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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

Background Oral health is important for maintaining general health and is associated with components of physical frailty among the elderly. Oral health problems are common in hospitalized patients; however, no reports on oral health problems pertain to patients with cardiovascular diseases (CVD). The present study aimed to evaluate the association between oral health and physical frailty in these patients. Methods In this retrospective cohort study, we included consecutive patients admitted for CVD to our hospital between May 2014 and December 2018. Physical frailty was assessed using the Short Physical Performance Battery (SPPB). Oral health characteristics, such as the number of remaining teeth, denture use, occlusal support, and periodontal status, were assessed. Results In our cohort (n = 457), 111 (24.3%) patients had physical frailty. Univariate linear regression showed that the number of teeth present and the prevalence of occlusal support were significantly lower in patients with than without physical frailty. Pearson correlation indicated that the number of teeth significantly correlated with the nutritional status (r = 0.27) and SPPB score (r = 0.24), grip strength (r = 0.33), and 6-minute walking distance (r = 0.26). Multiple linear regression analysis showed that the number of teeth was independently associated with physical frailty after adjusting for confounders. Conclusions Oral health was closely associated with physical frailty, and nutritional status in patients with CVD; thus, it could be an important screening marker for early frailty symptoms and a predictor of future malnutrition risk.

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.

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.

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.

Background Elderly patients undergoing cardiac surgery often show poor nutritional status, muscle wasting, and sarcopenia, which are reported to affect postoperative functional recovery and incidence of complications. Amino acids are essential in maintaining nutritional status, synthesizing muscle protein, and promoting beneficial energy balance of the heart muscle. β-Hydroxy β-methylbutyric acid (HMB) is a leucine metabolite known to increase muscle protein synthesis and inhibit protein catabolism; it has been used to more effectively support patients with muscle wasting due to wearing diseases. However, the efficacy of amino acid administration comprising HMB in patients undergoing open heart surgery remains unclear. This study aims to examine whether preoperative short-term aggressive amino acid administration helps support postoperative recovery of physical function and prevent complications. Methods This is a single-center prospective randomized controlled trial (UMIN000030490). Patients aged ≥65 years who will be hospitalized for medical examination before cardiac surgery will be recruited. The participants will be randomly assigned to the experimental or control group. The experimental group will be administered with an amino acid supplement with HMB 1200 mg, l -glutamine 7000 mg, and l -arginine 7000 mg once or twice per day depending on the degree of renal dysfunction, for 14–28 days preoperatively. The control group will not receive any nutritional intervention. The main outcome will be a change in the 6-min walking test distance pre- and postoperatively as a sign of functional recovery. Secondary outcomes such as the incidence of complications; physical, nutritional, and psychological states; mortality; and length of hospital stay will also be evaluated. Conclusion This clinical study will determine the effects of preoperative short-term oral amino acid supplementation with HMB, l -glutamine, and l -arginine on postoperative physical function in elderly patients undergoing cardiac surgery.

Objective: To elucidate the roles of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) in cell cycle regulation and proliferation of rheumatoid arthritis fibroblast-like synovial cells (RA-FLSs). Methods: Under stimulation with IL-6/soluble interleukin-6 receptor (sIL-6R) and TNF-α, we examined the expression of cell cycle regulators [p16INK4a, p21Cip1, p27Kip1, cyclin-dependent kinase-4 (CDK4), CDK6, Cyclin D, Cyclin E, and retinoblastoma protein (pRB)] by quantitative polymerase chain reaction, Western blotting, and immunofluorescence staining. The expression of pRB, with or without 10% foetal bovine serum, was examined by Western blotting. DNA synthesis and cell viability were examined by the BrdU assay and WST-8 assay, respectively. After transfection with siRNA/p16INK4a, siRNA/p21Cip1, siRNA/p27Kip1, siRNA/CDK4, or siRNA/CDK6, RA-FLSs were successively stimulated with or without IL-6/sIL-6R or TNF-α to determine cell viability. Results: IL-6/sIL-6R significantly decreased the expression of p16INK4a, and increased p21Cip1, Cyclin E1, CYCLIN D, and pRB. TNF-α decreased the expression of CDK4, and significantly increased p27Kip1, CDK6, Cyclin E1/E2, CYCLIN D, CYCLIN E, pRB, and phosphorylated pRB (phospho-pRB). By immunofluorescence staining, CYCLIN D and phospho-pRB were simultaneously stained in the single cell. In serum-free culture, the expression of pRB was apparently decreased. DNA synthesis and cell viability were significantly increased by IL-6/sIL-6R and TNF-α. Silencing of CDK6 attenuated the cell viability induced by IL-6 and TNF-α. Conclusion: The results indicate that IL-6 and TNF-α interact with each other in regulating the cell cycle and accelerate the proliferation of RA-FLSs.

