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ID PMID Title PublicationDate abstract
16684006 Pathogenesis of haemophilic arthropathy. 2006 Jul The pathogenetic mechanism of haemophilic arthropathy is multifactorial and includes degenerative cartilage-mediated and inflammatory synovium-mediated components. Intra-articular blood first has a direct effect on cartilage, as a result of the iron-catalysed formation of destructive oxygen metabolites (resulting in chondrocyte apoptosis), and subsequently affects the synovium, in addition to haemosiderin-induced synovial triggering. Both processes occur in parallel, and while they influence each other they probably do not depend on each other. This concept resembles degenerative joint damage as found in osteoarthritis as well as inflammatory processes in rheumatoid arthritis. These processes finally result in a fibrotic and destroyed joint.
18466474 Association mapping through heuristic evolutionary history reconstruction-application to G 2007 This paper presents a novel method of identifying phenotypically important regions of the genome. It involves a form of association mapping that works by summarizing properties of the ancestral recombination graph (ARG) of a sample of unrelated phenotyped and genotyped individuals. By breaking the sample into many small sub-samples and averaging the results, it becomes computationally tractable to measure the degree to which the evolutionary history of any locus is consistent with the distribution of the phenotypes in the sample. Analysis of simulated rheumatoid arthritis data demonstrates the efficiency and effectiveness of this method in identifying loci of large phenotypic effect.
16751698 [Bone and bone related biochemical examinations. Bone and collagen related metabolites. Bi 2006 Jun Now, it is becoming known that the mechanisms of cartilage matrix destruction such as roles of degradative enzymes and cytokines. It is important to develop the reliable biomarkers to detect the early stage of cartilage destruction. The biomarker could be useful tool not only to understand the progression of joint destruction in osteoarthritis and rheumatoid arthritis but also to develop new treatment.
17920687 Mycobacterium other than tuberculosis (MOTT) infection: an emerging disease in infliximab- 2007 Dec OBJECTIVES: Infliximab has revolutionized treatment of rheumatologic diseases and inflammatory bowel disease. However, it increases the risk of tuberculosis. Less is known about the development of Mycobacterium other than tuberculosis (MOTT) infection. We review the literature on non-tuberculous mycobacterial infections in infliximab-treated patients and report the first case of disseminated Mycobacterium avium complex in an infliximab-treated patient complicated by immune reconstitution inflammatory syndrome. METHODS AND RESULTS: MEDLINE search with the keywords mycobacteria and infliximab revealed four cases of MOTT in patients treated with infliximab: fatal Mycobacterium peregrinum pneumonia in a patient with polymyositis and dermatomyositis; a patient with rheumatoid arthritis with skin and soft tissue infection with Mycobacterium abscessus; Mycobacterium fortuitum in a patient with rheumatoid arthritis; and a case of pulmonary MAC without dissemination. Review of US data from 1998 to 2002 published by Wallis et al. revealed that out of more than 233,000 patients treated with infliximab, 30 developed unspecified mycobacterial species infection. No further data was available regarding these cases. CONCLUSION: MOTT infection is a rare but emerging complication of infliximab therapy. MOTT cases tend to progress rapidly in infliximab-treated patients and withdrawal of infliximab therapy can result in immune reconstitution.
17244418 Measuring disease prevalence: a comparison of musculoskeletal disease using four general p 2007 Jan BACKGROUND: Primary care consultation data are an important source of information on morbidity prevalence. It is not known how reliable such figures are. AIM: To compare annual consultation prevalence estimates for musculoskeletal conditions derived from four general practice consultation databases. DESIGN OF STUDY: Retrospective study of general practice consultation records. SETTING: Three national general practice consultation databases: i) Fourth Morbidity Statistics from General Practice (MSGP4, 1991/92), ii) Royal College of General Practitioners Weekly Returns Service (RCGP WRS, 2001), and iii) General Practice Research Database (GPRD, 1991 and 2001); and one regional database (Consultations in Primary Care Archive, 2001). METHOD: Age-sex standardized persons consulting annual prevalence rates for musculoskeletal conditions overall, rheumatoid arthritis, osteoarthritis and arthralgia were derived for patients aged 15 years and over. RESULTS: GPRD prevalence of any musculoskeletal condition, rheumatoid arthritis and osteoarthritis was lower than that of the other databases. This is likely to be due to GPs not needing to record every consultation made for a chronic condition. MSGP4 gave the highest prevalence for osteoarthritis but low prevalence of arthralgia which reflects encouragement for GPs to use diagnostic rather than symptom codes. CONCLUSION: Considerable variation exists in consultation prevalence estimates for musculoskeletal conditions. Researchers and health service planners should be aware that estimates of disease occurrence based on consultation will be influenced by choice of database. This is likely to be true for other chronic diseases and where alternative symptom labels exist for a disease. RCGP WRS may give the most reliable prevalence figures for musculoskeletal and other chronic diseases.
