a cost effective and efficient manner are a necessity. Here we describe the development, validation and implementation of a protein microarray platform for the quantitative and simultaneous analysis of six proteins: IL-1beta, IL-1ra, IL-6, IL-8, MCP-1 and TNFalpha. The platform utilizes a 96-well plate as a solid support on which antibodies are immobilized using non-contact piezoelectric printing. The reaction is based on a sandwich ELISA and the signal is quantified by chemiluminescence with a CCD camera. The robustness and reproducibility of the methodology was investigated using the Food and Drug Administration (FDA) regulatory guidelines for pharmacokinetic assay validation, in which a spike-recovery validation test was elaborated and run over 3 days. The method was shown to be both quantitative and reproducible, with assay accuracy between 70% and 130%, and an assay precision of less than 30%. In addition, protein microarray performance was compared with the classical ELISA approach. Sera collected from a total of 78 individuals were assayed using both approaches. Correlation coefficients (R2) between the two technologies were calculated for each of the analytes: 0.90 for IL-1beta, 0.60 for IL-1ra, 0.93 for IL-6, 0.96 for IL-8, 0.94 for MCP-1 and 0.95 for TNFalpha. The results obtained demonstrate the applicability of this protein microarray for quantitative and simultaneous analysis of IL-1beta, IL-1ra, IL-6, IL-8, MCP-1 and TNFalpha in clinical samples.

Biomarkers↗
PubMed2006

Biological therapies directed against cells in autoimmune disease.

Among the cells of the immune system involved in the pathogenesis of autoimmune disease, T cells have received the most attention. The central role of these cells in several animal models of autoimmune diseases and in human disease counterparts has provided the rationale for specific therapeutic targeting of T cell subsets, especially CD4 T cells. So far, the applicability of this approach has not been clearly evident in clinical trials, which was also the case when nondepleting "coating" anti-CD4 monoclonal antibodies was used. In the past several years, experimental evidence supporting a major role of B cells in systemic autoimmune disease has grown. This includes the pathogenicity of certain autoantibodies, the potential of B cells to present antigen in the context of MHC Class II and to signal via costimulatory molecules, and to secrete proinflammatory cytokines. In some instances, engagement of the B cell receptor and other surface receptors is sufficient to stimulate B cells to produce antibodies. The depletion of B cells by targeting the surface marker CD20 has been shown to be effective in treating rheumatoid arthritis with a good side effect profile. Series of cases with other systemic autoimmune diseases indicate that this strategy may be effective in these conditions too. The clinical data add weight to the importance of B cells in the pathogenesis of autoimmune diseases.

Animals↗
PubMed2006

Induction of neutrophil extracellular DNA lattices by placental microparticles and IL-8 and their presence in preeclampsia.

Preeclampsia, a severe pregnancy-related disorder, involves an overt activation of the maternal innate immune system, proposed to result from the elevated release of inflammatory syncytiotrophoblast microparticles (STBM) and cytokines from underlying placental anomaly involving abnormal trophoblast differentiation. Activation of circulating neutrophils has recently been shown to lead to the generation of fibrous extracellular lattices containing DNA, termed NETs (neutrophil extracellular traps). Therefore, we examined whether placentally derived factors activated peripheral neutrophils to generate NETs, and whether NETs formation was increased in preeclamptic placenta. Activation of isolated circulatory neutrophils on treatment with placentally derived factors (interleukin-8 and STBM) was assessed by measuring CD11b expression using Flow cytometry. Furthermore, NETs generation by these activated neutrophils in vitro and in vivo in the placental tissue sections were examined using electron microscopy and fluorescence microscopy. We report that placentally-derived interleukin-8 and STBM efficiently activated neutrophils and triggered NETs formation. Large numbers of NETs were present directly in the intervillous space of preeclamptic placentae. NETs, therefore, appear to be an integral part of neutrophil activation, and their increased presence in preeclampsia suggests that NETs may play a role in the underlying pathology.

Cell-Derived Microparticles↗
PubMed2006

Occurrence of neutrophil extracellular DNA traps (NETs) in pre-eclampsia: a link with elevated levels of cell-free DNA?