Background: Data of vitamin D sufficiency in Asian patients with osteoporotic fragility hip fractures are limited. This study aimed to obtain data from the Japanese population. Methods: Patients aged 60 years or older with hip fractures were prospectively enrolled. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured. Levels were compared between patients receiving and not receiving treatment for osteoporosis, those with and without previous contralateral hip fractures, and those with femoral neck versus trochanteric fractures. Sex-based differences were also assessed. The serum levels in patients younger than 60 years with extremity fractures were assessed, and differences between elderly and younger patients were evaluated. The individual correlation between 25(OH)D levels and the ultraviolet (UV) index and age was analyzed in elderly patients with hip fractures. Results: The data of 360 patients (aged 84.7 ± 8.2 years), comprising 80 men and 280 women, were analyzed. The mean 25(OH)D level was 16.5 ± 7.2 ng/mL. The prevalence of vitamin D insufficiency (25(OH)D Conclusion: Perennial vitamin D insufficiency is prevalent in elderly Japanese patients with hip fractures.

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 (CO(2)) 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 CO(2) 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 CO(2) after spinal cord injury. The rats were treated with CO(2) 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 CO(2) 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: CO(2) 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). CO(2) 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). CO(2) therapy did not improve shortening of the synovial intima at all timepoints (all p > 0.05). CO(2) 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: CO(2) therapy may be useful for preventing and treating contractures after spinal cord injuries. CO(2) 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 CO(2) therapy may be able to improve the loss of ROM after spinal cord injury.

Objectives The aim of the present study was to investigate the impact of preoperative cachexia on postoperative length of stay (LOS) in elderly patients with gastrointestinal cancer. Methods This prospective cohort study enrolled 98 patients (≥60 y of age) with gastric or colorectal cancer who were scheduled to undergo curative surgery and were categorized as either having cachexia or as being in a non-cachexia group. The definition of cachexia was patients with >5% loss of stable body weight over the previous 6 mo, a body mass index (BMI) 2%, or sarcopenia and ongoing weight loss >2%. Multivariable Poisson regression analysis was performed with postoperative LOS as the dependent variable and the presence of cachexia as the independent variable, and age, sex, Eastern Cooperative Oncology Group performance status, education, cancer type, clinical stage, surgical approach, and the Charlson Comorbidity Index as confounding variables. Results Twenty-two patients (22.4%) were diagnosed with cachexia. Postoperative LOS was 17.1 ± 8.7 d in the non-cachexia group and 20.6 ± 10.8 d in the cachexia group. Multivariable Poisson analysis showed that preoperative cachexia was significantly associated with prolonged postoperative LOS after adjustment (2.41 d; 95% confidence interval, 0.28 to 4.55; P = 0.027). Conclusions Our results suggested that preoperative cachexia prolongs postoperative LOS in elderly patients with gastrointestinal cancer, implying that cachexia should be assessed and treated before surgery.

