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ID PMID Title PublicationDate abstract
21044313 Identification of a variant form of tyrosine phosphatase LYP. 2010 Nov 2 BACKGROUND: Protein tyrosine phosphatases (PTPs) are important cell signaling regulators with major pathological implications. LYP (also known as PTPN22) is an intracellular enzyme initially found to be predominately expressed in lymphocytes. Importantly, an allelic R620W variant of LYP is strongly associated with multiple autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and autoimmune thyroid disease. RESULTS: In this study, we isolated a novel isoform of LYP designated LYP3. LYP3 differs from LYP1, the known isoform of LYP, in that it lacks a 28 amino acid segment right after the R620W site embedded in a proline-rich protein-protein interaction motif. Genomic sequence analysis revealed that LYP3 resulted from alternative splicing of the LYP gene located on chromosome 1p 13.3-13.1. Reverse transcription PCR analyses of 48 human tissues demonstrated that both LYP1 and LYP3 are predominantly expressed in primary and secondary lymphoid tissues but the relative expression levels of the two isoforms varies in different human tissues and individuals. CONCLUSIONS: We thus identified a new variant form of LYP and conducted a comprehensive analysis of LYP tissue expressions. Considering the pathogenesis of LYP R620W, we believe that the expression of LYP3 may have an important role in regulating activity and function of LYP and may be implicated in autoimmune diseases.
20737265 Ethnic differences in femur geometry in the women's health initiative observational study. 2011 May SUMMARY: Participants in the observational study of the Women's Health Initiative (WHI) were studied to determine if ethnic differences in femur geometry can help to explain differences in hip fracture rates. Structural differences in femurs of African and Mexican-American women appear to be consistent with lower rates of hip fractures vs. whites. INTRODUCTION: Ethnic origin has a major influence on hip fractures, but the underlying etiology is unknown. We evaluated ethnic differences in hip fracture rates among 159,579 postmenopausal participants in the WHI then compared femur bone mineral density (BMD) and geometry among a subset with dual X-ray absorptiometry (DXA) scans of the hip and total body. METHODS: The subset included 8,206 non-Hispanic whites, 1,476 African-American (AA), 704 Mexican-American (MA), and 130 Native Americans (NA). Femur geometry derived from hip DXA using hip-structure analysis (HSA) in whites was compared to minority groups after adjustment for age, height, weight, percent lean mass, neck-shaft angle and neck length, hormone use, chronic disease (e.g., diabetes, rheumatoid arthritis, cancer), bone active medications (e.g., corticosteroids, osteoporosis therapies), and clinical center. RESULTS: Both AA and MA women suffered hip fractures at half the rate of whites while NA appeared to be similar to whites. The structural advantage among AA appears to be due to a slightly narrower femur that requires more bone tissue to achieve similar or lower section moduli (SM) vs. whites. This also underlies their higher BMD (reduces region area) and lower buckling ratios (buckling susceptibility). Both MA and NA women had similar advantages vs. whites at the intertrochanter region where cross-sectional area and SM were higher but with no differences at the neck. NA and MA had smaller bending moments vs. whites acting in a fall on the hip (not significant in small NA sample). Buckling ratios of MA did not differ from whites at any region although NA had 4% lower values at the IT region. CONCLUSION: Differences in the geometry at the proximal femur are consistent with the lower hip fracture rates among AA and MA women compared to whites.
20520647 B cells as therapeutic targets in SLE. 2010 Jun The use of B-cell targeted therapies for the treatment of systemic lupus erythematosus (SLE) has generated great interest owing to the multiple pathogenic roles carried out by B cells in this disease. Strong support for targeting B cells is provided by genetic, immunological and clinical observations that place these cells at the center of SLE pathogenesis, as initiating, amplifying and effector cells. Interest in targeting B cells has also been fostered by the successful use of similar interventions to treat other autoimmune diseases such as rheumatoid arthritis, and by the initial promise shown by B-cell depletion to treat SLE in early studies. Although the initial high enthusiasm has been tempered by negative results from phase III trials of the B-cell-depleting agent rituximab in SLE, renewed vigor should be instilled in the field by the convergence of the latest results using agents that inhibit B-cell-activating factor (BAFF, also known as BLyS and tumor necrosis factor ligand superfamily, member 13b), further analysis of data from trials using rituximab and greatly improved understanding of B-cell biology. Combined, the available information identifies several new avenues for the therapeutic targeting of B cells in SLE.
