Tomonori Tetsunaga

Regulation of mechanical stress-induced MMP-13 and ADAMTS-5 expression by RUNX-2 transcriptional factor in SW1353 chondrocyte-like cells

OBJECTIVE To investigate the mechanism of mechanical stress-induced expression and regulation of aggrecanases and examine the role of runt-related transcription factor 2 (RUNX-2) in chondrocyte-like cells. METHODS SW1353 cells were seeded onto stretch chambers at a concentration of 5×10⁴ cells/chamber, and a uni-axial cyclic tensile strain (CTS) (0.5 Hz, 10% stretch) was applied for 30 min. Total RNA was extracted, reverse transcribed, and analyzed by polymerase chain reaction (PCR) and real-time PCR. RUNX-2 overexpression and small interfering RNA (siRNA) targeting RUNX-2 were used to investigate the role of RUNX-2 in CTS-induced gene expression. The involvement of diverse mitogen-activated protein kinase (MAPK) pathways in the activation of RUNX-2, MMP-13 and ADAMTS-5 during CTS was examined by Western blotting. RESULTS CTS induced expression of RUNX-2, MMP-13, ADAMTS-4, -5, and -9. Overexpression of RUNX-2 up-regulated expression of MMP-13 and ADAMTS-5, whereas RUNX-2 siRNA resulted in significant down-regulation of mechanically-induced MMP-13 and ADAMTS-5 expression. CTS induced activation of p38 MAPK, and CTS induction of RUNX-2, MMP-13 and ADAMTS-5 mRNA was down-regulated by the selective p38 MAPK inhibitor SB203580 but not by the p44/42 MAPK inhibitor U0126, or the JNK MAPK inhibitor JNK inhibitor II. CONCLUSIONS RUNX-2 might have a role as a key downstream mediator of p38s ability to regulate mechanical stress-induced MMP-13 and ADAMTS-5 expression.

Mechanical stretch stimulates integrin αVβ3-mediated collagen expression in human anterior cruciate ligament cells

Biomechanical stimuli have fundamental roles in the maintenance and remodeling of ligaments including collagen gene expressions. Mechanical stretching signals are mainly transduced by cell adhesion molecules such as integrins. However, the relationships between stress-induced collagen expressions and integrin-mediated cellular behaviors are still unclear in anterior cruciate ligament cells. Here, we focused on the stretch-related responses of different cells derived from the ligament-to-bone interface and midsubstance regions of human anterior cruciate ligaments. Chondroblastic interface cells easily lost their potential to produce collagen genes in non-stretched conditions, rather than fibroblastic midsubstance cells. Uni-axial mechanical stretches increased the type I collagen gene expression of interface and midsubstance cells up to 14- and 6-fold levels of each non-stretched control, respectively. Mechanical stretches also activated the stress fiber formation by shifting the distribution of integrin alphaVbeta3 to the peripheral edges in both interface and midsubstance cells. In addition, integrin alphaVbeta3 colocalized with phosphorylated focal adhesion kinase in stretched cells. Functional blocking analyses using anti-integrin antibodies revealed that the stretch-activated collagen gene expressions on fibronectin were dependent on integrin alphaVbeta3-mediated cellular adhesions in the interface and midsubstance cells. These findings suggest that the integrin alphaVbeta3-mediated stretch signal transduction might have a key role to stimulate collagen gene expression in human anterior cruciate ligament, especially in the ligament-to-bone interface.

The Minimally Invasive Plate Osteosynthesis (MIPO) Technique with a Locking Compression Plate for Femoral Lengthening

A minimally invasive plate osteosynthesis technique using a locking compression plate (LCP) has been used widely in trauma cases. Its advantages are that the MIPO technique does not interfere with the fracture site and thus provides improved biological healing, and that the LCP has excellent angular stability. Its use in bone lengthening, however, has not been established. In such cases, it is desirable to shorten the external skeletal fixation period as much as possible. Here, the MIPO technique using an LCP was applied to femoral distraction osteogenesis in an attempt to shorten the external skeletal fixation period. For femoral lengthening, the MIPO technique was performed in 2 stages. Orthofix external fixators (Orthofix, England) were used to insert screws from the anterolateral side rather than from the lateral side of the femur for bone lengthening. When sufficient callus formation was detected postoperatively at the site of bone lengthening, and the absence of infection was ensured, limb draping was performed, including a whole external fixator, and then the MIPO technique was applied with an LCP.In 3 cases (5 limbs), the average duration of external skeletal fixation was 134 days, the average external-fixation index was 24 days/cm, and the average consolidation index was 22 days/cm. The MIPO technique using an LCP made it possible to shorten the external skeletal fixation-wearing period in femoral lengthening.

