Evaluation of Changes in Activities of Daily Living and Quality of Life of Patients with Bone Metastasis Who Underwent Conservative Therapy through Bone Metastasis Cancer Boards.

Background and Objectives: Changes in activities of daily living (ADL) and quality of life (QOL) of patients with bone metastasis who underwent surgical treatment through Bone Metastasis Cancer Boards (BMCBs), a recent multidisciplinary approach for managing bone metastases, have been reported; however, no reports exist on patients who undergo conservative treatment. In this study, we aimed to evaluate these patients' ADL and QOL and examine the factors influencing changes in these parameters. Materials and Methods: We retrospectively reviewed 200 patients with bone metastases who underwent conservative therapy through BMCBs between 2013 and 2021. A reassessment was conducted within 2-8 weeks after the initial assessment. Patients' background and changes in performance status (PS), Barthel Index (BI), EuroQol five-dimension (EQ-5D) scores, and Numerical Rating Scale (NRS) scores were initially assessed. Furthermore, we categorized patients into two groups based on improvements or deteriorations in ADL and QOL and performed comparative analyses. Results: Significant improvements in EQ-5D (0.57 ± 0.02 versus [vs.] 0.64 ± 0.02), NRS max (5.21 ± 0.24 vs. 3.56 ± 0.21), and NRS average (2.98 ± 0.18 vs. 1.85 ± 0.13) scores were observed between the initial assessment and reassessment (all p < 0.001). PS (1.84 ± 0.08 vs. 1.72 ± 0.08) and BI (83.15 ± 1.68 vs. 84.42 ± 1.73) also showed improvements (p = 0.06, and 0.054, respectively). In addition, spinal cord paralysis (odds ratio [OR]: 3.69, p = 0.049; OR: 8.42, p < 0.001), chemotherapy (OR: 0.43, p = 0.02; OR: 0.25, p = 0.007), and NRS average scores (OR: 0.38, p = 0.02; OR: 0.14, p < 0.001) were independent factors associated with ADL and QOL. Conclusions: Patients with bone metastases who underwent conservative treatment through BMCBs exhibited an increase in QOL without a decline in ADL. The presence of spinal cord paralysis, absence of chemotherapy, and poor pain control were associated with a higher risk of deterioration in ADL and QOL.

Combining age, sex, body mass index, sport level, and preoperative quadriceps strength improves the predictive ability of quadriceps strength recovery after anterior cruciate ligament reconstruction.

PURPOSE: This study compared the predictive ability of each independent predictor with that of a combination of predictors for quadriceps strength recovery one year after anterior cruciate ligament (ACL) reconstruction. METHODS: Patients who underwent primary ACL reconstruction using hamstring autografts were enrolled. Quadriceps strength, hamstring strength, and anterior tibial translation were measured, and the limb symmetry index (LSI) of the quadriceps and the hamstrings was calculated preoperatively and one year after surgery. Patients were classified into two groups according to the LSI of the quadriceps strength at one year postoperatively (≥ 80% or < 80%). Multivariate logistic regression analysis identified the independent predictors of quadriceps strength recovery, and the cut-off value was calculated using the receiver operating characteristic curve. A model assessing predictive ability of the combination of independent predictors was created, and the area under the curve (AUC) for each independent predictor was calculated by using the receiver-operating characteristic curves and the DeLong method. RESULTS: Of the 646 patients, 414 (64.1%) had an LSI of at least 80% for quadriceps strength one year after surgery, and 232 patients (35.9%) had an LSI of < 80%. Age, sex, body mass index (BMI), preinjury sport level, and LSI of preoperative quadriceps strength were independently associated with quadriceps strength recovery one year after ACL reconstruction. The cut-off values were age: 22.5 years; sex: female; BMI: 24.3 kg/m2; preinjury sport level: no sport; and LSI of preoperative quadriceps strength: 63.3%. The AUC of the model assessing the predictive ability of the combination of age, sex, BMI, preinjury sport level, and LSI of preoperative quadriceps strength was significantly higher (0.73) than that of similar factors of preoperative quadriceps strength (AUC: 0.63, 0.53, 0.56, 0.61, and 0.68, p < 0.01, respectively). CONCLUSION: The combination of age, sex, BMI, preinjury sport level, and LSI of preoperative quadriceps strength had a superior predictive ability for quadriceps strength recovery at one year after ACL reconstruction than these predictors alone. Multiple factors, including patient characteristics and preoperative quadriceps strength, should be considered when planning rehabilitation programs to improve quadriceps strength recovery after ACL reconstruction. LEVEL OF EVIDENCE: III.

Involvement of orthopaedic surgeons for cancer patients in orthopaedic training facilities certified by the Japanese Orthopaedic Association - A nationwide survey.