20445007 Delayed addition of glucocorticoids selectively suppresses cytokine production in stimulat 2010 Jun Glucocorticoids (GC) are potent drugs proven to effectively treat inflammatory diseases, although patients typically begin therapy after the onset of symptoms. Clinical studies with cytokine inhibitors prove that these mediators drive inflammatory responses in diseases such as rheumatoid arthritis and Crohn's disease. Despite the clear sequence of cytokine-induced inflammation followed by effective GC treatment, most basic science investigations have examined the ability of GC to prevent an inflammatory response rather than halt its progression. The current studies used the Toll-like receptor 2 (TLR2) agonist palmitoyl(3)-cysteine-serine-lysine(4) (PAM) or the TLR4 agonist lipopolysaccharide (LPS) to stimulate human whole blood and determine whether postponing the addition of the GC dexamethasone (DEX) limits its ability to decrease cytokine production. Twenty-four hours after stimulation, tumor necrosis factor (TNF), interleukin-1beta (IL-1beta), IL-6, and IL-8 levels were measured, in addition to the cytokine inhibitors IL-1 soluble receptor II (SRII), IL-1 receptor antagonist, and TNF SRII. LPS rapidly induced all of the proinflammatory mediators over 24 h while failing to induce any of the cytokine inhibitors. PAM stimulation also induced IL-1beta, IL-6, and IL-8. Concomitant addition of DEX plus LPS or PAM significantly suppressed all cytokine levels. Delaying the addition of DEX until 6 h after LPS stimulation failed to decrease TNF or IL-6. In contrast, delayed DEX addition significantly suppressed PAM-induced IL-1beta, IL-6, or IL-8 and also suppressed LPS-induced IL-1beta and IL-8. Our results show that cytokines which typically increase in concentration between 6 and 24 h after stimulation were significantly suppressed by the addition of DEX 6 h after stimulation.
20353769 Inhibition of osteoclastogenic differentiation by Ikarisoside A in RAW 264.7 cells via JNK 2010 Jun 25 Osteoclasts are specialized bone-resorbing cells derived from multipotent myeloid progenitor cells. They play a crucial homeostatic role in skeletal modeling and remodeling and destroy bone in many pathologic conditions. Receptor activator of NF-kappaB ligand (RANKL) is essential to osteoclastogenesis. In this study, we investigated the effects of Ikarisoside A, isolated from Epimedium koreanum (Berberidaceae), on osteoclastogenesis in RANKL-treated murine monocyte/macrophage RAW 264.7 cells. The results indicate that Ikarisoside A is a potent inhibitor of osteoclastogenesis in RANKL-stimulated RAW 264.7 cells as well as in bone marrow-derived macrophages. The inhibitory effect of Ikarisoside A resulted in decrease of osteoclast-specific genes like matrix metalloproteinase 9 (MMP9), tartrate-resistant acid phosphatase (TRAP), receptor activator of NF-kappaB (RANK), and cathepsin K. Moreover, Ikarisoside A blocked the resorbing capacity of RAW 264.7 cells on calcium phosphate-coated plates. Ikarisoside A also has inhibitory effects on the RANKL-mediated activation of NF-kappaB, JNK, and Akt. Finally, Ikarisoside A clearly decreased the expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1) as well as the transcriptional activity of NFATc1, the master regulator of osteoclast differentiation. The data indicate that Ikarisoside A has potential for use in treatment of diseases involving abnormal bone lysis such as osteoporosis, rheumatoid arthritis, and periodontal bone erosion.
20304810 Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting 2010 Jul 15 The bone and immune systems are closely related through cellular and molecular interactions. Because bone-resorbing osteoclasts (OCs) are derived from the monocyte/macrophage lineage, similar to dendritic cells (DCs), we hypothesized that OCs could serve as antigen-presenting cells (APCs) to activate T cells. In this study, OCs were generated from human monocytes with stimulation by receptor activator of nuclear factor kappaB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Results showed that, similar to DCs, OCs express major histocompatibility complex (MHC) classes I and II, and CD80, CD86, and CD40; and uptake soluble antigens. OCs secrete interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha), but not IL-12p70. OCs present allogeneic antigens and activate both CD4+ and CD8+ alloreactive T cells in an MHC-restricted fashion. OCs also present soluble protein tetanus toxoid to activate autologous CD4+ T cells. These findings indicate that OCs can function as APCs and activate both CD4+ and CD8+ T cells. Thus, our study provides new insight into the effect of OCs on the immune system and may help develop novel strategies for treating diseases such as rheumatoid arthritis and multiple myeloma, which affect both the bone and immune systems.