Background and aim Among elderly patients undergoing cardiac surgery, malnutrition is very common and related to muscle wasting known as sarcopenia. Cardiac surgery causes a further decline of nutritional status due to reduced dietary intake (DI); however, the impact of postoperative DI on functional recovery is unclear. Methods and results We enrolled 250 consecutive patients undergoing cardiac surgery. Daily DI was measured between postoperative days 3 and 7. Patients were categorized as having sufficient or insufficient DI based on whether their DI met or was less than estimated total energy requirements. Functional capacity was measured using the 6-minute walking distance (6MWD) preoperatively and at discharge. Mean postoperative DI was 22.4 ± 3.0 kcal/kg/day, and postoperative DI was insufficient in 92 patients (36.8%). The prevalence of sarcopenia was not different by postoperative DI. Although there was no significant difference in preoperative 6MWD results (P = 0.65), the sufficient DI group had longer 6MWD at discharge than the insufficient DI group (P = 0.04). In multivariate regression analysis, preoperative poor nutritional status (β = −0.29), duration of surgery (β = −0.18), and postoperative DI (β = 0.40) remained statistically significant predictors for improvement of 6MWD (P Conclusions Postoperative DI was independently associated with functional recovery, but preoperative sarcopenia was not. Regardless of preoperative nutritional status or the presence of sarcopenia, aggressive nutritional intervention in the early stage after surgery helps support functional recovery.

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.

Carbon dioxide (CO2) treatment is reported to have an antitumor effect owing to the improvement in intratumoral hypoxia. Previous studies were based on histological analysis alone. In the present study, the improvement in intratumoral hypoxia by percutaneous CO2 treatment in vivo was determined using 18F-fluoromisonidazole positron emission tomography-computed tomography (18F-FMISO PET-CT) images. Twelve Japanese nude mice underwent implantation of LM8 tumor cells in the dorsal subcutaneous area 2 weeks before percutaneous CO2 treatment and 18F-FMISO PET-CT scans. Immediately after intravenous injection of 18F-FMISO, CO2 and room air were administered transcutaneously in the CO2-treated group (n=6) and a control group (n=6), respectively; each treatment was performed for 10 minutes. PET-CT was performed 2 h after administration of 18F-FMISO. 18F-FMISO tumor uptake was quantitatively evaluated using the maximum standardized uptake value (SUVmax), tumor-to-liver ratio (TLR), tumor-to-muscle ratio (TMR), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Mean ± standard error of the mean (SEM) of the tumor volume was not significantly different between the two groups (CO2-treated group, 1.178±0.450 cm3; control group, 1.368±0.295 cm3; P=0.485). Mean ± SEM of SUVmax, TLR, MTV (cm3) and TLG were significantly lower in the CO2-treated group compared with the control group (0.880±0.095 vs. 1.253±0.071, P=0.015; 1.063±0.147361 vs. 1.455±0.078, P=0.041; 0.353±0.139 vs. 1.569±0.438, P=0.015; 0.182±0.070 vs. 1.028±0.338, P=0.015), respectively. TMR was not significantly different between the two groups (4.520±0.503 vs. 5.504±0.310; P=0.240). In conclusion, 18F-FMISO PET revealed that percutaneous CO2 treatment improved intratumoral hypoxia in vivo. This technique enables assessment of the therapeutic effect in CO2 treatment by imaging, and may contribute to its clinical application.

Objectives Frailty is a multidimensional syndrome. However, typical frailty scales used in oncology clinics assess physical impairment and/or malnutrition but do not consider the social domain. Our study aimed to clarify the relationship between preoperative social frailty and overall survival (OS) and cancer-specific survival (CSS) among older patients with gastrointestinal cancer. Design This was a prospective cohort study. Setting and Participants This single-center study recruited 195 patients with gastrointestinal cancer scheduled for curative surgery and aged >60 years. Methods The outcomes considered were the OS and CSS of surgery. Primary associated factors included frailty defined as a Geriatric 8 score ≤14; social frailty defined as 2 or more of the following—going out less frequently, rarely visiting friends, feeling unhelpful to friends or family, living alone, and not talking with someone daily, and combinations therein [no frailty without social frailty (−/−), frailty without social frailty (+/−), no frailty with social frailty (−/+), and frailty with social frailty (+/+)]. We used the Cox proportional hazards model and the Fine and Gray proportional subdistribution hazard model adjusting for confounding factors. Results Of the 195 patients, 181 (mean age, 72.0 years) were included for analysis. The median follow-up time was 994 days. Social frailty (hazard ratio 3.10) and their combinations [6.35; frailty with social frailty (+/+) vs no frailty without social frailty (−/−)] were significant predictors of OS. Social frailty (subdistribution hazard ratio 3.23) and their combinations (7.57) were significant predictors of CSS. Conclusions and Implications Preoperative social frailty is a predictor of OS and CSS in older patients with gastrointestinal cancer. Screening for social frailty, frailty, and their combinations in older patients with cancer is important.