BACKGROUND: In order to improve cancer care in Japan further, it is now required for orthopaedic surgeons to get actively involved in managing locomotive organs such as bones, muscles and nerves in cancer patients. In 2018, the Japanese Orthopaedic Association (JOA) conducted a questionnaire survey to investigate the current status of cancer treatment at the orthopaedic training facilities certified by the JOA. We analyzed the results of that questionnaire survey, focusing on the data from the core hospitals for cancer care (designated cancer hospitals), to clarify the involvement of orthopaedic surgeons in cancer treatment. MATERIALS AND METHODS: A nationwide survey was conducted in the orthopaedic training facilities certified by the JOA using an online questionnaire from March 15th to 31st, 2018. To clarify the involvement of orthopaedic surgeons in cancer treatment, we analyzed the results of that questionnaire survey, focusing on the data from the designated cancer hospitals in Japan. RESULTS: From the questionnaire survey, it became clear that 24% of the orthopaedic training facilities certified by the JOA are designated cancer hospitals. There were significant differences concerning cancer treatment and the prospect of orthopaedic surgeons' involvement in the treatment for bone metastases between institutions classified according to number of both certified orthopaedic surgeons by the JOA and specialists for bone and soft tissue tumors. In addition, in 45% of the designated cancer hospitals, orthopaedic surgeons treated bone metastases that occur in cancer patients, but in the rest of the institutions, orthopaedic surgeons did not yet adequately respond. CONCLUSION: In order to further improve the locomotive function and quality of life (QOL) in cancer patients, it was seemed to be necessary that all medical professionals engaged in cancer treatment, including orthopaedic surgeons, recognize the importance of locomotive management for cancer patients. In addition, the results of this study suggested that the presence of more than six certified orthopaedic surgeons by the JOA, including one or more specialists for bone and soft tissue tumors, may be able to create an environment conducive to the involvement of orthopaedic surgeons in cancer treatment at the facility.

Effect of Bone Metastasis Cancer Board on Spinal Surgery Outcomes: A Retrospective Study.

Background and Objectives: Bone metastasis cancer boards (BMCBs) focusing on the management of bone metastases have been gathering much attention. However, the association of BMCBs with spinal surgery in patients with spinal metastases remains unclear. In this retrospective single-center observational study, we aimed to clarify the effect of a BMCB on spinal metastasis treatment. Materials and Methods: We reviewed consecutive cases of posterior decompression and/or instrumentation surgery for metastatic spinal tumors from 2008 to 2019. The BMCB involved a team of specialists in orthopedics, rehabilitation medicine, radiation oncology, radiology, palliative supportive care, oncology, and hematology. We compared demographics, eastern cooperative oncology group performance status (ECOGPS), Barthel index (BI), number of overall versus emergency surgeries, and primary tumors between patients before (2008-2012) and after (2013-2019) BMCB establishment. Results: A total of 226 patients including 33 patients before BMCB started were enrolled; lung cancer was the most common primary tumor. After BMCB establishment, the mean patient age was 5 years older (p = 0.028), the mean operating time was 34 min shorter (p = 0.025), the mean hospital stay was 34.5 days shorter (p < 0.001), and the mean BI before surgery was 12 points higher (p = 0.049) than before. Moreover, the mean number of surgeries per year increased more than fourfold to 27.6 per year (p < 0.01) and emergency surgery rates decreased from 48.5% to 29.0% (p = 0.041). Patients with an unknown primary tumor before surgery decreased from 24.2% to 9.3% (p = 0.033). Postoperative deterioration rates from 1 to 6 months after surgery of ECOGPS and BI after BMCB started were lower than before (p = 0.045 and p = 0.027, respectively). Conclusion: The BMCB decreased the emergency surgery and unknown primary tumor rate despite an increase in the overall number of spinal surgeries. The BMCB also contributed to shorter operation times, shorter hospital stays, and lower postoperative deterioration rates of ECOGPS and BI.

Human Non-Hypertrophic Nonunion Tissue Contains Osteoblast Lineage Cells and E-BMP-2 Activates Osteogenic and Chondrogenic Differentiation.