18372237 Adipose tissue loss in adjuvant arthritis is associated with a decrease in lipogenesis, bu 2008 Apr Adjuvant-induced arthritis is a model of rheumatoid arthritis that induces cachexia. In other cachectic situations, there is an increase in lipolysis resulting in a loss of adipose tissue mass. The aim of this work was to analyse the effect of chronic arthritis, induced by adjuvant injection, on white adipose tissue (WAT). For this purpose, rats were killed 10 days after adjuvant injection, when the first external symptoms appeared, on days 15 and 22 when the external signs of the illness reach their severest level. As arthritis decreases food intake, a pair-fed group was also included. Serum concentrations of insulin, leptin, adiponectin, glycerol and nitrites, as well as gene expression of leptin, adiponectin, hormone-sensitive lipase (HSL), fatty acid synthase (FAS), tumour necrosis factor alpha and zinc-alpha(2)-glycoprotein (ZAG) were determined. Arthritis decreased food intake between days 5 and 16, but not during the last 5 days of the experiment. There was a marked decrease in relative adipose tissue weight and in serum leptin and adiponectin as well as in their gene expression in WAT in arthritic rats. Arthritis decreased the gene expression of FAS in the WAT. However, none of these effects was found in pair-fed rats. Arthritis did not increase lipolysis, since arthritic rats have lower serum concentrations of glycerol, HSL mRNA in WAT, as well as liver ZAG mRNA than the pair-fed or control rats. These data suggest that in chronic arthritis the decrease in white adipose mass is secondary to a reduced adipose lipogenesis, and this effect is not mainly due to the decrease in food intake.
16356194 THR0921, a novel peroxisome proliferator-activated receptor gamma agonist, reduces the sev 2006 THR0921 is a novel peroxisome proliferator-activated receptor gamma (PPARgamma) agonist with potent anti-diabetic properties. Because of the proposed role of PPARgamma in inflammation, we investigated the potential of orally active THR0921 to inhibit the pathogenesis of collagen-induced arthritis (CIA). CIA was induced in DBA/1J mice by the injection of bovine type II collagen in complete Freund's adjuvant on days 0 and 21. Mice were treated with THR0921 (50 mg/kg/day) starting on the day of the booster injection and throughout the remaining study period. Both clinical disease activity scores as well as histological scores of joint destruction were significantly reduced in mice treated with THR0921 compared to untreated mice. Proliferation of isolated spleen cells, as well as circulating levels of IgG antibody to type II collagen, was decreased by THR0921. Moreover, spleen cell production of IFN-gamma, tumor necrosis factor (TNF)-alpha and IL-1beta in response to exposure to lipopolysaccharide or type II collagen was reduced by in vivo treatment with THR0921. Steady state mRNA levels of TNF-alpha, IL-1beta, monocyte chemotactic protein-1 and receptor activator of nuclear factor kappaB ligand (RANKL) in isolated joints were all decreased in mice treated with THR0921. Finally, THR0921 inhibited osteoclast differentiation of bone marrow-derived cells stimulated with macrophage colony-stimulating factor and RANKL. In conclusion, THR0921 attenuates collagen-induced arthritis in part by reducing the immune response. As such, PPARgamma may be an important therapeutic target for rheumatoid arthritis.