20231195 Lack of association between the rs6920220 (G/A) polymorphism of the 6q23 region and biopsy 2010 May OBJECTIVE: Recently, 2 independent studies have identified an association between several single-nucleotide polymorphisms (SNP) located in the 6q23 chromosomal region and rheumatoid arthritis (RA). Like RA, giant cell arteritis (GCA) is also a complex polygenic disease in which more than 1 genetic locus is likely to contribute to disease susceptibility and clinical expression. We analyzed the involvement of the rs6920220 (G/A) polymorphism from the 6q23/TNFAIP3 gene region in susceptibility to GCA. METHODS: Two hundred twenty patients with biopsy-proven GCA and 490 matched controls were assessed. DNA from patients and controls was obtained from peripheral blood. Samples were geno-typed for the 6q23 region rs6920220 using a TaqMan allele discrimination assay and by polymerase chain reaction (PCR) amplification. After PCR, the genotype of each sample was attributed automatically by allelic-specific fluorescence using the ABI Prism 7900 sequence detection system. RESULTS: No significant differences in the genotype distribution between patients with GCA and controls for the rs6920220 (G/A) polymorphism were found. No significant differences were observed when patients with GCA were stratified according to the presence of specific clinical features of the disease such as polymyalgia rheumatica or severe ischemic manifestations or specific visual ischemic complications. CONCLUSION: Our results show no involvement of this 6q23/TNFAIP3 gene region SNP in the susceptibility to or clinical expression of GCA.
20170852 Large diameter head metal-on-metal bearings total hip arthroplasty: preliminary results. 2010 Feb INTRODUCTION: Although the use of the metal-on-metal bearings has been validated over the long term in total hip arthroplasty (THA) for standard 28 and 32 mm diameters, and over the medium term in resurfacing procedures, the use of larger metal head size in conventional THA has not yet been extensively reported. HYPOTHESIS: The large-diameter metal-on-metal head is beneficial in terms of implant stability without altering the result in terms of function and bone fixation compared to the standard 28 and 32 mm diameters. OBJECTIVE: The objective was to test this hypothesis by assessing the short-term clinical and radio graphic results of a metal-on-metal large-diameter heads THA system, using cups from the resurfacing hip concept. MATERIAL AND METHODS: We conducted a retrospective study on a continuous series of 106 uncemented acetabular cups (Durom) implanted in 102 patients (mean age, 66 years): 93 cases of primary or secondary coxarthrosis, 11 cases of aseptic osteonecrosis, one fracture of the femoral neck, and one case of rheumatoid arthritis of the hip. At 30 months of follow-up,the Harris Hip Score and the Merle d'Aubigné (PMA) score were calculated. The radiological investigation included comparison of the implant head with native head diameters, variations of acetabular center of rotation, inspection for implant migration, and search for a gap or radiolucent line. RESULTS: The series included two post-traumatic dislocations as well as spontaneously receding tendinitis of the gluteus medius with no further recurrence. The mean Harris Hip Score improved from 49.3 preoperatively to 91.6 at the latest follow-up and the mean PMA score ranged from 12 to 17. The results were excellent for 70 cases, good for 31 cases, fair for three cases, and poor for two cases. In the last five cases, the overall results were undermined by low pain subscore,with no identifiable explanation. Restoration of the original head diameter was verified for 65 hips. No cup migration was observed. Measurement of the acetabular centre of rotation showed a mean lateralization of 1.1mm. Of the 67 immediate postoperative gaps, only two did no disappear at follow-up. Implant head diameter, cup position, and the existence of a gap were not correlated with the clinical results. DISCUSSION: These results are comparable to 28 mm-diameter metal-on-metal heads in uncemented cups but with improved stability but without demonstrable alteration of the quality of the bone fixation. We found no mechanical or medical cause that could explain the five cases of persistent pain leading to fair or poor results. Long-term follow-up will validate these theoretical advantages in terms of wear and implant survival. LEVEL OF EVIDENCE: IV. Retrospective series.