In this study, we examined the proliferation capability and osteogenic and chondrogenic differentiation potential of non-hypertrophic nonunion cells (NHNCs), and the effect of Escherichia coli-derived BMP-2 (E-BMP-2) on them. We enrolled five patients with non-hypertrophic nonunion. NHNCs isolated from nonunion tissue sampled during surgery were cultured, passaged, counted every 14 days, and analyzed. NHNCs were homogenous fibroblastic adherent cells and long-lived through at least 10 passages, with a slight decline. The cells were consistently positive for mesenchymal stem cell-related markers CD73 and CD105, and negative for the hematopoietic markers CD14 and CD45. NHNCs could differentiate into osteoblast lineage cells; however, they did not have strong calcification or sufficient chondrogenic differentiation capability. E-BMP-2 did not affect the proliferative capability of the cells but improved their osteogenic differentiation capability by increasing alkaline phosphatase activity and upregulating the gene expression of osterix, bone sialoprotein, and osteocalcin. E-BMP-2 enhanced their chondrogenic differentiation capability by upregulating the gene expression of aggrecan and collagen type II. We showed, for the first time, that NHNCs have the capacity to differentiate into osteoblast-lineage cells, although the chondrogenic differentiation potential was poor. Local application of E-BMP-2 with preservation of nonunion tissue is a potential treatment option for non-hypertrophic nonunion.

Preoperative frailty affects postoperative complications, exercise capacity, and home discharge rates after surgical and transcatheter aortic valve replacement.

Assessment of frailty is important for risk stratification among the elderly with severe aortic stenosis (AS) when considering interventions such as surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR). However, evidence of the impact of preoperative frailty on short-term postoperative outcomes or functional recovery is limited. This retrospective study included 234 consecutive patients with severe AS who underwent SAVR or TAVR at Kobe University Hospital between Dec 2013 and Dec 2019. Primary outcomes were postoperative complications, postoperative 6-min walking distance (6MWD), and home discharge rates. The mean age was 82 ± 6.6 years. There were 169 (SAVR: 80, TAVR: 89) and 65 (SAVR: 20, TAVR: 45) patients in the non-frail and frail groups, respectively (p = 0.02). The postoperative complication rates in the frail group were significantly higher than those in the non-frail group [30.8% (SAVR: 35.0%, TAVR: 28.9%) vs. 10.7% (SAVR: 15.0%, TAVR: 6.7%), p < 0.001]. The home discharge rate in the non-frail group was significantly higher than that in the frail group [85.2% (SAVR: 81.2%, TAVR: 88.8%) vs. 49.2% (SAVR: 55.0%, TAVR: 46.7%), p < 0.001]. The postoperative 6MWD in the non-frail group was significantly longer than that in the frail group [299.3 ± 87.8 m (SAVR: 321.9 ± 90.8 m, TAVR: 281.1 ± 81.3 m) vs. 141.9 ± 92.4 m (SAVR: 167.8 ± 92.5 m, TAVR: 131.6 ± 91.3 m), p < 0.001]. The TAVR group did not show a decrease in the 6MWD after intervention, regardless of frailty. We report for the first time that preoperative frailty was strongly associated with postoperative complications, 6MWD, and home discharge rates following both SAVR and TAVR. Preoperative frailty assessment may provide useful indications for planning better individualized therapeutic interventions and supporting comprehensive intensive care before and after interventions.

Physical activity among patients with breast cancer receiving aromatase inhibitors is associated with bone health: a cross-sectional observational study.

PURPOSE: To examine the association of physical activity (PA) with bone health among patients with breast cancer receiving adjuvant aromatase inhibitor (AI) treatment. METHODS: In this single-center observational study, we enrolled postmenopausal women with primary hormone receptor-positive breast cancer who were receiving adjuvant AI treatment. We assessed patient bone health [bone mineral density (BMD) and biomarkers of bone turnover] as main outcomes. PA was assessed using Baecke physical activity questionnaires (BPAQ) and an accelerometer. Multiple regression analysis was performed after adjustment for age, body mass index, smoking history and duration of AI treatment. For missing data, multiple imputation analysis was adapted. RESULTS: The mean age of the 53 enrolled patients was 67.4 ± 8.4 years. The mean duration of AI administration was 25.7 ± 18.9 months. The most frequently administered AI was anastrozole (73.6%). Although not related to BMD, PA was related to bone turnover. Serum collagen type I amino-terminal propeptide, a bone formation marker, was associated with only light PA (t = - 2.55, p = 0.015), while tartrate-resistant acid phosphatase 5b, a bone absorption marker, was associated with work index in the BPAQ subscale and light PA (t = - 2.28, p = 0.028, t = - 2.26, p = 0.031, respectively). The results for all patients were similar to those observed in the multiple imputation analysis. CONCLUSION: PA was significantly associated with bone turnover among cancer patients receiving AI treatment. Light PA and PA in the work domain were the most important factors among various PA intensities and PA domains.

Transcutaneous carbon dioxide application inhibits muscle atrophy after fracture in rats.

