Characterization of Spz5 as a novel ligand for Drosophila Toll-1 receptor.

The Drosophila Toll-1 receptor is involved in embryonic development, innate immunity, and tissue homeostasis. Currently, as a ligand for the Toll-1 receptor, only Spätzle (Spz) has been identified and characterized. We previously reported that Drosophila larva-derived tissue extract contains ligand activity for the Toll-1 receptor, which differs from Spz based on the observation that larval extract prepared from spz mutants possessed full ligand activity. Here, we demonstrate that Spz5, a member of the Spz family of proteins, functions as a ligand for the Toll-1 receptor. Processing of Spz5 by Furin protease, which is known to be important for ligand activity of Spz5 to Toll-6, is not required for its function to the Toll-1 receptor. By generating a spz5 null mutant, we further showed that the Toll-1 ligand activity of larva-derived extract is mainly derived from Spz5. Finally, we found a genetic interaction between spz and spz5 in terms of developmental processes. This study identified a novel ligand for the Drosophila Toll-1 receptor, providing evidence that Toll-1 is a multi-ligand receptor, similar to the mammalian Toll-like receptor.

Neglected spontaneous rupture of the Achilles tendon in elderly patients with rheumatoid arthritis.

Spontaneous Achilles tendon rupture associated with rheumatoid arthritis (RA) is a very rare complication. In this report, we have experienced neglected spontaneous rupture of the Achilles tendon in 5 elderly RA patients, and report its clinical features and management. These patients had taken corticosteroids for a long time for RA control. Moreover, they did not show any signs, such as click or impact on the rear foot at the moment of the rupture, and had few complaints or obvious symptoms around their ankles or the rear of the foot after the rupture. This suggests that the lack of severe symptoms prevented the early diagnosis of the Achilles tendon rupture, and that this injury had been neglected during treatment for RA. Therefore, careful diagnosis of the Achilles tendon rupture is needed in elderly patients with RA, even if they have little or no history of trauma.

Complications and features after joint surgery in rheumatoid arthritis patients treated with tumour necrosis factor-alpha blockers: perioperative interruption of tumour necrosis factor-alpha blockers decreases complications?

OBJECTIVE: TNF-alpha blockers reportedly increase the risk of complications in rheumatic patients following surgery. Whereas deep venous thrombosis (DVT) is a significant complication after orthopaedic surgery of the lower limbs, the risk for DVT in RA patients receiving TNF blockers remains unclear. The aim of this study was to identify complications that can be attributed to the use of TNF-alpha blocker therapy. METHODS: In a retrospective 1:1 pair-matched case-control study, 64 anti-TNF-treated RA surgeries (TNF group) and 64 surgeries treated with conventional DMARDs (DMARDS group) were evaluated for surgical site infection (SSI), DVT and recurrence of arthritis (flare-up). Multivariate logistic regression analysis was performed to test the association of SSI or DVT with the putative risk factors. RESULTS: Regression analysis identified the use of TNF blockers as a risk factor for SSI [P = 0.036; odds ratio (OR) = 21.80] and development of DVT (P = 0.03; OR = 2.83) after major orthopaedic surgery: 12.5% (8/64) of the patients in the TNF group had SSI, whereas 2% (1/64) of those in the DMARDs group had SSI. Fifty-one per cent (23/45) of the TNF group, but only 26% (12/45) of the DMARDs group was DVT positive. Flare-ups during the perioperative period were found in 17.2% (11/64) of all patients, and no delay in wound healing occurred in either group. CONCLUSIONS: These data suggest that the use of TNF blockers is a likely cause of SSI and DVT development in RA patients following major orthopaedic surgery.

Risk factors for wrist surgery in rheumatoid arthritis.

To assess the risk factors for wrist surgery in a cohort of rheumatoid arthritis (RA) patients recruited and followed prospectively for 6 years. A linked registry study was performed using information from a large observational cohort of RA patients followed at the Institute of Rheumatology, Tokyo Women's Medical University. Baseline routine clinical and laboratory assessments were recorded. The data were analyzed using the multivariate Cox regression model that included variables such as gender, age, disease duration, a visual analog scale (VAS) generated by physicians, a patient-reported VAS for pain (VAS-pain), a VAS for general health, disability level using the Japanese version of the Health Assessment Questionnaire (J-HAQ), erythrocyte sedimentation rate, and serum levels of C-reactive protein and rheumatoid factor as potential risk factors. Of the 5,497 patients registered at baseline, 122 (2.22%) had surgery on one or both wrist joints. Multivariate Cox regression analysis of the variables revealed positive coefficients for J-HAQ and VAS-pain and that advanced age and long RA duration were associated with a reduced risk of wrist surgery. The hazard ratios were: 1.515 for J-HAQ, 1.126 for VAS-pain, 0.985 for age, and 0.964 for RA duration. Advanced age and long RA duration were associated with a decreased risk of wrist surgery, while J-HAQ and VAS-pain were associated with an increased risk. The identification of the risk factors for wrist surgery provides important insights into the course of the disease and its impact on patients, as well as the potential consequences for health care resource utilization planning.