Background MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that regulate gene expression. There is increasing evidence that some miRNAs are involved in the pathology of diabetes mellitus (DM) and its complications. We hypothesized that the functions of certain miRNAs and the changes in their patterns of expression may contribute to the pathogenesis of impaired fractures due to DM. Methods In this study, 108 male Sprague–Dawley rats were divided into DM and control groups. DM rats were created by a single intravenous injection of streptozotocin. Closed transverse femoral shaft fractures were created in both groups. On post-fracture days 5, 7, 11, 14, 21, and 28, miRNA was extracted from the newly generated tissue at the fracture site. Microarray analysis was conducted with miRNA samples from each group on post-fracture days 5 and 11. The microarray findings were validated by real-time polymerase chain reaction (PCR) analysis at each time point. Results Microarray analysis revealed that, on days 5 and 11, 368 and 207 miRNAs, respectively, were upregulated in the DM group, compared with the control group. The top four miRNAs on day 5 were miR-339-3p, miR451-5p, miR-532-5p, and miR-551b-3p. The top four miRNAs on day 11 were miR-221-3p, miR376a-3p, miR-379-3p, and miR-379-5p. Among these miRNAs, miR-221-3p, miR-339-3p, miR-376a-3p, miR-379-5p, and miR-451-5p were validated by real-time PCR analysis. Furthermore, PCR analysis revealed that these five miRNAs were differentially expressed with dynamic expression patterns during fracture healing in the DM group, compared with the control group. Conclusions Our findings will aid in understanding the pathology of impaired fracture healing in DM and may support the development of molecular therapies using miRNAs for the treatment of impaired fracture healing in patients with DM.

Summary Introduction Skin flap procedures are widely used to reconstruct skin and soft tissue defects. Skin flap necrosis is a serious postoperative complication. Many researchers have introduced pharmacological agents to improve flap ischemia in experimental studies. However, outcomes of these studies remain controversial. We previously demonstrated that transcutaneous CO2 application improves hypoxia in fracture repair. In this study, we hypothesized that improving hypoxia by transcutaneous CO2 application can improve the blood flow in skin flaps and increase angiogenesis. We investigated whether transcutaneous CO2 application can increase the survival of random-pattern skin flaps. Materials and methods Six-week-old male Sprague-Dawley rats were divided into two equal groups: the control group (n = 6) and CO2 group (n = 6). A random-pattern skin flap was constructed in these rats. Topical CO2 was applied using a hydrogel every day for 5 days in the CO2 group. The flap survival area was measured on postoperative days 1, 3, and 5. The vessel density and expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hypoxia-inducible factor-1α (HIF-1α) were evaluated on postoperative day 5. Results A statistically significant difference was found in the percentage of the flap survival area between the two groups on postoperative days 3 and 5 (p Conclusions Transcutaneous CO2 application can improve the blood flow in skin flaps and increase angiogenesis, thus increasing the survival of random-pattern skin flaps.