BACKGROUND: Muscle atrophy causes difficulty in resuming daily activities after a fracture. Because transcutaneous carbon dioxide (CO2) application has previously upregulated oxygen pressure in the local tissue, thereby demonstrating its potential in preventing muscle atrophy, here we investigated effects of CO2 application on muscle atrophy after femoral shaft fracture. METHODS: Thirty fracture model rats were produced and randomly divided into a no treatment (control group) and treatment (CO2 group) groups. After treatment, the soleus muscle was dissected at post-fracture days 0, 14, and 21. Evaluations were performed by measuring muscle weight and performing histological examination and gene expression analysis. RESULTS: Muscle weight was significantly higher in the CO2 group than in the control group. Histological analysis revealed that the muscle fiber cross-sectional area was reduced in both groups. Nevertheless, the extent of atrophy was lesser in the CO2 group. Muscle fibers in the control group tended to change into fast muscle fibers. Vascular staining revealed that more capillary vessels surrounded the muscle fibers in the CO2 group than in the control group. Messenger RNA (mRNA) analysis revealed that the CO2 group had a significantly enhanced expression of genes that were related to muscle synthesis. CONCLUSION: Transcutaneous CO2 application may be a novel therapeutic strategy for preventing skeletal muscle atrophy after fracture.

Effects of the duration of transcutaneous CO2 application on the facilitatory effect in rat fracture repair.

BACKGROUND: Carbon dioxide therapy has been reported to be effective in treating certain cardiac diseases and skin problems. Although a previous study suggested that transcutaneous carbon dioxide application accelerated fracture repair in association with promotion of angiogenesis, blood flow, and endochondral ossification, the influence of the duration of carbon dioxide application on fracture repair is unknown. The aim of this study was to investigate the effect of the duration of transcutaneous carbon dioxide application on rat fracture repair. METHODS: A closed femoral shaft fracture was created in each rat. Animals were randomly divided into four groups: the control group; 1w-CO2 group, postoperative carbon dioxide treatment for 1 week; 2w-CO2 group, postoperative carbon dioxide treatment for 2 weeks; 3w-CO2 group, postoperative carbon dioxide treatment for 3 weeks. Transcutaneous carbon dioxide application was performed five times a week in the carbon dioxide groups. Sham treatment, where the carbon dioxide was replaced with air, was performed for the control group. Radiographic, histological, and biomechanical assessments were performed at 3 weeks after fracture. RESULTS: The fracture union rate was significantly higher in the 3w-CO2 group than in the control group (p < 0.05). Histological assessment revealed promotion of endochondral ossification in the 3w-CO2 group than in the control group. In the biomechanical assessment, all evaluation items related to bone strength were significantly higher in the 3w-CO2 group than in the control group (p < 0.05). CONCLUSIONS: The present study, conducted using an animal model, demonstrated that continuous carbon dioxide application throughout the process of fracture repair was effective in enhancing fracture healing.

Expressions of circadian clock genes represent disease activities of RA patients treated with biological DMARDs.

Objectives: Rheumatoid Arthritis (RA) is the autoimmune disease representing the circadian variations of symptoms such as morning stiffness of joints or increased production of cytokines around midnight. Clock genes have been reported to affect on the pathogenesis of RA, however, the detailed relation between clock genes and disease activities of RA has remained unclear.Methods: In this study, 15 RA patients treated with biological disease modifying anti-rheumatic drugs (bDMARDs) were enrolled (TNF inhibitor, 5; IL-6 inhibitor, 5; CTLA4-IgG, 5). Blood samples were collected from RA patients before treatment and at the study end-point fulfilling DAS28-ESR < 3.2. Total RNA was extracted from leukocytes to examine the expressions of the clock genes. We then evaluated the correlation of the clock gene expression with disease activity and the diagnostic values of the clock genes.Results: The expressions of the clock genes were significantly modulated by bDMARDs treatments. Disease activities were significantly correlated with the clock genes expressions, and disease remission/low disease activity could be distinguished from moderate/high disease activity due to the sensitivities, the specificities and the areas under the curves of that.Conclusion: The expressions of the clock genes in leukocytes could be useful as novel biomarkers predicting disease activities and therapeutic efficacies for bDMARDs in RA treatments.

Longitudinal Quadriceps Strength Recovery After Anterior Cruciate Ligament Reconstruction With Hamstring Autograft: Patients Stratified by Preoperative Quadriceps Strength Deficit.

