Daisaku Tokunaga

A Critical Role for Allograft Inflammatory Factor-1 in the Pathogenesis of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is characterized by massive synovial proliferation, angiogenesis, subintimal infiltration of inflammatory cells and the production of cytokines such as TNF-α and IL-6. Allograft inflammatory factor-1 (AIF-1) has been identified in chronic rejection of rat cardiac allografts as well as tissue inflammation in various autoimmune diseases. AIF-1 is thought to play an important role in chronic immune inflammatory processes, especially those involving macrophages. In the current work, we examined the expression of AIF-1 in synovial tissues and measured AIF-1 in synovial fluid (SF) derived from patients with either RA or osteoarthritis (OA). We also examined the proliferation of synovial cells and induction of IL-6 following AIF-1 stimulation. Immunohistochemical staining showed that AIF-1 was strongly expressed in infiltrating mononuclear cells and synovial fibroblasts in RA compared with OA. Western blot analysis and semiquantitative RT-PCR analysis demonstrated that synovial expression of AIF-1 in RA was significantly greater than the expression in OA. AIF-1 induced the proliferation of cultured synovial cells in a dose-dependent manner and increased the IL-6 production of synovial fibroblasts and PBMC. The levels of AIF-1 protein were higher in synovial fluid from patients with RA compared with patients with OA (p < 0.05). Furthermore, the concentration of AIF-1 significantly correlated with the IL-6 concentration (r = 0.618, p < 0.01). These findings suggest that AIF-1 is closely associated with the pathogenesis of RA and is a novel member of the cytokine network involved in the immunological processes underlying RA.

Load Response of the Tarsal Bones in Patients with Flatfoot Deformity: In Vivo 3D Study

Background: The objective of this study was to evaluate the bone rotation of each joint in the hindfoot and compare the load response in healthy feet with that in flatfeet by analyzing the reconstructive three-dimensional (3D) CT image data during weightbearing. Methods: CT scans of 21 healthy feet and 21 feet with flatfoot deformity were taken in non-load condition followed by full-body weightbearing load condition. The images of the hindfoot bones were reconstructed into 3D models. The volume merge method in three planes was used to calculate the position of the talus relative to the tibia in the tibiotalar joint, the navicular relative to the talus in talonavicular joint, and the calcaneus relative to the talus in the talocalcaneal joint. Results: The talar position difference to the load response relative to the tibia in the tibiotalar joint in a flatfoot was 1.7 degrees more plantarflexed in comparison to that in a healthy foot (p = 0.031). The navicular position difference to the load response relative to the talus in the talonavicular joint was 2.3 degrees more everted (p = 0.0034). The calcaneal position difference to the load response relative to the talus in the talocalcaneal joint was 1.1 degrees more dorsiflexed (p = 0.0060) and 1.7 degrees more everted (p = 0.0018). Conclusion: Referring to previous cadaver study, regarding not only the cadaveric foot, but also the live foot, joint instability occurred in the hindfoot with load in patients with flatfoot. Clinical Relevance: The method used in this study might be applied to clinical analysis of foot diseases such as the staging of flatfoot and to biomechanical analysis to evaluate the effects of foot surgery in the future. Level of Evidence: III

Mycoplasma fermentans glycolipid-antigen as a pathogen of rheumatoid arthritis.

Mycoplasma fermentans has been suspected as one of the causative pathogenic microorganisms of rheumatoid arthritis (RA) however, the pathogenic mechanism is still unclear. We, previously, reported that glycolipid-antigens (GGPL-I and III) are the major antigens of M. fermentans. Monoclonal antibody against the GGPL-III could detect the existence of the GGPL-III antigens in synovial tissues from RA patients. GGPL-III antigens were detected in 38.1% (32/84) of RA patients tissues, but not in osteoarthritis (OA) and normal synovial tissues. Immunoelectron microscopy revealed that a part of GGPL-III antigens are located at endoplasmic reticulum. GGPL-III significantly induced TNF-alpha and IL-6 production from peripheral blood mononulear cells, and also proliferation of synovial fibroblasts. Further study is necessary to prove that M. fermentans is a causative microorganism of RA; however, the new mechanisms of disease pathogenesis provides hope for the development of effective and safe immunotherapeutic strategies based on the lipid-antigen, GGPL-III, in the near future.