20135960 [Artificial total hip arthroplasty with collum femoris preserving for treating hip joint]. 2010 Jan OBJECTIVE: To evaluate the therapeutic outcome of artificial total hip arthroplasty (THA) with collum femoris preserving for hip joint disease in young and middle-aged patients. METHODS: From March 2002 to March 2005, 26 cases (31 hips) of hip joint disease were treated with artificial THA with collum femoris preserving, including 19 males (23 hips) and 7 females (8 hips) and aged 32-48 years with an average of 37 years. In 31 hips, 17 left hips and 14 right hips were involved. There were 9 cases of osteoarthritis of the hip joint caused by avascular necrosis of the femoral head (ANFH), 7 cases of ANFH, 3 cases of femoral head necrosis caused by dysplasia of acetabular, 1 case of osteoarthritis of the hip joint caused by ankylosing spondylitis, and 2 cases of rheumatoid arthritis; the course of disease was 2-11 years (5.6 years on average). Two cases of femoral neck fracture (Garden IV), and 2 cases of non-union femoral neck fractures (1 for Garden III and 1 for Garden IV), the course of disease was 5 days, 24 months, and 26 months. The prime symptoms were pain, difficult walk and limp. All patients were taken X-ray to exclude osteoporosis. RESULTS: The right distal femur prosthesis of a bilateral patient cracked owing to excessive amputation of collum femoris, and fracture healed after symptomatic treatment. All the incisions healed by first intention and no complications occurred. All patients were followed up for 4-7 years, with an average of 5.6 years. One case had poor hip function because he did not follow rehabilitation procedure, and the others achieved good outcome with normal gait. One case complained of persistent pain 6 months after operation, and was relieved by administration of some non-steroidal anti-inflammatory drugs and anti-osteoporosis drugs 6 months later. The X-ray films after operation and at last follow up showed good location of prosthesis and no bone resorption. Harris score at last follow-up was 91.31 +/- 0.77, and it was significantly higher than that before operation (50.88 +/- 0.90), (P < 0.05). The excellent and good rate was 93.5% (excellent in 11 hips, good in 18 hips, and fair in 2 hips). CONCLUSION: Artificial THA with collum femoris preserving can retain more bone, be easier for revision, and has an excellent outcome.
19933746 Acid-sensing ion channel 3 expressed in type B synoviocytes and chondrocytes modulates hya 2010 May BACKGROUND: Rheumatoid arthritis is an inflammatory disease marked by intra-articular decreases in pH, aberrant hyaluronan regulation and destruction of bone and cartilage. Acid-sensing ion channels (ASICs) are the primary acid sensors in the nervous system, particularly in sensory neurons and are important in nociception. ASIC3 was recently discovered in synoviocytes, non-neuronal joint cells critical to the inflammatory process. OBJECTIVES: To investigate the role of ASIC3 in joint tissue, specifically the relationship between ASIC3 and hyaluronan and the response to decreased pH. METHODS: Histochemical methods were used to compare morphology, hyaluronan expression and ASIC3 expression in ASIC3+/+ and ASIC3-/- mouse knee joints. Isolated fibroblast-like synoviocytes (FLS) were used to examine hyaluronan release and intracellular calcium in response to decreases in pH. RESULTS: In tissue sections from ASIC3+/+ mice, ASIC3 localised to articular cartilage, growth plate, meniscus and type B synoviocytes. In cultured FLS, ASIC3 mRNA and protein was also expressed. In FLS cultures, pH 5.5 increased hyaluronan release in ASIC3+/+ FLS, but not ASIC3-/- FLS. In FLS from ASIC3+/+ mice, approximately 50% of cells (25/53) increased intracellular calcium while only 24% (14/59) showed an increase in ASIC3-/- FLS. Of the cells that responded to pH 5.5, there was significantly less intracellular calcium increases in ASIC3-/- FLS compared to ASIC3+/+ FLS. CONCLUSION: ASIC3 may serve as a pH sensor in synoviocytes and be important for modulation of expression of hyaluronan within joint tissue.