ObjectivesDiabetes mellitus (DM) is known to impair fracture healing. Increasing evidence suggests that some microRNA (miRNA) is involved in the pathophysiology of diabetes and its complications. We hypothesized that the functions of miRNA and changes to their patterns of expression may be implicated in the pathogenesis of impaired fracture healing in DM.MethodsClosed transverse fractures were created in the femurs of 116 rats, with half assigned to the DM group and half assigned to the control group. Rats with DM were induced by a single intraperitoneal injection of streptozotocin. At post-fracture days five, seven, 11, 14, 21, and 28, miRNA was extracted from the newly generated tissue at the fracture site. Microarray analysis was performed with miRNA samples from each group on post-fracture days five and 11. For further analysis, real-time polymerase chain reaction (PCR) analysis was performed at each timepoint.ResultsMicroarray analysis showed that there were 14 miRNAs at day five and 17 miRNAs at day 11, with a greater than twofold change in the DM group compared with the control group. Among these types of miRNA, five were selected based on a comparative and extended literature review. Real-time PCR analysis revealed that five types of miRNA (miR-140-3p, miR-140-5p, miR-181a-1-3p, miR-210-3p, and miR-222-3p) were differentially expressed with changing patterns of expression during fracture healing in diabetic rats compared with controls.ConclusionsOur findings provide information to further understand the pathology of impaired fracture healing in a diabetic rat model. These results may allow the potential development of molecular therapy using miRNA for the treatment of impaired fracture healing in patients with DM. Cite this article: S. Takahara, S. Y. Lee, T. Iwakura, K. Oe, T. Fukui, E. Okumachi, T. Waki, M. Arakura, Y. Sakai, K. Nishida, R. Kuroda, T. Niikura. Altered expression of microRNA during fracture healing in diabetic rats. Bone Joint Res 2018;7:139–147. DOI: 10.1302/2046-3758.72.BJR-2017-0082.R1.

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.

Background Few studies have addressed the impact of palliative surgery for cervical spine metastasis on patients’ performance status (PS) and quality of life (QOL). We investigated the surgical outcomes of patients with cervical spine metastasis and the risk factors for a poor outcome with a focus on the PS and QOL. Methods We prospectively analyzed patients with cervical spine metastasis who underwent palliative surgery from 2013 to 2018. The Eastern Cooperative Oncology Group PS (ECOGPS) and EuroQol 5-Dimension (EQ5D) score were assessed at study enrollment and 1, 3, and 6 months postoperatively. Neurological function was evaluated with Frankel grading. Univariate and multivariate analyses were performed to identify the risk factors for a poor surgical outcome, defined as no improvement or deterioration after improvement of the ECOGPS or EQ5D score within 3 months. Results Forty-six patients (mean age, 67.5 ± 11.7 years) were enrolled. Twelve postoperative complications occurred in 11 (23.9%) patients. The median ECOGPS improved from PS3 at study enrolment to PS2 at 1 month and PS1 at 3 and 6 months postoperatively. The mean EQ5D score improved from 0.085 ± 0.487 at study enrolment to 0.658 ± 0.356 at 1 month and 0.753 ± 0.312 at 3 months. A poor outcome was observed in 18 (39.1%) patients. The univariate analysis showed that variables with a P value of P = 0.025). Conclusions Palliative surgery for cervical spine metastasis improved the PS and QOL, but a cervicothoracic junction lesion could be a risk factor for a poor outcome.

The acceleration of nerve regeneration remains a clinical challenge. We previously demonstrated that transcutaneous CO2 application using a novel hydrogel increases the oxygen concentration in local tissue via an "artificial Bohr effect" with the potential to prevent muscle atrophy. In this study, we investigated the effect of transcutaneous CO2 administration on limb function after peripheral nerve injury in a rat sciatic nerve injury model. In total, 73 Sprague-Dawley rats were divided into a sham group, a control group (crush injury to sciatic nerve and no treatment) or a CO2 group (crush injury with transcutaneous CO2 application). CO2 was administered percutaneously for 20 min five times per week. Scores for the sciatic function index and pinprick test were significantly higher in the CO2 group than control group. The muscle wet weight ratios of the tibialis anterior and soleus muscles were higher in the CO2 group than control group. Electrophysiological examination showed that the CO2 group had higher compound motor action potential amplitudes and shorter distal motor latency than the control group. Histological examination of the soleus muscle sections at postoperative week 2 showed shorter fiber diameter in the control group than in the CO2 group. The mRNA expression of Atrogin-1 and MuRF-1 was lower, mRNA expression of VEGF and myogenin and MyoD was higher in CO2 group at postoperative week 2 compared to the control group. Clinical significance Transcutaneous CO2 application has the therapeutic potential to accelerate the recovery of muscle atrophy in peripheral nerve injury. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1653-1658, 2018.