Iliopsoas bursitis-associated femoral neuropathy exacerbated after internal fixation of an intertrochanteric hip fracture in rheumatoid arthritis: a case report.

We present the case of a 63-year-old woman with a six-year history of rheumatoid arthritis (RA) and a left iliopsoas bursitis. Radiography had detected destructive changes in her hip joint associated with her bursitis, and she had reported some paresthesia along the left anterior distal thigh. Her pain and numbness remained tolerable, and her disease activity was well controlled until she accidentally fell on the floor, which resulted in an unstable intertrochanteric fracture of left femur with displacement of the proximal portion. The fracture was successfully treated with open reduction and internal fixation, but after the surgery, her femoral nerve palsy worsened. She subsequently underwent bursa excision after the failure of conservative treatment. Accordingly, after bursa excision, the postoperative course was uneventful, and her neurological symptoms gradually disappeared. We would recommend that bursa excision be considered even in cases of iliopsoas bursitis associated with mild femoral neuropathy when destructive changes in the hip joint are also present.

Risk factors for total knee arthroplasty in rheumatoid arthritis.

We conducted a study to assess the predictive factors for total knee arthroplasty (TKA) in a cohort of rheumatoid arthritis (RA) patients recruited and followed prospectively for 5 years. A linked registry study using information from a large observational cohort of RA patients followed at the Institute of Rheumatology, Tokyo Women's Medical University (IORRA) was done. Baseline routine clinical and laboratory assessments were recorded. The data were analyzed using the multivariate piecewise-linear Cox (PL-Cox) regression model; the model initially included variables such as gender, age, duration of the disease, visual analog scale (VAS) generated by physicians (VAS-physician), patient-reported VAS for pain (VAS-pain), VAS for general health (VAS-GH), disability level using the Japanese version of the Health Assessment Questionnaire (J-HAQ), C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor (RF), and hemoglobin. Of the 3945 patients registered at baseline, 955 (24.2%) had pain or tenderness in their knee joints, and 114 (11.9%) had TKA surgery in one or both knee joints. On PL-Cox regression, the variables with positive coefficients were J-HAQ, VAS-pain, VAS-physician, and RF positive; advanced age was associated with a reduced risk of TKA. The hazard ratios were: 0.920 for age >60 years; 2.64 for J-HAQ <1.5; 1.01 for J-HAQ >1.5; 1.47 for VAS-pain >6 (cm); 1.20 for VAS-physician >4 (cm); and 2.08 for RF positive. The consistently predictive factors for TKA in RA were age, J-HAQ, VAS-pain, VAS-physician, and RF positive. Age greater than 60 years was associated with a decreased risk of TKA, while J-HAQ from 0 to 1.5, VAS-pain >6 (cm), and VAS-physician >4 (cm) were associated with an increased risk for TKA surgery. These results suggest that, when treating RA patients, physicians should pay particular attention to pain complaints, the patient's daily activity level, and the RF factor status.

A case of Castleman's disease associated with diffuse idiopathic skeletal hyperostosis and ossification of the posterior longitudinal ligament of the spine.

Castleman's disease (CD), diffuse idiopathic skeletal hyperostosis (DISH), and ossification of the posterior longitudinal ligament of the spine (OPLL) are three different entities. Castleman's disease displaying a variety of calcifications in the abdomen and/or pelvis has been reported in some papers. However, there were no reports suggesting an association between CD and ossification/calcification in spine and joints. So far, there has been no case report regarding the coexistence of these diseases in the literature. Herein, we detail a 75-year-old man suffering from CD who demonstrated the features of DISH with coexisting features of OPLL. The cardinal symptoms such as fatigue, high fever, and swollen glands in this case were reduced by corticosteroid therapy. However, it is possible to produce actual symptoms of ossifying/calcified diathesis of entheses and ligaments as a consequence, like the pathology of calcification found in the region of the spleen. In this paper, we describe this patient in order to discuss the association of these diseases.

Disturbances of the symphysis pubis in rheumatoid arthritis: report of two cases.

We present two rheumatoid arthritis (RA) patients suffering from disturbances of the symphysis pubis. Radiography revealed one with pelvic ring disruption with symphysis pubis diastasis, and the other with osteolysis at both pubic rami and disruption of the superior aspect of the symphysis pubis. Both cases had received long-term corticosteroid therapy, including pulse therapy. We recommend reducing the corticosteroid dose to prevent disturbances of the symphysis pubis especially in RA patients on long-term steroid therapy.

The serum concentration of infliximab in cases of autologous blood donation for patients with rheumatoid arthritis.

