Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
16709321 Co-occurrence and comorbidities in patients with immune-mediated inflammatory disorders: a 2006 May OBJECTIVE: Research in immune-mediated inflammatory disorders (IMIDs) suggests that several diseases share disruptions in key cytokines. A common pathogenesis may present as similar patterns of disease co-occurrence and comorbidity, which could be observed through the analysis of healthcare claims datasets. METHODS: Adult patients continuously enrolled from 2001-2002 were identified in two US healthcare datasets containing medical and drug claims from health plans and self-insured employers. Patients with treatment records indicating an IMID were selected (e.g., rheumatoid arthritis, psoriasis, Crohn's disease); controls for each disorder were matched 3:1 based on age, gender, region, and previous insurance coverage. IMID cohorts and comorbidities were identified using International Classification of Diseases, 9th revision codes. Prevalence relative risk was used to assess co-occurrence and comorbidity rates in IMID cohorts and controls. Medical and drug utilization patterns were also explored. RESULTS: Findings were similar across the two datasets. IMID patients represented about 4% of the population; specific IMID prevalence matched the epidemiology literature. Patients with at least one IMID had a higher risk for another IMID when compared to controls. The risk for infectious, renal, liver, and ulcerative comorbidities was also elevated. Selected drug utilization patterns confirmed comorbidity findings. IMID patients used more healthcare resources compared to controls; findings were robust under sensitivity analyses. CONCLUSIONS: IMID patients were generally more likely than controls to have another IMID, supporting the concept that the diseases are related. These patients also had higher comorbidity rates. Findings may be limited by the nature of claims datasets and the confounding effect of current treatments. Prospective studies are needed to determine whether IMIDs have a common pathogenesis.
16567522 Atorvastatin fails to prevent the development of autoimmune diabetes despite inhibition of 2006 Apr Statins, the widely used inhibitors of cholesterol biosynthesis, also have immunomodulatory properties. Statins have recently been shown to have beneficial prophylactic and therapeutic effects in actively induced, short-term animal models of the autoimmune diseases multiple sclerosis and rheumatoid arthritis, leading to clinical trials. We therefore investigated whether statins' protective effects could be reproduced in the nonobese diabetic (NOD) mouse, a spontaneous, chronic model of autoimmune diabetes. Mice were treated with 0, 1, 10, or 50 mg x kg(-1) x day(-1) oral atorvastatin from 6 or 12 weeks of age, without effect on the rate or prevalence of diabetes development, islet infiltration, or islet major histocompatibility complex class II expression. However, there was clear evidence of a disease-relevant immunological effect of statins in vivo, since short-term (12-day) treatment significantly reduced the number of proinflammatory (gamma-interferon-producing) CD8 cells recognizing a dominant pathogenic epitope. This effect was absent in mice treated for longer periods, suggesting that atorvastatin loses efficiency in inhibiting autoantigen-specific T-cells over time. This observation may explain the discrepancy between the reported success of statins in acutely induced models and the lack of it in a chronic, spontaneous model of autoimmune disease and has implications for the adoption of such therapy in humans.
16510263 Sublethal concentrations of diverse gold compounds inhibit mammalian cytosolic thioredoxin 2006 Sep Thioredoxin reductase (TrxR) reduces thioredoxin (Trx), thereby contributing to cellular redox balance, facilitating the synthesis of deoxy-ribose sugars for DNA synthesis, and regulating redox-sensitive gene expression. Auranofin is a gold compound that potently inhibits TrxR. This inhibition is one suspected mechanism of auranofin's therapeutic benefit in the treatment of rheumatoid arthritis. The use of other gold compounds to treat cancer or inflammatory disease may rely on their ability to inhibit TrxR. In the current study, we tested the hypothesis that a variety of gold compounds may inhibit TrxR. METHODS: We exposed rat-TrxR1 to auranofin, gold sodium thiomalate, sodium aurothiosulfate, triphenyl phosphine gold chloride, or gold acetate, and measured TrxR activity ex vivo. We then compared TrxR1 inhibitory levels of gold compounds to those that inhibited mitochondrial activity of THP1 monocytes and OSC2 epithelial cells, estimated by succinate dehydrogenase activity. RESULTS: All gold compounds inhibited TrxR1 at concentrations ranging from 5 to 4000 nM (50% inhibitory concentration). The oxidation state of gold did not correlate with inhibitory potency, but ligand configuration was important. Au(I)-phosphine compounds (triphenyl phosphine gold chloride and auranofin) were the most potent inhibitors of TrxR. All TrxR1 inhibitory concentrations were sublethal to mitochondrial activity in both THP1 and OSC2 cells. CONCLUSIONS: Diverse types of gold compounds may be effective inhibitors of TrxR1 at concentrations that do not suppress cellular mitochondrial function. Inhibition may be optimized to some degree by altering the ligand configuration of the compounds. These results support future study of a variety of Au compounds for therapeutic development as inhibitors of TrxR1.