Manifest pre-eclampsia is associated with activation of peripheral neutrophils as well as elevations in maternal cell-free DNA. For this reason, we were very intrigued by recent reports indicating that activated circulatory neutrophils secrete nuclear DNA to generate extracellular DNA lattices, termed NETs (neutrophil extracellular traps). Our preliminary data indicate that placental syncytiotrophoblast microparticles, which are released in elevated amounts in pre-eclampsia, can induce NETs in isolated neutrophils. Furthermore, we found evidence for the increased presence of NETs directly in the intervillous space of pre-eclamptic placentae. Therefore, these newly discovered entities may be implicated in the underlying etiology of this disorder.

DNA↗
PubMed2006

B lymphocytes as therapeutic targets in systemic lupus erythematosus.

In recent years, experimental evidence supporting a major role of B cells in the pathogenesis of autoimmune diseases has grown. This includes the discovery of novel mechanisms of autoantibody pathogenicity and the potential of B cells to mediate inflammation and tissue injury. In some instances, engagement of the B cell receptor and other surface receptors is sufficient to stimulate B cells to produce antibody. As a result, B cells have become targets for immunointervention. In lupus, targeting B cell activation factor (BAFF, BLys) indicates that specific blockade of this longevity factor might be sufficient to suppress systemic autoimmunity. Targeting CD20 represents another promising avenue for the treatment of refractory lupus in both adults and children. Although the clinical data add weight to the importance of B cells in the pathogenesis of lupus, new targets for B cell depletion therapy are being investigated. In experimental models, combining CD19 and CD20 antibodies was more effective than either treatment alone.

B-Lymphocytes↗
PubMed2005

Immune receptor signaling, aging, and autoimmunity.

With advancing age, the immune system undergoes changes that predispose to autoimmune reactivity. Aging reduces the efficiency of physical barriers, decreasing protection against invasive pathogens, and exposing previously hidden antigens in the body's own tissues. Self-antigens acquire alterations that increase their immunogenicity. In addition, the ability of innate immunity to eliminate infectious agents deteriorates, resulting in inappropriate persistence of immune stimulation and antigen levels exceeding the threshold for the activation of B or T cells. B cell turnover is reduced and numbers of naïve T cells decline to the advantage of increasing numbers of memory T cells. In parallel, the loss of co-stimulatory T cell molecules may increase reactivity of T cells, and render them less susceptible to downregulation. Since optimal immune reactivity requires a tight balance of transduction pathways in both T and B lymphocytes, and because these pathways are altered in systemic autoimmune diseases, we would like to propose that, with age, alterations of the immune receptor signaling machinery underlie the higher incidence of autoimmune phenomena in the elderly. Consistently, aging is associated with alterations in several components of the signaling complex in B cells, memory and naïve T cells, and a reduced activation of several lipid rafts-associated proteins. Because the coincidence of autoimmune disease with other ailments increases the burden of disease and limits therapeutic options in the aged, further investigation of these pathways in the elderly represents a challenge that will need to be addressed in order to devise effective preventive and therapeutic interventions.

Aging↗
PubMed2005

Staphylococcus aureus in patients with rheumatoid arthritis under conventional and anti-tumor necrosis factor-alpha treatment.

OBJECTIVE: To compare the prevalence of nasal and oral Staphylococcus aureus in patients with rheumatoid arthritis (RA) with the prevalence in controls with other rheumatic diseases, and to determine predictors of S. aureus carriage and the influence of treatment with anti-tumor necrosis factor-a (anti-TNF-alpha) agents. METHODS: Eighty-one patients with RA and 83 other control patients of 2 outpatient rheumatology clinics were cultured for nasal and oral carriage of S. aureus. Quantitative nasal cultures for S. aureus were performed from swabs of the anterior nares, the posterior pharynx, and the soft palate. Information on medications, medical conditions, and risk factors for S. aureus carriage was collected from all participants by a questionnaire and confirmed by chart review. RESULTS: The S. aureus carriage rate (nasal and/or oral colonization) was 34.6% among RA patients and 32.5% among controls (p = 0.87). Being treated with an anti-TNF-alpha agent plus methotrexate (MTX) was the only independent predictor of S. aureus carriage (OR 3.24, 95% CI 1.16-9.05, p = 0.025). The S. aureus carriage rate among RA patients treated with an anti-TNF-alpha agent plus MTX was 60% (9/15) versus 23.1% (3/13) in RA patients treated with an anti-TNF-alpha agent only (p = 0.049). All S. aureus isolates were susceptible to oxacillin. CONCLUSION: The S. aureus carriage rate among patients with RA was not higher than among controls. Treatment with anti-TNF-alpha agents was not associated with an increased S. aureus carriage rate. However, treatment with an anti-TNF-alpha agent plus MTX may predispose patients to S. aureus carriage.