Atlantoaxial subluxation in different intraoperative head positions in patients with rheumatoid arthritis

Background: Disorders of the cervical spine are often observed in patients with rheumatoid arthritis (RA). However, the best head position for RA patients with atlantoaxial subluxation in the perioperative period is unknown. This study investigated head position during general anesthesia for the patients with RA and proven atlantoaxial subluxation. Methods: During anesthesia of patients with RA and proven atlantoaxial subluxation, the authors used fluoroscopy to obtain a lateral view of the upper cervical spine in four different positions: the mask position, the intubation position, the flat pillow position, and the protrusion position. Copies of the still fluoroscopic images were used to determine the anterior atlantodental interval, the posterior atlantodental interval, and the angle of atlas and axis (C1–C2 angle). Results: The anterior atlantodental interval was significantly smaller in the protrusion position (2.3 mm) than in the flat pillow position (5.1 mm) (P < 0.05). The posterior atlantodental interval was significantly greater in the protrusion position (18.9 mm) than in the flat pillow position (16.2 mm) (P < 0.05). The C1–C2 angle was, on average, 9.3° greater in the protrusion position than in the flat pillow position (P < 0.05). Conclusion: This study showed that the protrusion position using a flat pillow and a donut-shaped pillow during general anesthesia reduced the anterior atlantodental interval and increased the posterior atlantodental interval in RA patients with atlantoaxial subluxation. This suggests that the protrusion position, which involves support of the upper cervical spine and extension at the craniocervical junction, might be advantageous for these patients.

In Vivo Three-Dimensional Analysis of Hindfoot Kinematics:

Background: Knowledge of normal bone motion of the foot is important for understanding the gait as well as for various pathologies; however, the pattern of 3D motion is not completely understood. The aim of this study was to quantify the in vivo motion of the tibiotalar joint, talocalcaneal joint, and talonavicular joint in normal adult feet using a noninvasive (e.g., nonsurgical) measurement technique. Materials and Methods: CT images were taken of both feet of ten normal young adults (six males, four females) in neutral, plantarflexion, and dorsiflexion positions of the ankle joint, from which 3D virtual models were made of each mid-hind foot bones. The 3D bone motion of these models was calculated using volume merge methods in three major planes. These data were used to analyze the relationship between the motion of the ankle joint and each other joint. Results: Tibiotalar rotation was observed in dorsiflexion, abduction, and eversion during maximal dorsiflexion of the ankle joint. Talocalcaneal and talonavicular rotation was very small because the ankle joint motion was limited to the sagittal plane. Tibiotalar rotation was also observed in plantarflexion and adduction during maximal plantarflexion of the ankle joint, and talocalcaneal rotation was very small. Talonavicular rotation was observed in plantarflexion and inversion. The motion of the x-axis and the z-axis of tibiotalar joint, and the x-axis and the y-axis of the talonavicular and talocalcaneal joint were associated with the ankle motion. Conclusion: Bone motion could be easily and accurately calculated using volume merge methods more effectively than it could with other methods. Clinical Relevance: The data elucidates the baseline segmental motion for comparison with symptomatic subjects which could help us to better understand pathokinematics of various foot and ankle pathologies.

Effects of alternating current electrical stimulation on lengthening callus.

Limb lengthening by the callotasis method has been clinically applied to patients who suffered from limb length inequality, micromelia, angular deformation and partial bone defect on long bones. However, this technique was time consuming and led to various complications, such as infection at the pin insertion sites, limitation of the range of motion in adjacent joints, muscular weakness and peripheral neuroparalysis. This study was undertaken to investigate whether alternating current electric (AC) stimulation could shorten the maturation period during callotasis. The tibiae of 20 immature male Japanese white rabbits were osteotomized and fixed with external lengthener (Orthofix M100; Orthofix Srl, Bussolengo, Italy). The experimental schedule lasted 5 weeks consisting of 1 week for the latency period, 2 weeks for distraction and 2 weeks for maturation. Twenty rabbits were equally divided into two groups: the control group and the electrical stimulation (ES) group. The control group was not stimulated with an AC stimulator. The ES group was stimulated for 5 weeks just after osteotomy. The obtained results revealed radiologically, electrophysiologically and histologically that AC stimulation accelerated the maturation of lengthened callus and that it could shorten the time course of callus lengthening.

Load response of the medial longitudinal arch in patients with flatfoot deformity: in vivo 3D study.