16461798 Appreciating the heterogeneity in autoimmune disease: multiparameter assessment of intrace 2005 Dec Autoimmune disease pathologies are multifactorial with complex interactive networks of cells and chemical messengers that initiate cascades of aberrant cellular activity. Rheumatoid arthritis (RA) is a chronic inflammatory disease that is characterized by systemic inflammation, destruction of the joints, and production of autoantibodies recognizing dozens of putative autoantigens. The presence of autoreactive T cells in individuals leads to pathological autoimmunity by activating additional cellular constituents to mediate inflammation and joint destruction. The etiology of RA is unknown, and knowledge is lacking of the molecular mechanisms underlying the production and subsequent regulation of autoreactive T cells and predicting patient responses to treatments. Biochemical investigations into mechanisms of the disease have relied on animal models that are helpful in dissecting elements of the disease but that are not necessarily reflective of human RA development. The study of multiple activated signaling pathways in complex populations of cells, such as peripheral blood, at the single-cell level has not previously been possible. This article describes how intracellular phosphoepitope staining methodology in conjunction with surface-cell immunophenotyping can be used to deconvolute cellular subsets and allow functional characterization of patient-derived material. Multiparameter flow cytometric analysis allows for small subpopulations-representing different cellular subsets and differentiation or activation states-to be discerned and simultaneously assessed for intracellular biochemical activities. This article also describes how single-cell signal network analysis can be used to stratify patients and may be useful for understanding mechanisms of disease progression, treatment resistance, and development of diagnostic indicators.
16436009 Ethnicity greatly influences the interleukin-1 gene cluster(IL-1b promoter, exon-5 and IL- 2005 Oct There is considerable evidence that polymorphisms in the regulatory regions of cytokine genes are highly influenced by ethnicity. Polymorphisms in interleukin 1-beta (IL-1beta) and IL-1 receptor antagonist (IL-1Ra) genes, respectively encoding a potent inflammatory agent and an antagonist, which combines with IL-1 receptors competitively, have been associated with a number of diseases like systemic lupus erythematosus, rheumatoid arthritis, sepsis, kidney diseases, and cancer. In this study, we therefore evaluated the distribution of interleukin-1 gene cluster (IL-1beta promoter region, exon-5 and IL-1Ra) gene polymorphisms in 206 healthy north Indian subjects, using PCR-based restriction analysis. We also constructed various haplotypes and estimated the linkage disequilibrium (LD). We found that genotype and allelic frequencies for these cytokines were conspicuously different when compared among different ethnic populations. The haplotype 'T-E1-1' predominated (41.7%) while the least common was 'C-E2-2' (2%) in our population. Genetic linkage between three loci of IL-1 gene showed strong association among the variants in controls (D'=0.42, p<0.001). Our results suggest that the frequency and distribution of the polymorphisms in India are substantially different from other populations and ethnic groups. Thus they signify an impact of ethnicity and provide a basis for future epidemiological and clinical studies.