16984225 Intraarticular interferon-beta gene therapy ameliorates adjuvant arthritis in rats. 2006 Oct Interferon (IFN)-beta has significant immunomodulatory properties and has received much interest as a potentially therapeutic agent for rheumatoid arthritis (RA). Systemic IFN-beta treatment of patients with RA was not effective, probably because of pharmacokinetic issues. Therefore, we studied the effect of local IFN-beta production by adenovirus-mediated gene transfer to the ankle joints of arthritic rats. Adjuvant arthritis (AA) in rats was used as a model to study intraarticular gene therapy with an adenoviral vector encoding the rat IFN-beta gene (Ad.IFN-beta). The effect on paw swelling was measured by water displacement plethysmometry. Synovial tissue of the hind paws was examined by immunohistochemistry. Bone destruction was analyzed on the basis of radiographs. In addition, quantitative real-time polymerase chain reaction was used to assess IFN-beta expression. Levels of IFN-beta mRNA and protein peaked 2 days after intraarticular injection and declined thereafter. Local delivery of Ad.IFN-beta after the onset of disease reduced paw swelling significantly. This was accompanied by a reduction in synovial inflammation. The clinical effects in rat AA lasted up to 9 days. Strikingly, Ad.IFN-beta treatment protected bone from erosion, reduced levels of c-Cbl and Cbl-b (both signaling molecules essential for osteoclast activity), and reduced the matrix metalloproteinase-3:tissue inhibitor of metalloproteinase-1 ratio in the joint. Immunohistochemical analysis of the synovial tissue revealed a clear shift toward a more antiinflammatory cytokine profile. Local overexpression of IFN-beta inhibits arthritis progression and protects against bone destruction in rat AA. These findings validate IFN-beta as a therapeutic molecule for intraarticular gene therapy of arthritis.
17586472 Targeted delivery of catalase and superoxide dismutase to macrophages using folate. 2007 Aug 17 Reactive oxygen species (ROS) secreted by activated macrophages play a central role in causing rheumatoid arthritis, and therapeutics that can inhibit the production of ROS by macrophages have great clinical potential. Superoxide dismutase (SOD) and catalase (CAT) are two enzymes that scavenge ROS and have great potential for treating rheumatoid arthritis. However, clinical trials with these enzymes have been ineffective, due to drug delivery problems, and effective SOD and CAT delivery vehicles are greatly needed. In this communication, we demonstrate that CAT and SOD can be effectively targeted to activated macrophages, via the folate receptor. Folate was conjugated to CAT and SOD using NHS/EDC chemistry with high efficiency. Cell culture experiments demonstrated that folate conjugation increased their ability to scavenge ROS, produced by the macrophages, and also enhanced their uptake into activated macrophages. We anticipate numerous applications of folate-conjugated CAT and SOD in treating inflammatory diseases, based on their efficacy and straightforward synthesis.
21794400 [Evaluation of two proposals based on clinical factors for selecting what male patients wi 2007 Mar Criteria based on age, inflammation, and immobility have been proposed to identify which patients with rheumatoid arthritis (RA) should be examined by dual energy X-ray absorptiometry (DXA) to diagnose osteoporosis. Recently, a modified version of the criteria by including weight and the use of corticosteroids has been proposed. These two set of criteria have not been tested in male patients in a clinical setting. OBJECTIVE: To analyse, in a group of patients followed in a teaching hospital, the value of two proposals to select men with RA for bone densitometry. PATIENTS AND METHOD: Clinical and demographic data were collected from the charts of a total of 65 men with RA, submitted to the bone densitometry unit during a fouryear period. Bone mineral density (BMD) was measured in spine and femoral neck by DXA. Two set of criteria were tested: a) three item criteria (age, inflammation and immobility), and b) five item criteria (age, inflammation, immobility, weight, and ever use of corticosteroids). Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS: Thirty five (54%) patients fulfilled the three item criteria and 38 (59%) the five item criteria. For the diagnosis of osteoporosis using the three item criteria, the sensitivity was 62%, specificity 48%, PPV 23% and NPV 83%; using the 5 item criteria the sensitivity was 90%, specificity 47%, PPV 23%, and NPV 96%. CONCLUSIONS: The five item criteria are a more accurate tool to identify, in clinical practice, male patients with RA and osteoporosis than the three item criteria. It seems a good screening method for the selection of those patients with RA whose BMD should be assessed, as the sensitivity and NPV seem acceptable.