19279127 Urinary endothelin-1 in chronic kidney disease and as a marker of disease activity in lupu 2009 Jun Chronic inflammation contributes to the development and progression of chronic kidney disease (CKD). Identifying renal inflammation early is important. There are currently no specific markers of renal inflammation. Endothelin-1 (ET-1) is implicated in the pathogenesis of CKD. Thus, we investigated the impact of progressive renal dysfunction and renal inflammation on plasma and urinary ET-1 concentrations. In a prospective study, plasma and urinary ET-1 were measured in 132 subjects with CKD stages 1 to 5, and fractional excretion of ET-1 (FeET-1) was calculated. FeET-1, serum C-reactive protein (CRP), urinary ET-1:creatinine ratio, and urinary albumin:creatinine ratio were also measured in 29 healthy volunteers, 85 subjects with different degrees of inflammatory renal disease but normal renal function, and in 10 subjects with rheumatoid arthritis without renal involvement (RA). In subjects with nephritis associated with systemic lupus erythematosus (SLE), measurements were done before and after 6 mo of treatment. In subjects with CKD, plasma ET-1 increased linearly as renal function declined, whereas FeET-1 rose exponentially. In subjects with normal renal function, FeET-1 and urinary ET-1:creatinine ratio were higher in SLE subjects than in other groups (7.7 +/- 2.7%, 10.0 +/- 3.0 pg/mumol, both P < 0.001), and correlated with CRP, and significantly higher than in RA subjects (both P < 0.01) with similar CRP concentrations. In SLE patients, following treatment, FeET-1 fell to 3.6 +/- 1.4% (P < 0.01). Renal ET-1 production increases as renal function declines. In subjects with SLE, urinary ET-1 may be a useful measure of renal inflammatory disease activity while measured renal function is still normal.
18951733 EBV-associated diffuse large B-cell lymphoma in a psoriatic treated with methotrexate. 2009 Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a lymphoid proliferation or lymphoma in a patient immunosuppressed with MTX, which is usually administered for treating autoimmune diseases. The majority of MTX-LPD cases develop in patients with rheumatoid arthritis and occasionally with psoriasis who had been treated with MTX. Here, we report on a 50-year-old Taiwanese male with severe psoriasis, who received high doses of MTX. The patient developed EBV-positive MTX-LPD at nodal and extranodal sites. The diffuse and polymorphic lymphoid infiltrate consisted predominantly of immunoblasts and plasmablasts expressing B-cell markers, CD138, Epstein-Barr virus (EBV)-LMP1, and EBNA2, and these were monotypic for kappa light chain. The tumor cells were also positive for EBV by in situ hybridization. These findings indicated a type III latency infection of EBV. The patient died of progressive disease after 19 months. A review of the previously reported cases shows that MTX-LPD, in association with psoriasis, occurs in middle-aged males. The tumors are diffuse large B-cell lymphomas with immunoblastic morphology, and frequently show plasmacytic differentiation.
19204730 Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. 2009 Mar 26 Osteoclasts are the only somatic cells with bone-resorbing capacity and, as such, they have a critical role not only in normal bone homeostasis (called 'bone remodelling') but also in the pathogenesis of bone destructive disorders such as rheumatoid arthritis and osteoporosis. A major focus of research in the field has been on gene regulation by osteoclastogenic cytokines such as receptor activator of NF-kappaB-ligand (RANKL, also known as TNFSF11) and TNF-alpha, both of which have been well documented to contribute to osteoclast terminal differentiation. A crucial process that has been less well studied is the trafficking of osteoclast precursors to and from the bone surface, where they undergo cell fusion to form the fully differentiated multinucleated cells that mediate bone resorption. Here we report that sphingosine-1-phosphate (S1P), a lipid mediator enriched in blood, induces chemotaxis and regulates the migration of osteoclast precursors not only in culture but also in vivo, contributing to the dynamic control of bone mineral homeostasis. Cells with the properties of osteoclast precursors express functional S1P(1) receptors and exhibit positive chemotaxis along an S1P gradient in vitro. Intravital two-photon imaging of bone tissues showed that a potent S1P(1) agonist, SEW2871, stimulated motility of osteoclast precursor-containing monocytoid populations in vivo. Osteoclast/monocyte (CD11b, also known as ITGAM) lineage-specific conditional S1P(1) knockout mice showed osteoporotic changes due to increased osteoclast attachment to the bone surface. Furthermore, treatment with the S1P(1) agonist FTY720 relieved ovariectomy-induced osteoporosis in mice by reducing the number of mature osteoclasts attached to the bone surface. Together, these data provide evidence that S1P controls the migratory behaviour of osteoclast precursors, dynamically regulating bone mineral homeostasis, and identifies a critical control point in osteoclastogenesis that may have potential as a therapeutic target.