Our aim was to determine whether the use of infliximab for rheumatoid arthritis (RA) patients is associated with an increased rate of postoperative complications. In this study we evaluated the serum concentration of infliximab to study the influence of autologous blood donation (AB donation) in patients who were administered infliximab and underwent total knee replacement (TKR). We examined five RA patients. Infliximab combined with methotrexate was administered at 3 mg/kg every 8 weeks for all patients. We carried out the TKR operation in the middle of the 8-week interval in which infliximab was administered. The AB donation consisted of 400 ml pooled AB drawn at one point 2 weeks following the final administration of infliximab. Serum infliximab levels were measured using an enzyme-linked immunosorbent assay. Mean serum infliximab levels were 5.46 +/- 5.62 microg/ml 2 weeks after the final administration of infliximab, 2.02 +/- 1.66 microg/ml just before the operation, and 1.48 +/- 1.31 microg/ml 1 day post operation. Moreover, the mean serum level in an autologous blood bag sampled just before AB donation was 5.02 +/- 4.79 microg/ml. This study indicated the serum level of infliximab in the stored blood remained at almost the same level as the collected autologous blood. However, even after autotransfusion those levels were decreased compared with levels measured just before the operation. Therefore, we conclude that there is little influence of AB donation on the risks of infliximab.

Acute destruction of the hip joints and rapid resorption of femoral head in patients with rheumatoid arthritis.

We report three rheumatoid arthritis (RA) cases with acute destruction of hip joint and rapid resorption of femoral head. The condition occurred in less than 6 months and closely resembled rapid destructive coxarthrosis. All three patients were postmenopausal women with active RA who had been taking steroids. Two of the patients were taking prednisolone (PSL) of over 20 mg as maximum dose per day, and all patients were resistant to disease-modifying anti-rheumatic drugs (DMARDs). Other than the problems of their hip joints, one had a giant bursitis around the pathological side of the hip joint, another had multiple rheumatoid nodules and skin infarction, and the other suffered from insufficiency fracture of the contralateral femoral subcapital lesion. As a result, all of them had total hip arthroplasty. We recommend taking repetitive radiographs for RA patients with continuing severe hip pain.

Adenoviral-mediated transfer of TGF-beta1 but not IGF-1 induces chondrogenic differentiation of human mesenchymal stem cells in pellet cultures.

OBJECTIVE: The objective of the present study was to investigate the potential of application of growth factor genes to induce chondrogenic differentiation of human-derived mesenchymal stem cells (MSCs). The growth factor genes evaluated in the present study were transforming growth factor 1 (TGF-beta1) and insulin-like growth factor 1 (IGF-1). METHODS: Human MSCs were transduced with the adenoviral vectors carrying either TGF-beta1 or IGF-1 (AdTGF-beta1 and AdIGF-1 respectively) or a combination of both growth factor genes at different multiplicities of infection (MOI) and were then made into pellets. Pellets were also made from nontransduced cells and maintained in culture medium supplemented with 10 ng/mL of TGF-beta1. At specified time points, histological analysis, cartilage matrix gene expression, and immunofluorescence were performed to determine the extent of chondrogenic differentiation. RESULTS: MSCs transduced with the AdTGF-beta1 demonstrated robust chondrogenic differentiation, while those made from AdIGF-1 did not. AdTGF-beta1 pellets demonstrated aggrecan gene expression as early as day 3 of pellet culture, while type II collagen gene expression was detected by day 10 of culture. The AdIGF-1, alone or in combination with TGF-beta1 pellets, did not show any type II collagen gene expression at any time point. By immunofluoresecence, type X collagen was distributed throughout the matrix in TGF-beta1 protein pellets while the growth factor gene pellets displayed scant staining. CONCLUSION: The results suggest that sustained administration of TGF-beta1 may be more effective in suppressing terminal differentiation than intermittent dosing and thus effective for cartilage repair.

[Alignment of lower extremity in rheumatoid arthritis patients with a history of both total hip replacement and total knee replacement].

OBJECTIVE: The following is a retrospective study on lower extremity alignment of rheumatoid arthritis (RA) patients with a history of both Total Hip Replacement (THR) and Total Knee Replacement (TKR). METHODS: From 1992 to 2000, our department had 26 rheumatoid arthritis patients who underwent both THR and TKR. We classified these patients into three groups based on radiographic alignment of the lower extremities in the standing position: Knock-knee (valgus deformity of the knees), Bowleg (varus deformity of the knees) and Windswept Deformity (one knee in severe varus alignment with the other in severe valgus alignment). Furthermore, we identified dominant weight bearing points of the hip as classified by the following new criteria: Central Shift, Lateral Shift, and Upward Shift. Mal-alignment was then evaluated based on these two classification systems. RESULTS: Of the 26 patients, 22 patients met our criteria and 4 did not. In mal-alignment, we had 11 cases in the knock-knee group, 5 cases in the bowleg group, and 6 cases in the Windswept deformity. Using the new criteria, central shift had 6 cases; lateral shift had 6 cases; and upward shift had 10 cases. The groups of Lateral shift and Central shift demonstrated deformities of the lower extremities were influenced by moving weight bearing points, pelvis obliquity, and adduction contractures of the hip joint. In upward shift, weight bearing lines did not change. Consequently, destruction of the joint in this group progressed symmetrically. Windswept deformity was asymmetric and had severe destruction on the other side of the knee and forefoot. DISCUSSION: Moving of weight bearing point, pelvis obliquity, and adduction contractures of the hip joint affected the severity of mal-alignment of the lower extremities.