Background One of the main complications in patients with muscular dystrophies is cardiac dysfunction. The literature on cardiac involvement in patients with Fukuyama congenital muscular dystrophy (FCMD) is limited. Aim To compare cardiac involvement between patients with FCMD and Duchenne muscular dystrophy (DMD). Methods We compared cardiac involvement between 30 patients with FCMD and 181 patients with DMD using echocardiography and serum biomarkers. All patients were receiving regular checkups at Kobe University Hospital. We used single regression analysis to compare echocardiographic parameters, age, and serum biomarkers. Results Almost all clinical and echocardiographic parameters were lower in patients with FCMD than DMD. The brain natriuretic peptide concentration in patients with FCMD showed no correlation with age or left ventricular ejection fraction ( r = 0.231, p = 0.22 and r = 0.058, p = 0.76, respectively). A log-rank test revealed that the risk of left ventricular systolic dysfunction was lower in patients with FCMD than DMD ( p = 0.046, hazard ratio = 0.348). Conclusion The clinical progression of cardiac dysfunction is significantly milder in patients with FCMD than DMD, while skeletal muscle involvement is significantly worse in patients with FCMD. These data suggest that the pathophysiological findings of FCMD can be explained by less severe cardiac dysfunction in FCMD than DMD.

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are the main subgroups of pulmonary hypertension (PH). Despite differences in their etiologies, both diseases are characterized by vascular remodeling, resulting in progressive right heart failure. Noninvasive periodic evaluation of exercise tolerance has become increasingly important. Cardiopulmonary exercise testing (CPET) and a 6-minute walk test (6MWT) are now both recommended for evaluating exercise tolerance, but there is insufficient knowledge about possible differences in the associations of exercise tolerance with right heart catheterization (RHC) data for patients with PAH and CTEPH.A retrospective study was performed with 57 patients with PH (24 with PAH and 33 with CTEPH) all of whom underwent echocardiography, CPET, 6MWT, and RHC.For both patients with PAH and CTEPH, peak heart rate during CPET was significantly higher than that from 6MWT, whereas minimum peripheral oxygen saturation during CPET and 6MWT was similar. For patients with PAH, significant correlations were observed between peak (Equation is included in full-text article.)O2 and cardiac index (CI) (r = 0.59; P = .002) and between (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 slopes and CI (r =-0.46, P = .02), as well as a nonsignificant correlation tendency for peak (Equation is included in full-text article.)O2 and pulmonary vascular resistance (PVR) and for (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 and PVR (r =-0.39; P = .05; and r = 0.39; P = .06, respectively). For patients with CTEPH, however, a significant correlation was observed only between (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 slopes and CI (r =-0.38; P = .02).PH etiology should be considered when assessing exercise tolerance, whereas CPET can be effective in addition to hemodynamic assessment by means of RHC for periodic evaluation during followup.

Carbon dioxide (CO2) therapy can be applied to treat a variety of disorders. We previously found that transcutaneous application of CO2 with a hydrogel decreased the tumor volume of several types of tumors and induced apoptosis via the mitochondrial pathway. However, only one condition of treatment intensity has been tested. For widespread application in clinical antitumor therapy, the conditions must be optimized. In the present study, we investigated the relationship between the duration, frequency, and treatment interval of transcutaneous CO2 application and antitumor effects in murine xenograft models. Murine xenograft models of three types of human tumors (breast cancer, osteosarcoma, and malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma) were used to assess the antitumor effects of transcutaneous CO2 application of varying durations, frequencies, and treatment intervals. In all human tumor xenografts, apoptosis was significantly induced by CO2 treatment for ≥10 min, and a significant decrease in tumor volume was observed with CO2 treatments of >5 min. The effect on tumor volume was not dependent on the frequency of CO2 application, i.e., twice or five times per week. However, treatment using 3- and 4-day intervals was more effective at decreasing tumor volume than treatment using 2- and 5-day intervals. The optimal conditions of transcutaneous CO2 application to obtain the best antitumor effect in various tumors were as follows: greater than 10 min per application, twice per week, with 3- and 4-day intervals, and application to the site of the tumor. The results suggest that this novel transcutaneous CO2 application might be useful to treat primary tumors, while mitigating some side effects, and therefore could be safe for clinical trials.