20484920 Deficiency in the serum-derived hyaluronan-associated protein-hyaluronan complex enhances 2010 BACKGROUND: Serum-derived hyaluronan (HA)-associated proteins (SHAPs), the heavy chains of inter-α-trypsin inhibitor, covalently bind to HA to form the SHAP-HA complex. The SHAP-HA complex is involved in the pathophysiology of inflammatory diseases, including rheumatoid arthritis. We investigated whether this complex is also involved in airway allergy. METHODS: SHAP-HA-deficient (bikunin knockout, KO) mice and wild-type (WT) mice were immunized twice by intraperitoneal injection of ovalbumin (OVA) and exposed to aerosol OVA for 30 min each day for 2 weeks. Twenty-four hours after the final OVA challenge, airway responsiveness to inhaled methacholine (MCh) was measured, and analysis of bronchoalveolar lavage fluid (BALF) and lung histological studies were done. RESULTS: Compared to WT mice, KO mice showed higher airway hyperresponsiveness to inhaled MCh and higher late-phase responses to OVA whereas the early-phase responses were similar. Cell differentials of BALF showed an increased number of macrophages and neutrophils in KO mice. Furthermore, decreased concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1) were found in BALF from KO mice whereas the levels of Th1 and Th2 cytokines were not different from WT mice. Immunochemical study of the lung tissues revealed stronger staining of sTNFR1 in KO than in WT mice. CONCLUSIONS: Our results suggest that in this murine asthma model, the SHAP-HA complex has an inhibitory role in the development of airway hyperresponsiveness and allergic airway inflammation which may be attributed, at least in part, to negative feedback mechanisms exerted by sTNFR1, the shedding of which from the cell surface might also be promoted by the SHAP-HA complex.
20483727 Structural and functional insights of RANKL-RANK interaction and signaling. 2010 Jun 15 Bone remodeling involves bone resorption by osteoclasts and synthesis by osteoblasts and is tightly regulated by the receptor activator of the NF-kappaB ligand (RANKL)/receptor activator of the NF-kappaB (RANK)/osteoprotegerin molecular triad. RANKL, a member of the TNF superfamily, induces osteoclast differentiation, activation and survival upon interaction with its receptor RANK. The decoy receptor osteoprotegerin inhibits osteoclast formation by binding to RANKL. Imbalance in this molecular triad can result in diseases, including osteoporosis and rheumatoid arthritis. In this study, we report the crystal structures of unliganded RANK and its complex with RANKL and elucidation of critical residues for the function of the receptor pair. RANK represents the longest TNFR with four full cysteine-rich domains (CRDs) in which the CRD4 is stabilized by a sodium ion and a rigid linkage with CRD3. On association, RANK moves via a hinge region between the CRD2 and CRD3 to make close contact with RANKL; a significant structural change previously unseen in the engagement of TNFR superfamily 1A with its ligand. The high-affinity interaction between RANK and RANKL, maintained by continuous contact between the pair rather than the patched interaction commonly observed, is necessary for the function because a slightly reduced affinity induced by mutation produces significant disruption of osteoclast formation. The structures of RANK and RANKL-RANK complex and the biological data presented in the paper are essential for not only our understanding of the specific nature of the signaling mechanism and of disease-related mutations found in patients but also structure based drug design.
20022534 Socioeconomic impact of ankylosing spondylitis in Tunisia. 2010 Jan OBJECTIVE: Ankylosing spondylitis (AS) is the second most common chronic inflammatory joint disease after rheumatoid arthritis and causes substantial functional impairment, two features that generate a heavy socioeconomic burden. Here, our objective was to assess the socioeconomic impact of AS and to identify factors associated with higher costs. PATIENTS AND METHODS: We retrospectively reviewed the medical charts of 50 patients with AS seen at the Monastir Public Health Service Hospital over the 6-month period from March to September 2006. The following were evaluated: direct costs of medical care; indirect costs related to work incapacity; and impact on marital life, offspring, social activities, and activities of daily living. RESULTS: There were 42 men and eight women (male-to-female ratio, 5.25) with a mean age of 38.9+/-10.8 years (range, 19-60 years). The median mean direct cost of medical care for AS was 426.072 Tunisian Dinars (TND) (266.295 euro) per year, and the interquartile range (IQR) was 270.468 TND. Of the 34 patients who had paid employment, 12 (35%) were on sick leave. The mean indirect cost was 447.4+/-294.3 TND (279.625+/-183.937 euro) per patient per year. The median mean total cost was 873.472 TND (545,92 euro) per patient per year with an IQR of 292,324 TND. Factors associated with higher costs were the use of nonsteroidal anti-inflammatory drugs and higher values of the BASDAI and BASRI. Among married patients, 44.4% reported sexual problems, which correlated with the BASMI; and 37% reported a negative reaction on the part of the healthy spouse. Adverse effects on schooling and quality of life of the children were noted in 29.6% of cases. Among single patients, 30.4% felt their disease was responsible for their unmarried status. The disease adversely affected the ability to carry out many activities of daily living (grooming in 38% of cases, housework in 76%, shopping in 92%, sporting activities in 96%, socializing in 68%, and traveling in 80%). The patients usually reported receiving support from their family, which was physical in 74% of cases, financial in 52%, and psychological in 90%. CONCLUSION: Our data indicate that AS generates a major socioeconomic burden. Most of the factors associated with higher costs were related to greater disease activity. Therefore, early appropriate treatment is crucial. Despite the many socioeconomic problems generated by AS, the patients remained connected to their social network thanks to support from their family and friends.