CONTEXT: Some studies have discussed postoperative quadriceps strength recovery after anterior cruciate ligament reconstruction (ACLR). However, the effect of preoperative quadriceps strength deficit on longitudinal postoperative quadriceps strength recovery after ACLR with hamstring autograft is unknown. OBJECTIVE: To reveal the longitudinal postoperative quadriceps strength recovery after ACLR with hamstring autograft among patient groups stratified by preoperative quadriceps strength deficit. DESIGN: Retrospective cohort study. SETTING: Single center. PATIENTS: In total, 420 patients (222 men and 218 women; age at the time of surgery 23.1 [8.9] y) who underwent ipsilateral ACLR with hamstring autograft and completed knee function tests preoperatively and 3, 6, and 12 months postoperatively were included in this study. INTERVENTION: The authors measured quadriceps strength at 60°/s, tested 1-leg hop performance (distance and anxiety), and calculated the quadriceps strength index (QSI) and limb symmetry index for 1-leg hop distance. Patients were divided into the following 4 groups according to their preoperative QSI: >80% (Excellent group), 80% to 60% (Good group), 60% to 40% (Moderate group), and ≤40% (Poor group). MAIN OUTCOME MEASURES: Postoperative QSI at 3, 6, and 12 months and 1-leg hop performance at 12 months after the surgery. RESULTS: The Excellent group had the highest postoperative QSI at all periods. Based on the 1-leg hop performance, the Poor group had the lowest limb symmetry index and significantly greater anxiety during jump performance in comparison with the Excellent and Good groups. CONCLUSION: The present study shows a longitudinal recovery process and the average postoperative quadriceps strength after ACLR with hamstring autograft in patient groups stratified by preoperative QSI. The results indicate that the difference in preoperative QSI affects not only the longitudinal postoperative QSI recovery but also high-level 1-leg hop performance after ACLR using hamstring autograft.

Association between preoperative sleep disturbance and low muscle mass in patients with gastrointestinal cancer.

[Purpose] Low muscle mass and sleep disturbance are common among geriatric patients with cancer. In patients with gastrointestinal cancer, low muscle mass is considered an indicator of poor prognosis. In the recent years, sleep disturbance has attracted much attention as a factor for low muscle mass among community-dwelling elderly individuals; however, such associations are unclear in patients with cancer. The present study investigated the relationship between preoperative sleep disturbance and low muscle mass in patients with gastrointestinal cancer. [Participants and Methods] This cross-sectional survey enrolled 86 elderly patients (aged more than 60 years) with gastrointestinal cancer who were scheduled for curative surgery. Low preoperative muscle mass was defined according to Asian Working Group for Sarcopenia criteria. Sleep disturbance was assessed using the Japanese version of the Pittsburgh Sleep Quality Index, including the subscales. [Results] Twenty-seven patients (31%) were classified as having low muscle mass. After adjusting for confounding factors, bad sleep quality, determined by the subscales, was significantly associated with low muscle mass. [Conclusion] Our results suggest that the evaluation of sleep quality is imperative for addressing low preoperative muscle mass in patients with gastrointestinal cancer.

Effects of hypertonia on contracture development in rat spinal cord injury.

STUDY DESIGN: Experimental animal study. OBJECTIVES: Spastic hypertonia is originally believed to cause contractures from clinical observations. Botulinum toxin is effective for the treatment of spasticity and is widely used in patients who have joints with contractures. Using an established rat model with knee contractures after spinal cord injuries, we aimed to verify whether hypertonia contributes to contracture development, and the botulinum toxin improves structural changes in muscles and joint components responsible for contractures. SETTING: University laboratory in Japan. METHODS: To evaluate the effect of hypertonia on contracture development, the rats received botulinum toxin injections after spinal cord injuries. Knee extension motion was measured with a goniometer applying a standardized torque under anesthesia, and the contribution by muscle or non-muscle structures to contractures were calculated by measuring joint motion before and after the myotomies. We quantitatively measured the muscle atrophy, muscle fibrosis, and synovial intima length. RESULTS: Botulinum toxin injections significantly improved contractures, whereas did not completely prevent contracture development. Botulinum toxin was effective in improving the muscular factor, but little difference in the articular factor. Spinal cord injuries induced muscle atrophy, and botulinum toxin significantly accelerated muscle atrophy and fibrosis. The synovial intima length decreased significantly after spinal cord injuries, and botulinum toxin did not improve this shortening. CONCLUSIONS: This animal study provides new evidence that hypertonia is not the sole cause rather is the partial contributor of contractures after spinal cord injuries. Furthermore, botulinum toxin has adverse effects in the muscle.

Transcutaneous Carbon Dioxide Improves Contractures After Spinal Cord Injury in Rats.