18240267 Suppressive role of leukocyte cell-derived chemotaxin 2 in mouse anti-type II collagen ant 2008 Feb OBJECTIVE: We previously reported that the Val58Ile polymorphism of the leukocyte cell-derived chemotaxin 2 gene (LECT2) is associated with the severity of rheumatoid arthritis (RA). To define the role of LECT2 in inflammatory arthritides, we investigated the development of collagen antibody-induced arthritis (CAIA) in LECT2-deficient (LECT2(-/-)) mice. METHODS: CAIA was induced in mice by administering anti-type II collagen antibodies followed by lipopolysaccharide. Daily assessment of hind paw swelling was used to monitor the development of arthritis. The histopathologic features and expression of inflammatory cytokines were also analyzed. We confirmed the role of LECT2 by introducing a LECT2 expression vector into LECT2(-/-) mice, using a hydrodynamic gene transfer method. RESULTS: Arthritis in LECT2(-/-) mice was significantly exacerbated compared with that in wild-type (WT) controls. Histopathologic assessment of the tarsal joints showed that inflammation and erosion of cartilage and bone in LECT2(-/-) mice were more severe than that in controls. Interleukin-1beta (IL-1beta), IL-6, and certain chemokines were present at significantly higher levels in the arthritic hind paws of LECT2(-/-) mice. In contrast, the amount of LECT2 in the serum and locally in the hind paws was higher in arthritic WT mice. Finally, hydrodynamic gene transfer experiments revealed that the severity of arthritis was reduced by the systemic expression of exogenous mouse LECT2 protein in LECT2(-/-) mice. CONCLUSION: These results strongly suggest that LECT2 directly suppresses the development of CAIA. Manipulation of LECT2 might provide a rationale for novel therapeutic approaches to the treatment of inflammatory arthritides such as RA.
17617630 B cell depletion delays collagen-induced arthritis in mice: arthritis induction requires s 2007 Jul 15 Rheumatoid arthritis is a systemic autoimmune disease. B cells are likely to play a critical role in arthritis pathogenesis, although it is unclear whether they are necessary for disease induction, autoantibody production, or disease progression. To assess the role of B cells in inflammatory arthritis, B cells were depleted using mouse anti-mouse CD20 mAbs in a mouse model of collagen-induced arthritis. CD20 mAbs effectively depleted mature B cells from adult DBA-1 mice. When B cells were depleted using CD20 mAbs before collagen immunization, there was a delay in disease onset and autoantibody production, with significantly diminished severity of arthritis both clinically and histologically. B cell depletion further delayed disease onset if initiated before, as well as after, collagen immunization. However, in both cases, the eventual reappearance of peripheral B cells triggered autoantibody production and the subsequent development of arthritis in collagen-sensitized mice. By contrast, B cell depletion after collagen immunizations did not have a significant effect on arthritis progression or severity. Thus, disease symptoms were only induced when peripheral B cells and their autoantibody products were present in collagen-immunized mice, documenting a critical role for B cells during the elicitation phase of collagen-induced arthritis. These studies suggest that B cell depletion strategies will be most effective when initiated early in the development of inflammatory arthritis, with sustained B cell depletion required to inhibit the production of isotype-switched pathogenic Abs and the evolution of joint inflammation and destruction.
18435845 Extensor-tendons reconstruction using autogenous palmaris longus tendon grafting for rheum 2008 Apr 24 BACKGROUND: The purpose of the study is to retrospectively review the clinical outcome of our study population of middle-aged RA patients who had suffered extensor-tendon rupture. We reported the outcome of autogenous palmaris tendon grafting of multiple extensor tendons at wrist level in 14 middle-aged rheumatoid patients. METHODS: Between Feb. 2000 to Feb. 2004, thirty-six ruptured wrist level extensor tendons were reconstructed in fourteen rheumatoid patients (11 women and three men) using autogenous palmaris longus tendon as a free interposition graft. In each case, the evaluation was based on both subjective and objective criteria, including the range of MCP joint flexion after surgery, the extension lag at the metacarpophalangeal joint before and after surgery, and the ability of the patient to work. RESULTS AND DISCUSSION: The average of follow-up was 54.1 months (range, 40 to 72 months). The average range of MCP joint flexion after reconstruction was 66 degrees . The extension lag at the metacarpophalangeal joint significantly improved from a preoperative mean of 38 degrees (range, 25 degrees -60 degrees ) to a postoperative mean of 16 degrees (range, 0 degrees -30 degrees ). Subjectively all patients were satisfied with the clinical results, and achieved a return to their level of ability before tendon rupture. We found good functional results in our series of interposition grafting using palmaris longus to reconstruct extensor tendon defects in the rheumatoid patients. CONCLUSION: Reconstruction for multiple tendon ruptures is a salvage procedure that is often associated with extensor lag and impairment of overall function. Early aggressive treatment of extensor tendon reconstruction using autogenous palmaris longus tendon as a free interposition graft in the rheumatoid wrist is another viable option to achieve good clinical functional result.