19910767 The kinematic relationships of the upper cervical spine. 2009 Nov 15 STUDY DESIGN: A retrospective radiographic study. OBJECTIVE: To elucidate the kinematic relationships of the upper cervical spine. SUMMARY OF BACKGROUND DATA: To our knowledge, few reports have described the kinematic relationships of the upper cervical spine in patients with general age-related cervical spondylosis. METHODS: We performed Kinetic magnetic resonance imaging for 295 consecutive patients experiencing neck pain without neurologic symptoms. Subjects with rheumatoid arthritis, traumatic history, and severe degenerative changes in the upper cervical spine were excluded. Anterior atlantodens interval (AADI) and the cervicomedullary angle in 3 different postures were measured, and the variations in each value between flexion and neutral (F-N), neutral and extension (N-E), and flexion and extension (F-E) were calculated. The subjects were classified into 3 groups according to the space available for the cord values (A: or=15 mm). RESULTS: AADI significantly increased from extension to flexion posture, however, no significant differences were observed in every posture among the groups. F-N variation in AADI showed no significant differences among the groups; however, N-E variation between Groups A and C and between Groups B and C and F-E variation between Groups A and C showed significant differences. The cervicomedullary angle significantly increased from flexion to extension posture, however, no significant differences were observed in every posture among the groups. Angle variations among the groups showed no significant differences, except for F-N angle variation between Groups B and C. None of the variations in AADI and the cervicomedullary angle were significantly correlated. CONCLUSION: Our results suggest that only the kinematics of the atlantoaxial movement, especially the posterior movement, was greatly affected by the narrowing of space available for the cord. The central atlantoaxial joint may be closely related to the mechanisms for protecting the spinal cord by restriction of the atlantoaxial movement.
19395451 Increased expression of soluble inducible costimulator ligand (ICOSL) in patients with sys 2009 May To investigate the level of costimulating molecules in systemic lupus erythematosus (SLE), we assessed the plasma concentrations of soluble forms of costimulatory molecules such as programmed death-1 (PD-1), B7-H1 (also called PD-L1 or CD274) and inducible costimulator ligand (ICOSL) in patients with SLE. Plasma concentrations of soluble PD-1, B7-H1 and ICOSL were measured by ELISA using plasma samples from 57 SLE patients with or without the active disease, 21 rheumatoid arthritis (RA) patients and 35 healthy subjects. We also evaluated surface ICOSL expression on B cells using flow cytometry to gain a better understanding of ICOSL expression. To compare the level of ICOSL mRNA expression, reverse transcriptase-polymerase chain reaction (RT-PCR) was performed using total RNA from peripheral blood mononuclear cells (PBMCs) isolated from eight healthy subjects and 11 patients with SLE. The concentration of plasma ICOSL was significantly higher in patients with SLE compared with healthy subjects (P = 0.005). Plasma ICOSL concentrations in patients with active SLE were also significantly higher than those of either patients with inactive SLE or patients with RA (P = 0.001, P = 0.015, respectively). Plasma ICOSL concentrations in patients with SLE correlated modestly with the SLE disease activity index score (r = 0.298, P = 0.024). We also found a significant inverse correlation between the soluble ICOSL expression and the surface ICOSL expression on B cells (r = -0.690, P = 0.001). However, ICOSL mRNA levels of patients with SLE were comparable with those of the control subjects. There was also no significant difference in plasma B7-H1 concentrations between groups, and plasma PD-1 was not detectable in any of the groups. The plasma concentration of soluble ICOSL might be correlated to the disease severity of lupus. The increased levels of ICOSL in active lupus suggest that this pathway is involved in the pathogenesis of SLE. The mechanism and physiological role of soluble ICOSL in the pathogenesis of SLE, however, remains to be investigated.