16397146 Acute antiinflammatory properties of statins involve peroxisome proliferator-activated rec 2006 Feb 17 Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase used in the prevention of cardiovascular disease (CVD). In addition to their cholesterol-lowering activities, statins exert pleiotropic antiinflammatory effects, which might contribute to their beneficial effects not only on CVD but also on lipid-unrelated immune and inflammatory diseases, such as rheumatoid arthritis, asthma, stroke, and transplant rejection. However, the molecular mechanisms involved in these antiinflammatory properties of statins are unresolved. Here we show that the peroxisome proliferator-activated receptor (PPAR) alpha mediates antiinflammatory effects of simvastatin in vivo in models of acute inflammation. The inhibitory effects of statins on lipopolysaccharide-induced inflammatory response genes were abolished in PPARalpha-deficient macrophages and neutrophils. Moreover, simvastatin inhibited PPARalpha phosphorylation by lipopolysaccharide-activated protein kinase C (PKC) alpha. A constitutive active form of PKCalpha inhibited nuclear factor kappaB transrepression by PPARalpha whereas simvastatin enhanced transrepression activity of wild-type PPARalpha, but not of PPARalpha mutated in its PKC phosphorylation sites. These data indicate that the acute antiinflammatory effect of simvastatin occurs via PPARalpha by a mechanism involving inhibition of PKCalpha inactivation of PPARalpha transrepression activity.
16358083 [Association between serum markers for celiac and thyroid autoimmune diseases]. 2005 Aug Celiac disease (CD) is an autoimmune disease of the small bowel characterized by a strong genetic association with HLA - DQ2 and DQ8. Gluten is the etiological factor and the tissue enzyme transglutaminase (TGase) is its autoantigen. CD is associated with several autoimmune diseases such as type 1 diabetes, systemic lupus erythematous, rheumatoid arthritis, Sjögrens syndrome and autoimmune thyroid diseases. The aim of this study was to investigate the occurrence of serum IgA anti-endomysial and anti-human TGase antibodies in individuals with positive anti-thyroid antibody (ATA). The concordance between these two tests was also evaluated. Anti-endomysial antibodies were positive in 10 out of 456 (2.2%) and anti-human TGase were positive in 14 of 454 (3.1%) individuals with positive ATA. In control subjects they were positive in 1 of 197 (0.5%) and 2 of 198 (1%) for anti-endomysial and anti-human tissue TGase antibodies, respectively. The odds ratio (OR) for the anti-endomysial antibodies was 4.42 and for the anti-human TGase 3.12 in individuals with ATA when compared with controls. An elevated concordance index (k= 0.84) was observed between anti-endomisyal antibodies and anti-human TGase. We conclude that the determination of anti-TGase antibodies is a good test for DC screening.
16104110 [Clinical implications of new insights into the regulation of bone resorption]. 2005 Jul 23 It has recently been discovered that the receptor activator of nuclear kappaB-ligand (RANKL) plays a key role in the activation, differentiation and proliferation ofosteoblasts. The effects of RANKL are counteracted by the decoy receptor osteoprotegerin (OPG), which protects against bone resorption by preventing RANKL from coupling to its receptor RANK. An increase in the balance between RANKL and OPG leads to increased bone resorption (both locally and generalised), e.g. in patients with postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, multiple myeloma, other malignancies with skeletal metastases, or rheumatoid arthritis. The development of new anti-osteoporotic drugs, based on the restoration of the imbalance between RANKL and OPG, may be a breakthrough in optimising the treatment of patients with bone diseases. However, the results of studies on fracture reduction, the safety profile, the costs of the new drugs and their comparison with bisphosphonates, currently the gold standard in osteoporosis treatment, must be awaited.
17195873 Mode of glucocorticoid actions in airway disease. 2006 Dec 28 Synthetic glucocorticoids are the most potent anti-inflammatory agents used to treat chronic inflammatory disease, such as asthma. However, a small number (<5%) of asthmatic patients and almost all patients with chronic obstructive pulmonary disease (COPD) do not respond well, or at all, to glucocorticoid therapy. If the molecular mechanism of glucocorticoid insensitivity is uncovered, it may in turn provide insight into the key mechanism of glucocorticoid action and allow a rational way to implement treatment regimens that restore glucocorticoid sensitivity. Glucocorticoids exert their effects by binding to a cytoplasmic glucocorticoid receptor (GR), which is subjected to post-translational modifications. Receptor phosphorylation, acetylation, nitrosylation, ubiquitinylation, and other modifications influence hormone binding, nuclear translocation, and protein half-life. Analysis of GR interactions to other molecules, such as coactivators or corepressors, may explain the genetic specificity of GR action. Priming with inflammatory cytokine or oxidative/nitrative stress is a mechanism for the glucocorticoid resistance observed in chronic inflammatory airway disease via reduction of corepressors or GR modification. Therapies targeting these aspects of the GR activation pathway may reverse glucocorticoid resistance in patients with glucocorticoid-insensitive airway disease and some patients with other inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease.