BACKGROUND: Joint contractures are a major complication in patients with spinal cord injuries. Positioning, stretching, and physical therapy are advocated to prevent and treat contractures; however, many patients still develop them. Joint motion (exercise) is crucial to correct contractures. Transcutaneous carbon dioxide (CO2) therapy was developed recently, and its effect is similar to that of exercise. This therapy may be an alternative or complementary approach to exercise. QUESTION/PURPOSES: Using an established model of spinal cord injury in rats with knee flexion contractures, we sought to clarify whether transcutaneous CO2 altered (1) contracture, as measured by ROM; (2) muscular and articular factors contributing to the loss of ROM; (3) fibrosis and fibrosis-related gene expression in muscle; and (4) the morphology of and fibrosis-related protein expression in the joint capsule. METHODS: Thirty-six Wistar rats were divided into three equal groups: caged control, those untreated after spinal cord injury, and those treated with CO2 after spinal cord injury. The rats were treated with CO2 from either the first day (prevention) or 15th day (treatment) after spinal cord injury for 2 or 4 weeks. The hindlimbs of rats in the treated group were exposed to CO2 gas for 20 minutes once daily. Knee extension ROM was measured with a goniometer and was measured again after myotomy. We calculated the muscular and articular factors responsible for contractures by subtracting the post-myotomy ROM from that before myotomy. We also quantified histologic muscle fibrosis and evaluated fibrosis-related genes (collagen Type 1, α1 and transforming growth factor beta) in the biceps femoris muscle with real-time polymerase chain reaction. The synovial intima's length was measured, and the distribution of fibrosis-related proteins (Type I collagen and transforming growth factor beta) in the joint capsule was observed with immunohistochemistry. Knee flexion contractures developed in rats after spinal cord injuries at all timepoints. RESULTS: CO2 therapy improved limited-extension ROM in the prevention group at 2 weeks (22° ± 2°) and 4 weeks (29° ± 1°) and in the treatment group at 2 weeks (31° ± 1°) compared with untreated rats after spinal cord injuries (35° ± 2°, mean difference, 13°; 39° ± 1°, mean difference, 9°; and 38° ± 1°, mean difference, 7°, respectively) (95% CI, 10.50-14.86, 8.10-10.19, and 4.73-9.01, respectively; all p < 0.001). Muscular factors decreased in treated rats in the prevention group at 2 weeks (8° ± 2°) and 4 weeks (14°± 1°) and in the treatment group at 2 weeks (14 ± 1°) compared with untreated rats (15° ± 1°, 4.85-9.42; 16° ± 1°, 1.24-3.86; and 17° ± 2°, 1.16-5.34, respectively; all p < 0.05). The therapy improved articular factors in the prevention group at 2 weeks (4° ± 1°) and 4 weeks (6° ± 1°) and in the treatment group at 2 weeks (8° ± 1°) compared with untreated rats (10° ± 1°, 4.05-7.05; 12° ± 1°, 5.18-8.02; and 11° ± 2°, 1.73-5.50, respectively; all p < 0.05). CO2 therapy decreased muscle fibrosis in the prevention group at 2 weeks (p < 0.001). The expression of collagen Type 1, α1 mRNA in the biceps femoris decreased in treated rats in the prevention group at 2 and 4 weeks compared with untreated rat (p = 0.002 and p = 0.008, respectively), although there was little difference in the expression of transforming growth factor beta (p > 0.05). CO2 therapy did not improve shortening of the synovial intima at all timepoints (all p > 0.05). CO2 therapy decreased transforming growth factor beta immunolabeling in joint capsules in the rats in the prevention group at 2 weeks. The staining intensity and Type I collagen pattern showed no differences among all groups at all timepoints. CONCLUSION: CO2 therapy may be useful for preventing and treating contractures after spinal cord injuries. CO2 therapy particularly appears to be more effective as a prevention and treatment strategy in early-stage contractures before irreversible degeneration occurs, as shown in a rat model. CLINICAL RELEVANCE: Our findings support the idea that CO2 therapy may be able to improve the loss of ROM after spinal cord injury.

Topical cutaneous application of carbon dioxide via a hydrogel for improved fracture repair: results of phase I clinical safety trial.

BACKGROUND: Clinicians have very limited options to improve fracture repair. Therefore, it is critical to develop a new clinically available therapeutic option to assist fracture repair biologically. We previously reported that the topical cutaneous application of carbon dioxide (CO2) via a CO2 absorption-enhancing hydrogel accelerates fracture repair in rats by increasing blood flow and angiogenesis and promoting endochondral ossification. The aim of this study was to assess the safety and efficacy of CO2 therapy in patients with fractures. METHODS: Patients with fractures of the femur and tibia were prospectively enrolled into this study with ethical approval and informed consent. The CO2 absorption-enhancing hydrogel was applied to the fractured lower limbs of patients, and then 100% CO2 was administered daily into a sealed space for 20 min over 4 weeks postoperatively. Safety was assessed based on vital signs, blood parameters, adverse events, and arterial and expired gas analyses. As the efficacy outcome, blood flow at the level of the fracture site and at a site 5 cm from the fracture in the affected limb was measured using a laser Doppler blood flow meter. RESULTS: Nineteen patients were subjected to complete analysis. No adverse events were observed. Arterial and expired gas analyses revealed no adverse systemic effects including hypercapnia. The mean ratio of blood flow 20 min after CO2 therapy compared with the pre-treatment level increased by approximately 2-fold in a time-dependent manner. CONCLUSIONS: The findings of the present study revealed that CO2 therapy is safe to apply to human patients and that it can enhance blood flow in the fractured limbs. TRIAL REGISTRATION: This study has been registered in the UMIN Clinical Trials Registry (Registration number: UMIN000013641, Date of registration: July 1, 2014).