BACKGROUND The acquisition of flatfoot by an adult is thought to primarily be caused by posterior tibial tendon dysfunction, although some other causes, such as congenital flexible flatfoot or an accessory navicular, may also be responsible. The objective of this study was to evaluate the bone rotation of each joint in the medial longitudinal arch (MLA) and compare the response in healthy feet with that in flat feet by analyzing the reconstructive three-dimensional (3D) CT image data during weightbearing. METHODS CT scans of 20 healthy feet and 24 feet with flatfoot deformity were taken in non-load condition followed by full-body weightbearing condition. Images of the tibia and MLA bones (first metatarsal bone, cuneiforms, navicular, talus, and calcaneus) were reconstructed into 3D models. The volume merge method in three planes was used to calculate the bone-to-bone relative rotations. FINDINGS Under loading conditions, the flatfoot dorsiflexed more in the first tarsometatarsal joint, and everted more in the talonavicular and talocalcaneal joints compared with the healthy foot. The total relative rotation was larger in the flatfoot compared with the healthy foot only in the first tarsometatarsal joint. INTERPRETATION Supporting the MLA in the sagittal direction and the subtalar joint in the coronal direction may be useful for treating flatfoot deformity. The first tarsometatarsal joint may play an important role in diagnosing or treating flatfoot deformity.

MDR1a/1b gene silencing enhances drug sensitivity in rat fibroblast-like synoviocytes.

Drug resistance mediated by P‐glycoprotein (P‐gp) is one of the major reasons for the failure of rheumatoid arthritis (RA) therapy with disease modifying anti‐rheumatic drugs and glucocorticoids. In the present study, we aimed to investigate the in vitro effectiveness of small interfering RNA (siRNA) to render rat fibroblast‐like synoviocytes (FLS) susceptible to drugs. We also attempted the electroporation‐mediated transfer of siRNA against multidrug resistance (MDR) genes into rat knee joints.

Three-dimensional morphology and kinematics of the craniovertebral junction in rheumatoid arthritis.

Study Design. A case-series study. Objectives. To measure the 3-dimensional (3D) morphology and kinematics of the craniovertebral junction (CVJ) using a 3D computed tomography (CT) model; to reveal abnormal patterns and the relationships between pathology and kinematics. Summary of Background Data. Evaluations using radiography, 2-dimensional (2D) CT and magnetic resonance imaging have limitations because of the complex 3D structure of the CVJ. Methods. Twenty-four rheumatoid arthritis patients (21 females, 3 males) with cervical involvement underwent CT scanning of the cervical spine from the basilar process of the occipital bone to the first thoracic vertebra in neutral and flexed positions. The 3D morphology of the occipital condyle, atlas, and axis were classified based on the type of deformity observed. Periodontoid lesions (continuous bony lesions between the atlas and the odontoid process) were also noted. The 3D kinematics in the atlanto-occipital and atlantoaxial joints were evaluated using the volume merge method. Results. Deformities in the atlanto-occipital joints appeared more frequently than those in the atlantoaxial joints. The most common instability pattern was flexural rotation during flexion at the CVJ. The direction of translational motions during flexion was posterior in the atlanto-occipital joint and anterior and caudal in the atlantoaxial joint. Conclusion. The results suggest that bilateral occipital condyle deformation, unilateral and bilateral mass collapse, and periodontoid lesions may affect flexion/extension rotational instability in the atlantoaxial joint. In addition, unilateral occipital condyle deformation and atlantoaxial joint stability may affect sagittal translational instability to the posterior side in the atlanto-occipital joint. The noninvasive 3D CT imaging technique employed here would be useful for predicting the prognosis of patients with rheumatoid deformities at the CVJ.

Weight-bearing three-dimensional computed tomography analysis of the forefoot in patients with flatfoot deformity

BACKGROUND The recent classifications for posterior tibial tendon dysfunction (PTTD) stage II are based on forefoot deformity, but there is still no consensus regarding a detailed explanation of the clinical condition. The purposes of this study were to clarify the clinical condition of flatfoot deformity using three-dimensional (3D) computed tomography (CT) imaging under loading on both healthy and flat feet and to compare 3D movement of the forefoot in response to load. METHODS Ten volunteers and 10 PTTD stage II patients with symptomatic flatfoot deformity were examined. CT scans of 20 healthy and 20 flat feet were performed under non-loading and full weight-bearing conditions. Images of the tibia and foot arch bones (talus, calcaneus, navicular, and first and fifth metatarsal bones) were reconstructed into 3D models. Rotations of individual tarsal bone or metatarsal bone were described by the Eulerian angles. RESULTS Compared with healthy feet, flat feet experienced plantarflexion of the fifth metatarsal bone relative to the first metatarsal bone under loading conditions. We defined this phenomenon as synonymous with forefoot varus on the coronal plane. CONCLUSIONS The results of this study have clarified part of the clinical condition of the forefoot in flatfoot deformity and may have applications in basic research of the staging advancement and substage classification of PTTD.