An infant boy underwent hip disarticulation for infantile fibrosarcoma immediately after birth. His rehabilitation began when he was 4 mos old and involved training with his left (residual) leg. He could stand with support at 12 mos. His initial prosthesis fitting was performed at the age of 13 mos. He could stand and walk with support at 15 mos of age and could walk with no additional support and go up and down stairs at 2 yrs. A single-axis prosthetic knee joint was introduced at the age of 2 yrs 3 mos. His first gait using a hip prosthesis was successful, and his prosthesis was replaced at appropriate intervals with no major problems. The authors believe that the key to achieving a successful prosthetic gait in children is good communication among the medical team, which should comprise an orthopedic doctor, rehabilitation doctor, nurse, physical therapist, prosthetist/orthotist, and the patient's parents.

To examine the association of physical activity (PA) with bone health among patients with breast cancer receiving adjuvant aromatase inhibitor (AI) treatment. 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. 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. 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.

BackgroundClinicians 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 CO2absorption-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 CO2therapy in patients with fractures.MethodsPatients with fractures of the femur and tibia were prospectively enrolled into this study with ethical approval and informed consent. The CO2absorption-enhancing hydrogel was applied to the fractured lower limbs of patients, and then 100% CO2was 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.ResultsNineteen 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 CO2therapy compared with the pre-treatment level increased by approximately 2-fold in a time-dependent manner.ConclusionsThe findings of the present study revealed that CO2therapy is safe to apply to human patients and that it can enhance blood flow in the fractured limbs.Trial registrationThis study has been registered in the UMIN Clinical Trials Registry (Registration number:UMIN000013641, Date of registration: July 1, 2014).

Objectives The provision of inpatient programs that reduce the incidence of readmission after cardiac surgery remains challenging. Investigators have focused on multidisciplinary cardiac rehabilitation (CR) because it reduces the postoperative readmission rate; however, most previous studies used outpatient models (phase II CR). We retrospectively investigated the effect of comprehensive multidisciplinary interventions in the acute inpatient phase (phase I CR) on unplanned hospital readmission. Methods In a retrospective cohort study, we compared consecutive patients after cardiac surgery. We divided them into the multidisciplinary CR (multi-CR) group or conventional exercise-based CR (conv-CR) group according to their postoperative intervention during phase I CR. Multi-CR included psychological and educational intervention and individualized counseling in addition to conv-CR. The primary outcome was unplanned readmission rates between the groups. A propensity score–matching analysis was performed to minimize selection biases and the differences in clinical characteristics. Results In our cohort (n = 341), 56 (18.3%) patients had unplanned readmission during the follow-up period (median, 419 days). Compared with the conv-CR group, the multi-CR group had a significantly lower unplanned readmission rate (multivariable regression analysis; hazard ratio, 0.520; 95% confidence interval, 0.28-0.95; P = .024). A Kaplan–Meier analysis of our propensity score–matched cohort showed that, compared with the conv-CR group, the multi-CR group had a significantly lower incidence of readmission (stratified log-rank test, P = .041). Conclusions In phase I, compared to conv-CR alone, multi-CR reduced the incidence of unplanned readmission. Early multidisciplinary CR can reduce hospitalizations and improve long-term prognosis after cardiac surgery.

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.

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.

Background Rich vascularity of the induced membrane (IM) is important for Masquelet reconstruction surgery. The factors affecting IM vascularity are not completely understood. This study aimed to investigate these factors using histological samples of human IMs. Methods We retrospectively evaluated 36 patients whose bone defects were treated using the Masquelet technique. Two clinical pathologists analyzed histological sections of IM pieces (1 cm2). The number of blood vessels per 1 mm2 was counted and compared among men and women, femur or tibia, with and without free flap surgery, antibiotic impregnation to the cement, osteogenesis inside the membrane, smoking, and diabetes mellitus. The number of blood vessels within the same patient was compared among different time points. Correlation analysis was performed among blood vessel numbers and patient age, duration of cement spacer placement, and histological grading scales (inflammation, foreign body reaction, and fibrosis). Results IM formation with rich vascularity and some inflammation, foreign body reaction, and fibrosis were histologically confirmed in all patients. We found 37.4 ± 19.1 blood vessels per 1 mm2. The number of blood vessels was significantly lower in patients with than in those without free flap surgery; it was higher in patients with osteogenesis inside the IM. No significant correlations were found in any of the analyses. Conclusion Sex, patient age, smoking, diabetes mellitus, femur or tibia, duration of cement spacer placement, and antibiotic impregnation to the cement did not affect IM vascularization. IM vascularization was reduced in patients with than in those without free flap surgery.