17016427 Signalling platforms that modulate the inflammatory response: new targets for drug develop 2006 Oct Therapeutically controlling inflammation is essential for the clinical management of many high-prevalence human diseases. Drugs that block the pro-inflammatory cytokines tumour-necrosis factor-alpha and interleukin-1 (IL-1) can improve outcomes for rheumatoid arthritis and other inflammatory diseases but many patients remain refractory to treatment. Here we explore the need for developing new types of anti-inflammatory drugs and the emergence of novel drug targets based on the clustering of IL-1 receptors into multi-protein aggregates associated with cell adhesions. Interference with receptor aggregation into multi-protein complexes effectively abrogates IL-1 signalling. The exploration of the crucial molecules required for receptor clustering, and therefore signal transduction, offers new targets and scope for anti-inflammatory drug development.
17008373 Interstitial matrix proteins determine hyaluronan reflection and fluid retention in rabbit 2007 Jan 1 Hyaluronan (HA) retention inside the synovial cavity of joints serves diverse protective roles. We tested the hypothesis that HA retention is mediated by the network of extracellular matrix proteins in the synovial lining. Cannulated rabbit knee joints were infused with HA solution with or without pretreatment by chymopapain, a collagen-sparing protease. Trans-synovial fluid escape rate was measured and, after a period of trans-synovial filtration, samples of intra-articular fluid and subsynovial fluid were analysed for HA to assess its trans-synovial ultrafiltration. In control joints, HA ultrafiltration was confirmed by postfiltration increases in intra-articular HA concentration (259 +/- 17% of infused concentration) and reduced subsynovial concentration (30 +/- 8%; n = 11). The proportion of HA molecules reflected by the synovium was 57-75%. Chymopapain treatment increased the hydraulic permeability of the synovial lining approximately 13-fold, almost abolished the trans-synovial difference in HA concentration and reduced the HA reflected fraction to 3-7% (n = 6; P < 0.001, ANOVA). Structural studies confirmed that chymopapain treatment depleted the matrix of proteoglycans but preserved its collagen. The findings thus demonstrate that HA ultrafiltration and synovial hydraulic permeability are determined by the network of non-collagen, extracellular matrix proteins. This may be important clinically, since protease activity is raised in rheumatoid arthritis, as are HA and fluid escape.
17004019 Patient-centred advice is effective in improving adherence to medicines. 2006 Jun OBJECTIVE: To assess the effects of pharmacists giving advice to meet patients' needs after starting a new medicine for a chronic condition. METHOD: A prospective health technology assessment including a randomised controlled trial of a pharmacist-delivered intervention to improve adherence using a centralised telephone service to patients at home in England. Patients were eligible for recruitment if they were receiving the first prescription for a newly prescribed medication for a chronic condition and were 75 or older or suffering from stroke, cardiovascular disease, asthma, diabetes or rheumatoid arthritis. MAIN OUTCOME MEASURES: Incidence of non-adherence, problems with the new medicine, beliefs about the new medicine, safety and usefulness of the interventions. RESULTS: Five hundred patients consented and were randomised. At 4-week follow-up, non-adherence was significantly lower in the intervention group compared to control (9% vs. 16%, P = 0.032). The number of patients reporting medicine-related problems was significantly lower in the intervention group compared to the control (23% vs. 34%, P = 0.021). Intervention group patients also had more positive beliefs about their new medicine, as shown by their higher score on the "necessity-concerns differential" (5.0 vs. 3.5, P = 0.007). The phone calls took a median of 12 min each. Most advice was judged by experts to be safe and helpful, and patients found it useful. CONCLUSION: Overall, these findings show benefits from pharmacists meeting patients' needs for information and advice on medicines, soon after starting treatment. While a substantially larger trial would be needed to confirm that the effect is real and sustained, these initial findings suggest the service may be safe and useful to patients.