19319132 Combined polymorphisms in genes encoding the inflammasome components NALP3 and CARD8 confe 2009 May OBJECTIVES: Crohn's disease (CD) is characterized by overproduction of proinflammatory cytokines like interleukin (IL)-1beta. Production of mature IL-1beta is dependent on a caspase-1-activating protein complex called the NALP3 inflammasome, composed of NALP3, ASC, and CARD8. NALP3 shares structural similarities with Nod2, and both of these proteins are required for bacteria-induced IL-1beta secretion. The combination of the polymorphisms CARD8 (C10X)and NALP3 (Q705K) was recently shown to be associated with rheumatoid arthritis.Our aim was to investigate whether these combined polymorphisms play a role in the susceptibility to CD. METHODS: The study included 498 CD patients in two cohorts from different regions and 742 control individuals from a Swedish population. DNA was isolated from whole blood. Polymorphisms of (Q705K) NALP3 and (C10X) CARD8, as well as the Nod2 variants, R702W and G908R, were genotyped using the Taqman single nucleotide polymorphism assay. The Nod2 frameshift mutation, L1007fs, was detected by Megabace SNuPe genotyping. RESULTS: Our results show that men who have both the C10X and Q705K alleles in CARD8 and NALP3, and who express wild-type alleles of Nod2 are at an increased risk of developing CD (odds ratio, OR: 3.40 range: 1.32-8.76); P = 0.011). No association with these polymorphisms was found in women (OR: 0.89 (range: 0.44-1.77); P = 0.74). CONCLUSIONS: We suggest a role for combined polymorphisms in CARD8 and NALP3 in the development of CD in men, with obvious sex differences in the genetic susceptibility pattern. These findings give further support to the importance of innate immune responses in CD.
19261955 Micafungin plus fluconazole in an infected knee with retained hardware due to Candida albi 2009 Mar OBJECTIVE: To describe the use of micafungin and fluconazole in the management of a fungal prosthetic joint infection caused by Candida albicans. CASE SUMMARY: A 55-year-old female who had undergone total left knee arthroplasty due to rheumatoid arthritis presented with symptoms of a left knee infection. Intravenous vancomycin 1 g every 12 hours and intravenous ampicillin/sulbactam 1.5 g every 6 hours were initiated. Arthrocentesis produced cloudy synovial fluid with a white blood cell (WBC) count of 5.995 x 10(3)/microL. C-reactive protein (CRP) was 19.8 mg/dL and erythrocyte sediment rate (ESR) was greater than 120 mm/h. Gram stain was negative, but intraoperative cultures grew C. albicans. Four days later the patient's condition worsened and repeat arthrocentesis showed WBC count of 16.8 x 10(3)/microL with budding yeast in the synovial fluid. Antibiotics were stopped and liposomal amphotericin B 5 mg/kg once daily was started but was stopped after a few doses due to renal failure. Intravenous micafungin 100 mg daily was initiated; intravenous fluconazole 400 mg daily was added 2 days later and subsequently changed to oral fluconazole after 2 days of therapy. The patient received combination micafungin/fluconazole therapy for 8 weeks. After approximately 8 weeks of therapy, the CRP level and ESR had decreased from 19.8 to 7.1 mg/dL and greater than 120 to 81 mm/h, respectively. The patient's pain and range of motion in her knee had returned to baseline levels at last follow-up after the total knee arthroplasty. After 8 weeks of combination therapy, micafungin was discontinued but oral fluconazole was continued; approximately 8 weeks later the patient relapsed, requiring removal of the prosthetic knee hardware. DISCUSSION: Fungal prosthetic joint infections are rare, but definitive data regarding appropriate treatment are lacking. Echinocandins are an attractive treatment option due to their enhanced biofilm penetration. In our patient, treatment with micafungin plus fluconazole for 8 weeks followed by fluconazole monotherapy was associated with an initial good outcome in the treatment of a C. albicans prosthetic knee infection with retained hardware. This was, to our knowledge, the first case using micafungin in a prosthetic joint infection. CONCLUSIONS: Although micafungin plus fluconazole showed positive results in our patient, more data are needed regarding combination therapy for fungal prosthetic joint infections.