Comparison of Continuous Epidural Analgesia, Patient-Controlled Analgesia with Morphine, and Continuous Three-in-One Femoral Nerve Block on Postoperative Outcomes after Total Hip Arthroplasty

Background Postoperative pain relief can be achieved with various modalities. However, there are only few reports that have analyzed postoperative analgesic techniques in total hip arthroplasty patients. The aim of this retrospective study was to compare the postoperative outcomes of three different analgesic techniques after total hip arthroplasty. Methods We retrospectively reviewed the influence of three analgesic techniques on postoperative rehabilitation after total hip arthroplasty in 90 patients divided into three groups (n = 30 patients per group). Postoperative analgesia consisted of continuous epidural analgesia (Epi group), patient-controlled analgesia with morphine (PCA group), or a continuous femoral nerve block (CFNB group). We measured the following parameters relating to postoperative outcome: visual analog scale scores, the use of supplemental analgesia, side effects, length of the hospital stay, plasma D-dimer levels, and the Harris hip score. Results Each group had low pain scores with no significant differences between the groups. The PCA group had a lower frequency of supplemental analgesia use compared to the Epi and CFNB groups. Side effects (nausea/vomiting, inappetence) and day 7 D-dimer levels were significantly lower in the CFNB group (p < 0.05). There were no significant differences between the groups in terms of the length of the hospital stay or the Harris hip score. Conclusions Although there were no clinically significant differences in outcomes between the three groups, the CFNB provided good pain relief which was equal to that of the other analgesics with fewer side effects and lower D-dimer levels in hospitalized patients following total hip arthroplasty.

Clinical Assessment of Postoperative Anemia Associated with Edoxaban in Patients Undergoing Total Knee Arthroplasty Compared to Fondaparinux.

Edoxaban, an oral direct factor Xa inhibitor, was developed and approved for anticoagulant thromboprophylaxis after total knee arthroplasty (TKA). We retrospectively investigated the postoperative anemia by oral administration of edoxaban 30 mg compared with fondaparinux 2.5 mg in TKA patients. Two hundred twenty nine patients who underwent TKA in National Hospital Organization Okayama Medical Center from July 2010 to June 2012 were divided into two groups; pre and post approval of edoxaban: fondaparinux-group (F-group) and edoxaban-group (E-group). As the primary endpoint, the frequency of postoperative anemia was evaluated. Blood coagulation values and relations between these parameters and postoperative anemia were also investigated. The frequency of postoperative anemia was significantly higher in E-group than F-group patients (52.7% vs. 37.8%; p<0.05). Hemoglobin (Hgb) levels were decreased with the peak at postoperative day (POD) 3 in both groups, and the change of Hgb values from POD1 (ΔHgb) was significantly increased in the E-group (p=0.04). At each POD, prothrombin time (PT) and international normalized ratio of PT (PT-INR) prolonged from the preoperative day in E-group were significantly higher than F-group. Additionally, PT and PT-INR in the E-group at POD3 were significantly prolonged in patients with postoperative anemia and the sensitivity of cut-off values to predict postoperative anemia was superior to the activated partial thromboplastin time (APTT). Thus, as the frequency of postoperative anemia tended to be higher in E-group, edoxaban 30 mg might require vigilance, and prolonged PT and PT-INR could potentially predict edoxaban-associated postoperative anemia after TKA.

Effect of Tramadol/Acetaminophen on Motivation in Patients with Chronic Low Back Pain

Background. The contribution of apathy, frequently recognized in individuals with neurodegenerative diseases, to chronic low back pain (LBP) remains unclear. Objectives. To investigate levels of apathy and clinical outcomes in patients with chronic LBP treated with tramadol-acetaminophen. Methods. A retrospective case-control study involving 73 patients with chronic LBP (23 male, 50 female; mean age 71 years) treated with tramadol-acetaminophen (n = 36) and celecoxib (n = 37) was performed. All patients were assessed using the self-reported questionnaires. A mediation model was constructed using a bootstrapping method to evaluate the mediating effects of pain relief after treatment. Results. A total of 35 (55.6%) patients met the criteria for apathy. A four-week treatment regimen in the tramadol group conferred significant improvements in the Apathy scale and numerical rating scale but not in the Rolland-Morris Disability Questionnaire, Pain Disability Assessment Scale, or Pain Catastrophizing Scale. The depression component of the Hospital Anxiety and Depression Scale was lower in the tramadol group than in the celecoxib group. The mediation analysis found that the impact of tramadol-acetaminophen on the change in apathy was not mediated by the pain relief. Conclusions. Tramadol-acetaminophen was effective at reducing chronic LBP and conferred a prophylactic motivational effect in patients with chronic LBP.

Four-year results of Summit stems for total hip arthroplasty in Japanese patients.