18466575 Comparison of the power of haplotype-based versus single- and multilocus association metho 2007 Accounting for interactions with environmental factors in association studies may improve the power to detect genetic effects and may help identifying important environmental effect modifiers. The power of unphased genotype-versus haplotype-based methods in regions with high linkage disequilibrium (LD), as measured by D', for analyzing gene x environment (gene x sex) interactions was compared using the Genetic Analysis Workshop 15 (GAW15) simulated data on rheumatoid arthritis with prior knowledge of the answers. Stepwise and regular conditional logistic regression (CLR) was performed using a matched case-control sample for a HLA region interacting with sex. Haplotype-based analyses were performed using a haplotype-sharing-based Mantel statistic and a test for haplotype-trait association in a general linear model framework. A step-down minP algorithm was applied to derive adjusted p-values and to allow for power comparisons. These methods were also applied to the GAW15 real data set for PTPN22.For markers in strong LD, stepwise CLR performed poorly because of the correlation/collinearity between the predictors in the model. The power was high for detecting genetic main effects using simple CLR models and haplotype-based methods and for detecting joint effects using CLR and Mantel statistics. Only the haplotype-trait association test had high power to detect the gene x sex interaction.In the PTPN22 region with markers characterized by strong LD, all methods indicated a significant genotype x sex interaction in a sample of about 1000 subjects. The previously reported R620W single-nucleotide polymorphism was identified using logistic regression, but the haplotype-based methods did not provide any precise location information.
18466538 Genetic Analysis Workshop 15: simulation of a complex genetic model for rheumatoid arthrit 2007 Data for Problem 3 of the Genetic Analysis Workshop 15 were generated by computer simulation in an attempt to mimic some of the genetic and epidemiological features of rheumatoid arthritis (RA) such as its population prevalence, sex ratio, risk to siblings of affected individuals, association with cigarette smoking, the strong effect of genotype in the HLA region and other genetic effects. A complex genetic model including epistasis and genotype-by-environment interaction was applied to a population of 1.9 million nuclear families of size four from which we selected 1500 families with both offspring affected and 2000 unrelated, unaffected individuals all of whose first-degree relatives were unaffected. This process was repeated to produce 100 replicate data sets. In addition, we generated marker data for 22 autosomes consisting of a genome-wide set of 730 simulated STRP markers, 9187 SNP markers and an additional 17,820 SNP markers on chromosome 6. Appropriate linkage disequilibrium between markers and between trait loci and markers was modelled using HapMap Phase 1 data http://www.hapmap.org/downloads/phasing/2005-03_phaseI/. The code base for this project was written primarily in the Octave programming language, but it is being ported to the R language and developed into a larger project for general genetic simulation called GenetSim http://genetsim.org/. All of the source code that was used to generate the GAW 15 Problem 3 data is freely available for download at http://genetsim.org/gaw15/.
18057140 Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone 2008 Apr Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts. The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle. Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture. Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor kappaB ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling. The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK. Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength. RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis. Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis.
17877526 Computer assessment and diagnostic classification of chronic pain patients. 2007 Oct OBJECTIVE: In order to establish a diagnosis of chronic pain, emphasis is placed on a patient's report of the pain's intensity, location, and character. The aim of this study was to evaluate the feasibility of a computer assessment method to collect self-reports of pain that were then used in discriminant analyses to distinguish among chronic pain diagnoses. METHODS: A convenience sample of 511 patients from two university-based pain clinics completed a computer pain assessment battery that elicited demographic information, pain drawings, pain and emotion intensity ratings, and intensity ratings of verbal descriptors. Patients classified themselves into one of six chronic pain diagnoses. Discriminant analyses were performed in an attempt to identify the unique features of patients' pain experience associated with each of the diagnostic categories. RESULTS: Pain drawings successfully classified patients into three of the diagnostic categories (back, head, and neck pain). In a second analysis, two pain descriptors (cramping and stabbing) separated rheumatoid arthritis patients from those with either fibromyalgia or neural pain. One descriptor of pain (cramping) and one descriptor of emotion (frustration) together distinguished between fibromyalgia and neural pain. CONCLUSIONS: 1) Computer assessment of a range of patient symptoms is feasible in the pain clinic. 2) Discriminant analysis based on pain drawings can distinguish among patient-reported diagnoses of back pain, headache, and neck pain. 3) Discriminant analysis based on three verbal descriptors can help to distinguish among diagnoses of fibromyalgia, neuralgia, and rheumatoid arthritis. 4) However, in general, most computerized descriptive information is not useful in distinguishing differences among pain patient diagnostic groups.