Topical cutaneous application of CO2 accelerates bone healing in a rat femoral defect model.

BACKGROUND: Bone defects may occur because of severe trauma, nonunion, infection, or tumor resection. However, treatments for bone defects are often difficult and have not been fully established yet. We previously designed an efficient system of topical cutaneous application of carbon dioxide (CO2) using a novel hydrogel, which facilitates CO2 absorption through the skin into the deep area within a limb. In this study, the effect of topical cutaneous application of CO2 on bone healing was investigated using a rat femoral defect model. METHODS: In this basic research study, an in vivo bone defect model, fixed with an external fixator, was created using a rat femur. The affected limb was shaved, and CO2 was applied for 20 min/day, 5 days/week. In the control animals, CO2 gas was replaced with air. Radiographic, histological, biomechanical, and genetic assessments were performed to evaluate bone healing. RESULTS: Radiographically, bone healing rate was significantly higher in the CO2 group than in the control group at 4 weeks (18.2% vs. 72.7%). The degree of bone healing scored using the histopathological Allen grading system was significantly higher in the CO2 group than in the control group at 2 weeks (1.389 ± 0.334 vs. 1.944 ± 0.375). The ultimate stress, extrinsic stiffness, and failure energy were significantly greater in the CO2 group than in the control group at 4 weeks (3.2 ± 0.8% vs. 38.1 ± 4.8%, 0.6 ± 0.3% vs. 41.5 ± 12.2%, 2.6 ± 0.8% vs. 24.7 ± 5.9%, respectively.). The volumetric bone mineral density of the callus in micro-computed tomography analysis was significantly higher in the CO2 group than in the control group at 4 weeks (180.9 ± 43.0 mg/cm3 vs. 247.9 ± 49.9 mg/cm3). Gene expression of vascular endothelial growth factor in the CO2 group was significantly greater than that in the control group at 3 weeks (0.617 ± 0.240 vs. 2.213 ± 0.387). CONCLUSIONS: Topical cutaneous application of CO2 accelerated bone healing in a rat femoral defect model. CO2 application can be a novel and useful therapy for accelerating bone healing in bone defects; further research on its efficacy in humans is warranted.

Transcutaneous carbon dioxide attenuates impaired oxidative capacity in skeletal muscle in hyperglycemia model.

Hyperglycemia impairs oxidative capacity in skeletal muscle. Muscle oxidative capacity is regulated by peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α). Transcutaneous carbon dioxide (CO2) enhances PGC-1α expression in skeletal muscle. Therefore, the aim of this study was to clarify the effects of CO2 therapy on muscle oxidative capacity impaired by streptozotocin (STZ)-induced hyperglycemia. Eight-week-old male Wistar rats were randomly divided into 4 groups: control, CO2 treatment, STZ-induced hyperglycemia, and STZ-induced hyperglycemia treated with CO2. STZ-induced hyperglycemia resulted in a decrease of muscle oxidative capacity and decreased PGC-1α and cytochrome c oxidase subunit 4 (COX-4) expression levels; while, application of transcutaneous CO2 attenuated this effect, and enhanced the expression levels of endothelial nitric oxide synthesis (eNOS). These results indicate that transcutaneous CO2 improves impaired muscle oxidative capacity via enhancement of eNOS and PGC-1α-related signaling in the skeletal muscle of rats with hyperglycemia.

Prediction of quadriceps strength recovery after anterior cruciate ligament reconstruction with a hamstring autograft: Decision tree analysis.