Purpose A retrospective study to evaluate the clinical and radiographic outcome of the Summit primary total hip arthroplasty (THA) at a minimum follow-up of 4 years. Methods 87 hips in 84 Japanese patients underwent THA using Summit stems. 3 patients were lost to follow-up, and 4 patients were excluded because a Summit stem was judged to be inappropriate for their narrow femoral canals. The remaining 80 hips in 77 patients were evaluated. Mean age was 66 years (range, 33-86 y). Mean postoperative follow-up period was 52 months (range, 48-66 m). Results There was no early stem subsidence after surgery. Of the 80 hips, 60 (75%) showed radiographic signs of stem osseointegration including zones 3 and 5 at final follow-up. Stress shielding occurred in 50 hips (62.5%), and third-degree stress shielding was observed in 12 hips (15%). 3 patients experienced postoperative thigh pain due to distal fixation. Conclusions These short-term results indicate that the Summit stem achieved good initial fixation, although there were some cases of distal fixation. Careful long-term follow-up and observation will be necessary for hips in which stress shielding occurs.

Calcar Femorale in Patients with Osteoarthritis of the Hip Secondary to Developmental Dysplasia

Background We investigated whether the calcar femorale, a cortical septum in the region of the lesser trochanter of the femur, correlates with results of femoral stem implantation in patients with osteoarthritis of the hip secondary to developmental dysplasia using computed tomography. Methods This retrospective study included 277 hips (41 males and 236 females; age, 37 to 92 years) of patients who had presented to Okayama Medical Center with hip pain. Of these, a total of 219 hips (31 males and 188 females) had previously undergone total hip arthroplasty. According to the Crowe classification, 147 hips were classified as Crowe grade I, 72 hips as Crowe grade II–IV, and 58 hips as normal. Results The calcar femorale was identified in 267 hips (96.4%). The calcar femorale was significantly shorter and more anteverted in Crowe grade II–IV hips than in Crowe grade I or normal hips. Significant differences in the shape of the calcar femorale were found according to the severity of hip deformity. Three stem designs were analyzed: single-wedge (59 hips), double-wedge metaphyseal filling (147 hips), and modular (13 hips). Single-wedge stems were inserted more parallel to the calcar femorale rather than femoral neck anteversion, while other types of stems scraped the calcar femorale. Conclusions The angle of the calcar femorale differs according to the severity of hip deformity, and the calcar femorale might thus serve as a more useful reference for stem insertion than femoral neck anteversion in total hip arthroplasty using a single-wedge stem.

Combination Therapy with Continuous Three-in-One Femoral Nerve Block and Periarticular Multimodal Drug Infiltration after Total Hip Arthroplasty

Background. Various postoperative pain relief modalities, including continuous femoral nerve block (CFNB), local infiltration analgesia (LIA), and combination therapy, have been reported for total knee arthroplasty. However, no studies have compared CFNB with LIA for total hip arthroplasty (THA). The aim of this study was to compare the efficacy of CFNB versus LIA after THA. Methods. We retrospectively reviewed the postoperative outcomes of 93 THA patients (20 men, 73 women; mean age 69.2 years). Patients were divided into three groups according to postoperative analgesic technique: CFNB, LIA, or combined CFNB+LIA. We measured the following postoperative outcome parameters: visual analog scale (VAS) for pain at rest, supplemental analgesia, side effects, mobilization, length of hospital stay, and Harris Hip Score (HHS). Results. The CFNB+LIA group had significantly lower VAS pain scores than the CFNB and LIA groups on postoperative day 1. There were no significant differences among the three groups in use of supplemental analgesia, side effects, mobilization, length of hospital stay, or HHS at 3 months after THA. Conclusions. Although there were no clinically significant differences in outcomes among the three groups, combination therapy with CFNB and LIA provided better pain relief after THA than CFNB or LIA alone, with few side effects.

The clinical impact of edoxaban for the patients with postoperative anemia after total hip arthroplasty

BackgroundPostoperative anemia is a common complication after total hip arthroplasty (THA). However, the effect of edoxaban on postoperative anemia after THA remains unclear. Here, we retrospectively evaluated the clinical assessment of postoperative anemia and the associated changes of coagulation parameters in patients undergoing thromboprophylaxis with edoxaban compared with fondaparinux as a conventional anticoagulant thromboprophylactic agent after THA.MethodsOne hundred and forty-nine patients who underwent THA from July 2010 to June 2012 were divided into two groups, according to whether they were operated on before or after the approval of edoxaban: the fondaparinux group (Group F: 86 patients) and the edoxaban group (Group E: 63 patients). The frequency of postoperative anemia and blood coagulation values were investigated.ResultsPostoperative anemia developed more frequently in Group E than in Group F after surgery. However, the degree of postoperative anemia showed no significant difference between the groups. Meanwhile, prothrombin time (PT), prothrombin time-international normalized ratio (PT-INR), and activated partial thromboplastin time were markedly higher in patients with edoxaban-associated postoperative anemia, which showed an increased potential to predict the occurrence of postoperative anemia. Additionally, both PT and PT-INR in Group E were also correlated with the volume of estimated blood loss.ConclusionThe frequency of postoperative anemia was increased in patients treated with edoxaban, compared to fondaparinux, after THA. Edoxaban thromboprophylaxis might, therefore, require more careful monitoring to prevent postoperative anemia. Additionally, particular prolongation of PT and PT-INR induced by edoxaban treatment might predict postoperative anemia.