16971954 Haplotype-specific gene expression profiles in a telomeric major histocompatibility comple 2006 Dec The telomeric class III region of the major histocompatibility complex is gene dense, but apart from the three tumour necrosis factor (TNF) superfamily members (TNF, lymphotoxin alpha and lymphotoxin beta) little is known of the expression and function of the majority of the genes. Recent genetic studies in autoimmune diseases, particularly rheumatoid arthritis (RA), have suggested a human leukocyte antigen (HLA)-DR-independent disease effect in this region. To gain further insights into these associations, we used lipopolysaccharide-stimulated human macrophages to examine inducible mRNA expression and genotype-phenotype relationships for genes in this region. Following stimulation in addition to the expected induction of TNF mRNA, a 14-fold increase of ATP6V1G2 at 18 h (P<0.001) was seen, whereas B-associated transcript (BAT)2 (P<0.001) and leucocyte-specific transcript (LST)1 (P<0.001) were both downregulated. By genotyping single-nucleotide polymorphisms spanning a 70 kb interval centred on the TNF locus, we constructed haplotypes and determined associated expression profiles for 10 genes in the cluster using quantitative real-time polymerase chain reaction. Overexpression of BAT1 mRNA was associated with carriers of a haplotype containing the LST1 marker transmitted to RA cases in a family study and also DRB1(*)15 associated with susceptibility to nephritis in systemic lupus erythematosus. The implications of our findings for the understanding of genetic associations with disease susceptibility in this region are discussed.
16939569 Etanercept decreases tumor necrosis factor-alpha activity in chronic wound fluid. 2006 Jul High levels of tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine, are present in the wound fluid of chronic nonhealing wounds. This leads to increased inflammation, cytokine expression, and ultimately results in impaired wound healing and tissue destruction. Etanercept is a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1. It is an effective inhibitor of TNF-alpha and has been shown to provide rapid and sustained improvement in rheumatoid arthritis by acting as a soluble receptor binding TNF-alpha and preventing its proinflammatory activities. Therefore, the aim of this study was to determine whether Etanercept could inhibit TNF-alpha activity in chronic wound fluid. Wound fluid was collected from the venous leg ulcers of 16 different patients. The effect of Etanercept on TNF-alpha activity was evaluated using both a TNF-alpha bioassay and an enzyme-linked immunoassay. Etanercept was found to reduce the cytotoxic effect of chronic wound fluid on L929 fibroblasts by approximately 30% and neutralized TNF-alpha binding in the enzyme-linked immunoassay by up to 80%. Direct application of Etanercept to chronic wounds may therefore reduce the inflammatory activity of TNF-alpha, which could reduce the chronicity of venous leg ulcers and thus aid in the healing of these wounds.
16886149 Comparison of epidemiological, clinical, and biological features of invasive aspergillosis 2006 Sep 1 BACKGROUND: Invasive aspergillosis is an opportunistic infection that occurs mainly among patients with prolonged neutropenia. Few data are available on invasive aspergillosis in nonneutropenic patients. METHODS: The aim of this survey was to compare neutropenic and nonneutropenic patients who had received a diagnosis of invasive aspergillosis at our institution during a 6-year period. RESULTS: Among the 88 cases of invasive aspergillosis analyzed here, 12 were histologically proven, 52 were probable, and 24 were possible. Forty-seven percent of cases were diagnosed in the intensive care unit, and 40% were diagnosed in hematology units. Neutropenia was a risk factor for 52 patients (59%), most of whom had hematological or solid malignancies. Among the 36 nonneutropenic patients (41%), the main underlying conditions were steroid-treated chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, giant-cell arteritis, and microvascular disorders; 10 patients were recipients of solid-organ transplants, and 1 patient was seropositive for human immunodeficiency virus. The distribution of proven and probable invasive aspergillosis was similar for neutropenic and nonneutropenic patients. The mortality rate was 71.5% overall and was significantly higher among nonneutropenic patients than among neutropenic patients (89% vs. 60%; P<.05). Compared with neutropenic patients, nonneutropenic patients were significantly less likely to have symptoms of invasive aspergillosis and more likely to have frequent intercurrent pneumonia due to another microorganism. The sensitivity of mycological examination of bronchoalveolar lavage fluid specimens was higher for nonneutropenic patients than for neutropenic patients (85% vs. 58%; P<.05), whereas the sensitivity of antigenemia was the same for the 2 populations (65% vs. 64%). Findings on thoracic computed tomographs were similar, except that segmental areas of consolidation occurred more frequently among neutropenic patients. CONCLUSION: This survey at a whole institution underlines the high number of cases of invasive aspergillosis among nonneutropenic patients, with an overall mortality rate that was significantly higher than that for neutropenic patients.