16433522 A fluoroacetamidine-based inactivator of protein arginine deiminase 4: design, synthesis, 2006 Feb 1 Protein arginine deiminase 4 (PAD4) is a calcium-dependent transcriptional corepressor that has been implicated in the onset and progression of rheumatoid arthritis. Herein we describe the synthesis and in vitro evaluation of a fluoroacetamidine-containing compound, N-alpha-benzoyl-N5-(2-fluoro-1-iminoethyl)-l-ornithine amide, 1, hereafter referred to as F-amidine, that is the most potent PAD4 inhibitor ever described. Additional studies described herein indicate that F-amidine can also inhibit PAD4 activity in vivo. The bioavailability of this compound suggests that F-amidine will be a powerful chemical probe of PAD4 function that can be used to dissect the roles of this enzyme in both rheumatoid arthritis and transcriptional control. The fact that inhibition is of an irreversible nature suggests that, with appropriate functionalization, F-amidine analogues will be robust activity-based protein-profiling and proteomic capture reagents.
19156222 Frequency of regulatory T cells is not affected by transient B cell depletion using anti-C 2008 OBJECTIVES: Transient B cell depletion with the monoclonal anti-CD20 antibody rituximab has shown favourable clinical responses in patients with rheumatoid arthritis (RA). Recently a characteristic regeneration pattern of B cell subpopulations has been reported. However, little is known about the impact of B-cell depletion on peripheral T cells in particular regulatory T cells. MATERIALS AND METHODOLOGY: 17 patients with RA having failed anti-TNF were treated with rituximab. Four colour staining was performed using CD19, CD3, CD4, CD8, CD16, CD56, CD25, HLA-DR, HLA-G and intracellular Foxp3 at five time points spanning up to 12 months after rituximab. In addition, quantification of the soluble form of the HLA class I molecule HLA-G by ELISA has been performed. RESULTS: Peripheral B cell depletion lasted 6 to 9 months. The absolute number of CD3+, CD4+ and CD8+ lymphocytes showed no significant changes up to 1 year after B-cell depletion compared to before therapy. Only the relative frequency for CD3 and CD4 showed a significant increase (p < 0.05). In particular, CD4+CD25++ and Foxp3 positive regulatory T cells remained constant. The percentage of HLA-G positive cells in the CD4+ or CD8+ population did not change significantly either. The amount of sHLA-G remained without significant changes. CONCLUSION: Absolute T cell counts showed no significant changes after rituximab compared to the time point before therapy.In particular, the frequency of regulatory T cells with a CD4+CD25++ phenotype as well as positive Foxp3 expression were numerically stable. Additionally, HLA-G positive regulatory T cells and soluble levels of HLA-G showed no significant changes.
18466471 Association testing by haplotype-sharing methods applicable to whole-genome analysis. 2007 We propose two new haplotype-sharing methods for identifying disease loci: the haplotype sharing statistic (HSS), which compares length of shared haplotypes between cases and controls, and the CROSS test, which tests whether a case and a control haplotype show less sharing than two random haplotypes. The significance of the HSS is determined using a variance estimate from the theory of U-statistics, whereas the significance of the CROSS test is estimated from a sequential randomization procedure. Both methods are fast and hence practical, even for whole-genome screens with high marker densities. We analyzed data sets of Problems 2 and 3 of Genetic Analysis Workshop 15 and compared HSS and CROSS to conventional association methods. Problem 2 provided a data set of 2300 single-nucleotide polymorphisms (SNPs) in a 10-Mb region of chromosome 18q, which had shown linkage evidence for rheumatoid arthritis. The CROSS test detected a significant association at approximately position 4407 kb. This was supported by single-marker association and HSS. The CROSS test outperformed them both with respect to significance level and signal-to-noise ratio. A 20-kb candidate region could be identified. Problem 3 provided a simulated 10 k SNP data set covering the whole genome. Three known candidate regions for rheumatoid arthritis were detected. Again, the CROSS test gave the most significant results. Furthermore, both the HSS and the CROSS showed better fine-mapping accuracy than straightforward haplotype association. In conclusion, haplotype sharing methods, particularly the CROSS test, show great promise for identifying disease gene loci.