BACKGROUND: The wide variations in patient demographics and concomitant injuries make the prediction of which patients will regain strength quickly following anterior cruciate ligament (ACL) reconstruction challenging. This study aimed to identify the dominant factor affecting quadriceps strength recovery after ACL reconstruction with a hamstring tendon autograft and to construct a predictive model for quadriceps strength recovery using decision tree analysis. METHODS: Three hundred and eighty-six patients who underwent ACL reconstruction with a hamstring tendon autograft were included in this study. The isokinetic quadriceps strength at 60°/s was measured preoperatively and at 6 months after surgery. The quadriceps strength index (QSI) was calculated by normalising the peak torque of the involved leg with the uninvolved leg and multiplying it by 100. A stepwise multiple linear regression and a decision tree analysis were performed to assess whether or not the following parameters affect quadriceps strength recovery at 6 months: socio-demographic data and maximum isokinetic quadriceps strength. RESULTS: The preoperative QSI, age, and pre-injury Tegner activity scale were independently correlated with quadriceps strength recovery at 6 month after surgery. The decision tree analysis demonstrated that patients were expected to have a QSI ≥85% at 6 months after surgery if they met one of the following conditions: (1) age <23 years with a preoperative QSI ≥78.8%, (2) age ≥29 years with a preoperative QSI ≥98.0%, or (3) age <16 years with a preoperative QSI <58.5% and pre-injury Tegner activity scale ≥9. By contrast, patients ≥29 years with a preoperative QSI <98.0% were likely to achieve a quadriceps strength index <70% at 6 months after surgery. CONCLUSIONS: Based on the results of the decision tree analysis, younger patients could achieve good quadriceps recovery even if they have a lower preoperative QSI, whereas patients ≥29 years need a higher preoperative QSI to obtain good muscle recovery.

TNF-α induces expression of the circadian clock gene Bmal1 via dual calcium-dependent pathways in rheumatoid synovial cells.

Tumor necrosis factor (TNF)-α is responsible for expressions of several clock genes and affects joint symptoms of rheumatoid arthritis (RA) with diurnal fluctuation. We tried to determine the mechanism involved in over-expression of Bmal1, induced by TNF-α, in primary cultured rheumatoid synovial cells. Cells were incubated with intra-cellular Ca2+ chelator BAPTA-AM, calcineurin inhibitor FK506 and p300/CBP (CREB binding protein) inhibitor C646, respectively, or transfected with p300 and CBP small interfering RNA (siRNA) before stimulation with TNF-α. Oscillation phase and amplitude of Bmal1, transcriptional activator Rorα, transcriptional repressor Rev-erbα, and histone acetyltransferases (p300 and Cbp) were evaluated by quantitative real-time PCR. As results, TNF-α did not influence the oscillation phase of Rev-erbα, while enhanced those of Rorα, resulting in over-expression of Bmal1. When Ca2+ influx was inhibited by BAPTA-AM, TNF-α-mediated up-regulation of Rorα was cancelled, however, that of Bmal1 was still apparent. When we further explored another pathway between TNF-α and Bmal1, TNF-α suppressed the expression of Rev-erbα in the absence of Ca2+ influx, as well as those of p300 and Cbp genes. Finally, actions of TNF-α, in increasing Bmal1/Rorα and decreasing Rev-erbα, were cancelled by C646 treatment or silencing of both p300 and Cbp. In conclusion, we determined a novel role of TNF-α in inducing Bmal1 via dual calcium dependent pathways; Rorα was up-regulated in the presence of Ca2+ influx and Rev-erbα was down-regulated in the absence of that. Results proposed that inhibition of p300/CBP could be new therapeutic targets for RA.

Impact of Sarcopenia on Unplanned Readmission and Survival After Esophagectomy in Patients with Esophageal Cancer.

BACKGROUND: Although sarcopenia increases postoperative complications following esophagectomy, its effects on prognosis remain unclear. This study was performed to identify the effect of sarcopenia on 90-day unplanned readmission and overall survival (OS) after esophagectomy. METHODS: Ninety-eight patients with esophageal cancer who underwent esophagectomy were enrolled in this study. Unplanned readmission was defined as any emergent hospitalization within 90 days after discharge. Sarcopenia, defined as low muscle mass plus low muscle strength and/or low physical performance according to the Asian consensus definition, was assessed prior to esophagectomy. Multivariate logistic regression analysis was performed to identify factors that contributed to 90-day unplanned readmission. OS was estimated using the Kaplan-Meier method, and a Cox proportional hazards model was used to assess the relationship between sarcopenia and OS. RESULTS: Thirty-one patients (31.6%) were diagnosed with sarcopenia. The 90-day unplanned readmission rate was significantly higher in patients with sarcopenia than those without (42.9% vs. 16.4%, respectively; p = 0.01). Multivariable logistic regression analysis showed that sarcopenia was an independent predictor of 90-day unplanned readmission [odds ratio 3.71, 95% confidence interval (CI) 1.29-11.05; p = 0.02], and the log-rank test showed that sarcopenia was associated with OS (p = 0.01). Moreover, sarcopenia was a significant predictor of OS after adjustment for age, sex, and pathological stage (hazard ratio 2.35, 95% CI 1.21-4.54; p = 0.01). CONCLUSIONS: Sarcopenia is a risk factor for 90-day unplanned readmission and OS following esophagectomy. Assessment of sarcopenia could help to identify patients at higher risk of a poor prognosis after esophagectomy.