16845632 Tumor-necrosis-factor blockers: differential effects on mycobacterial immunity. 2006 Aug 15 BACKGROUND: Tumor necrosis factor (TNF) plays a pathogenic role in rheumatoid arthritis but is essential for antimycobacterial host defenses. The risk of reactivation of latent Mycobacterium tuberculosis infection is greater with the TNF monoclonal antibody infliximab than with the soluble TNF receptor etanercept. The basis of this difference is not known. METHODS: The effects that the monoclonal antibodies infliximab and adalimumab and the receptor etanercept have on antimycobacterial immune functions were studied by use of therapeutic drug concentrations in whole-blood culture. RESULTS: Infliximab and adalimumab reduced the proportion of tuberculosis-responsive (CD69(+)) CD4 cells by 70% and 49%, respectively (P<.05), and suppressed antigen-induced interferon (IFN)- gamma production by 70% and 64% (P<.05), respectively; in contrast, etanercept produced no significant effect. Interleukin-10 production was equally suppressed by all 3 drugs. Adalimumab and etanercept had divergent, concentration-dependent effects on control of intracellular growth of M. tuberculosis. None of the drugs induced significant levels of apoptosis or necrosis, in either monocytes or T cells. CONCLUSIONS: The tuberculosis risk posed by infliximab may reflect its combined effects on TNF and IFN- gamma .
16796622 Quinine sulfate inhibits invasion of some bacterial skin pathogens. 2006 Jun BACKGROUND: As some of the many patients who receive antimalarials for the treatment of noninfective inflammatory diseases (lupus erythematosus, collagen vascular diseases, rheumatoid arthritis, and others) are also immunosuppressed because of their disease and/or treatments, and may have concomitant bacterial infections, we investigated the effect of these drugs on the growth and invasion of several bacteria that are commonly associated with skin and soft tissue infections to determine whether they could protect against such conditions and obviate the need for an additional antibiotic drug. METHODS: The effect of quinine sulfate (QS) at concentrations of 50 and 100 microm on the entry process of Enterobacter agglomerans, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae into Caco-2 cells was studied during the infection period. The invasive efficiency was expressed as the number of viable internalized bacteria obtained by counting the colony-forming units (CFUs). RESULTS: The invasive ability of E. agglomerans and S. aureus was significantly inhibited by 50 and 100 microm QS in a dose-dependent manner when the drug was added to Caco-2 cell monolayers during the infection period; however, QS had no significant effect on the internalization of P. aeruginosa or K. pneumoniae. DISCUSSION AND CONCLUSIONS: Antimalarial drugs are currently widely used to treat patients with autoimmune dermatologic and rheumatologic diseases, and have also been recently proposed as additional therapy for patients with human immunodeficiency virus (HIV) infection. These patients, who are often immunocompromised, may receive a secondary advantage from these antimalarials, which may provide some protection against staphylococci (amongst the most important human pathogens causing many superficial and systemic infections) and E. agglomerans.
16741469 An analysis of the risk of hip dislocation with a contemporary total joint registry. 2006 Jun Dislocation rates after total hip arthroplasty in a community setting have not been well documented. We used a community based joint registry to evaluate hip dislocations that occurred within 1 year after total hip arthroplasty. We evaluated patient, implant, and technical factors associated with dislocation, including primary versus revision surgery, femoral head size (28 mm versus > or = 32 mm), operative time, surgeon volume, surgical approach, age, gender, diagnosis, American Society of Anesthesiologists (ASA) classification, and body mass index (BMI). There were 1693 primary total hip arthroplasties and 277 revision procedures performed from 2001-2003. The overall dislocation rate was 1.7% for primary total hip arthroplasties and 5.1% for revision procedures. Patients with ASA scores of 3 or 4 had a 2.3-fold dislocation increase compared with patients with scores of 1 or 2. Patients with rheumatoid arthritis had an increased risk of dislocation. The dislocation rates for primary total hip arthroplasty were 2% for 28 mm heads and 0.7% for heads > or = 32 mm. The surgeon's patient volume, surgical approach, operative time, and body mass index had no effect on dislocation.