Adalimumab↗
PubMed2004

Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritis: a phase II, four-week, multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To compare the efficacy and tolerability of the novel cyclooxygenase 2-selective inhibitor lumiracoxib with placebo and diclofenac in osteoarthritis (OA). METHODS: Adults (n=583) with knee or hip OA were randomized to receive for 4 weeks lumiracoxib 50, 100, or 200 mg twice daily or 400 mg once daily; placebo; or diclofenac 75 mg twice daily. Efficacy assessments included overall joint pain intensity and Western Ontario and McMaster Universities Osteoarthritis Index subscales; tolerability was evaluated by adverse event and physician reporting. RESULTS: All lumiracoxib doses were superior to placebo in relieving pain, improving stiffness, and improving physical function after 4 weeks. At study endpoint, pain relief was comparable among all lumiracoxib dosages and similar to diclofenac. Lumiracoxib tolerability was superior to diclofenac and comparable to placebo. CONCLUSION: Lumiracoxib provides predictable and sustained relief from pain, stiffness, and impaired physical function in OA. Lumiracoxib shows clinically comparable efficacy and superior tolerability to diclofenac.

Aged↗
PubMed2003

Arthritis and interstitial granulomatous dermatitis (Ackerman syndrome) with pulmonary silicosis.

OBJECTIVE: To describe the case of a patient suffering from pulmonary silicosis associated with a rheumatoid factor negative, antinuclear antibody positive, symmetrical, nonerosive synovitis, and interstitial granulomatous dermatitis (IGD) and compare it with similar cases reported in the literature. METHODS: Literature search to identify published cases of IGD with arthritis and cases associated with silicosis. RESULTS: Thiry-eight cases of IGD with arthritis were found. These cases were associated with various conditions such as drug reactions, autoimmune diseases, chronic infections, or paraneoplastic syndromes for which no specific underlying cause was identified. The patient had skin lesions corresponding to the rope sign, as noted in other reports. Histology showed a histiocytic, granulomatous dermatitis, which, in association with arthritis, was first described by Ackerman et al. Circulating immune complexes or altered apoptosis have been discussed as mechanisms, although there is no experimental evidence to support either hypothesis. As in other cases, treatment had limited success. Most relief was achieved with hydroxychloroquine, dapsone, and corticosteroids. CONCLUSIONS: Arthritis and IGD associated with silicosis is a rare clinical entity that can be differentiated from other conditions. This condition should be considered when patients present with typical dermatologic features, such as the rope sign, and arthritis.

Adult↗
PubMed2003

Highlights of frontiers in autoimmunity: fundamental aspects and clinical perspectives.

The aim of this meeting, on the shores of Balaton lake, was to discuss the ins, outs, ups and downs of autoimmune diseases. Participants were encouraged to discuss existing paradigms and to base their work on continuously reworked hypotheses derived from discoveries, rather than have it driven by theories based on a hypothesis. This event provided proof of the utility of modern approaches in defining the origin of this group of diseases as well as acting as an international forum for collaboration and dispute. Whilst highlighting the unique aspects of autoimmunity, this meeting suggested many avenues for future research and the design of novel strategies for immuno-intervention.

Animals↗
PubMed2002

Posterior tibial tendon dysfunction and MR imaging in rheumatoid arthritis.

We present the case of a patient with long-standing rheumatoid arthritis and an acute onset of total dysfunction of the posterior tibial tendon. On MRI, a rupture of the tendon was apparent. Intraoperatively, however, massive tenosynovitis with stricture of the tendon was identified as the cause of posterior tibial tendon dysfunction. This case illustrates a pitfall in MRI imaging with potential diagnostic and therapeutic consequences.

Arthralgia↗