16529763 Improved solubilization of Celecoxib in U-type nonionic microemulsions and their structura 2006 Jul 1 Celecoxib (clxb) is an important drug for treatment of rheumatoid arthritis and osteoarthritis by specifically inhibiting the enzyme cyclooxygenase-2 (COX-2). Clxb is a type 2 drug characterized by low water solubility (<5 mug/ml) and fast transmembrane transport. The present formulations require high dosage since the transmembrane transport fluctuates and is very difficult to control. Dissolving the drug within an oil phase was not practical since its dissolution was very small and its dispersion in water was impossible. In our recent studies, we learned to construct U-type phase diagrams and to formulate reverse microemulsions (oil-based concentrates) that are progressively and fully dilutable with aqueous phase. In the present study, we solubilized clxb in nanostructures of reverse micelles of U-type nonionic microemulsions that consisted of R(+)-limonene, alcohol, propylene glycol (PG), and hydrophilic surfactant (Tween 60). The solubilization capacity of the drug in these systems is many times higher than in either the oil or the aqueous phase. The clxb solubilized microemulsions are fully diluted with aqueous phase without phase separation. The solubilization capacity decreases as the water content increases. Electrical conductivity, viscosity, and self-diffusion (SD) coefficients of the microemulsion components were measured along a suitable water dilution line. The three major microemulsion regions were detected and the transitions between the W/O to bicontinuous phase and from this phase to the O/W droplets were identified (at 30 and 70 wt% aqueous phase, respectively). From the SD coefficients, it was found that the drug is initially solubilized at the interface of the W/O droplets and there are no significant structural changes. The transition to a bicontinuous phase occurs at the same water content as in the empty (i.e., without drug) system. From the viscosity profiles, we concluded that the drug affects the structure of the bicontinuous phase as reflected in the water content at which the oil-continuous network is destroyed and full inversion occurs (50 vs 55 wt% in the drug-loaded system). Upon further dilution the drug remains solubilized at the interface and is oriented with its hydrophilic part facing the water, and is strongly affects the inversion to O/W droplets. From Small Angle X-ray Scattering (SAXS) measurements we learned that the drug effects the structure of microemulsion droplets and forms "ill-defined structures," probably less spherical. Yet, the overall droplet sizes at the high dilutions did not change very much.
16386648 DRB1-TNF-alpha-TNF-beta haplotype is strongly associated with severe aortoiliac occlusive 2005 Oct Severe aortoiliac occlusive disease (AOD) is a clinical manifestation of peripheral arteriosclerosis. Atherosclerosis has been associated with some human leukocyte antigen (HLA)-DRB1 alleles, stressing its relationship with autoimmune or inflammatory disorders. Additionally, in rheumatoid arthritis patients, the DRB1*0404 allele is specifically associated with endothelial dysfunction. Our objective was to assess the role of class II HLA alleles in the susceptibility to AOD; a combined study of the nearby tumor necrosis factor (TNF) locus was also performed. We included 104 AOD patients and 504 healthy controls from Madrid. DRB1 typing and DRB1*04 subtyping was done by polymerase chain reaction amplification followed by hybridization with specific oligonucleotides. TNF-alpha and TNF-beta microsatellites were studied by polymerase chain reaction and capillary electrophoresis. None of the markers was associated with AOD, although a trend was observed for DRB1*0404 (OR = 2.18; p = 0.05). However, among DRB1*0404 individuals, the TNFa11-b4 pair was present more frequently in patients than in controls (OR = 16.0; p = 0.007). The combined appearance of TNFa11-b4 and DRB1*0404 was much more frequent in patients than in controls (OR = 5.92; p = 0.0013), a result enhanced by haplotypic estimates (OR = 10.0; p = 0.00017). Our results show that the HLA region modulates the predisposition to AOD. More specifically, they suggest that an extended haplotype encompassing DRB1*0404 and TNFa11-b4 carries a genetic factor conferring susceptibility to AOD.