Highlights • Prognostic factors: primary tumor, visceral metastases, and surgical procedure. • PS, BI, EQ-5D, and NRS improved at 3 months after surgery. • The improvements of PS, BI, EQ-5D, and NRS were maintained for 6 M after surgery. • The management of bone metastases must be decided by a multidisciplinary team. • The proper management of bone metastasis will reduce postoperative complications., Background Skeletal related events due to metastatic bone tumors markedly affect the activities of daily living (ADL) and quality of life (QOL) in cancer patients. We focused on multidisciplinary therapy for metastatic bone tumors. This study aimed to evaluate the outcomes of surgical treatment for metastatic bone tumors in the extremities. Methods We retrospectively reviewed 114 patients who underwent surgical treatment for metastatic bone tumors of the extremities between 2008 and 2019 and 69 patients were reassessed for more than 6 months after surgery. The most common primary tumor was renal, followed by lung, thyroid, and breast cancers. We assessed 69 patients’ performance status (PS), Barthel Index (BI) for ADL, EuroQol 5 Dimensions (EQ-5D) for QOL, and numerical rating scale (NRS) for pain and analyzed these postoperative values relative to preoperative values using Friedman’s test. The postoperative overall survival and the prognostic factors were evaluated using the Kaplan-Meier method, the log-rank test and Cox proportional hazards analysis. Results The 1-year overall survival rate was 59%, and the median survival time after surgery was 20 months. Primary tumor, visceral metastasis, and surgical procedure were risk factors correlated with overall survival. PS, BI, EQ-5D, and NRS improved at 3 months after surgery and these improvements were maintained for 6 months after surgery regardless of the surgical procedure. Conclusions The significant factors affecting survival after surgical treatment for bone metastases included the primary tumor, presence of visceral metastases, and internal fixation without tumor resection or curettage. Surgical treatment for metastatic bone tumors effectively reduced pain and improved PS, ADL, and QOL postoperatively after 3 months.

Objectives The number of geriatric patients with esophageal cancer has been increasing. Geriatric syndromes such as sarcopenia might adversely affect postoperative recovery. The aim of this study was to evaluate the relationships between sarcopenia and postoperative complications, and the associations between sarcopenia and perioperative functional changes in patients with esophageal cancer following esophagectomy. Materials and Methods Participants comprised 104 patients who underwent esophagectomy from July 2011 to April 2015. Preoperative sarcopenia was diagnosed by the presence of low muscle mass and low physical functions according to Asian Working Group for Sarcopenia criteria. Low physical function was defined by loss of grip strength and/or slow walking speed. Postoperative pulmonary, cardiac, infectious, and surgical complications were extracted. Perioperative functional changes were calculated (value at postoperative day 30−value before surgery). For statistical analyses, both uni- and multivariate logistic regression analyses were performed. Results Twenty-nine patients (27.9%) were diagnosed with sarcopenia. The incidence of postoperative pulmonary complications was significantly higher in the sarcopenia group (37.9%) than in the non-sarcopenia group (17.3%; P =0.04). There was no relationship between sarcopenia and other complications or perioperative functional changes. Multivariate analysis identified sarcopenia (odds ratio (OR), 3.13; 95% confidence interval (CI), 1.12–8.93) and high Brinkman index (OR, 3.46; 95% CI, 1.20–11.77) as independent risk factors for the development of pulmonary complications. Conclusion The assessment of sarcopenia may be useful to predict the postoperative pulmonary complications following esophagectomy. On the other hand, sarcopenia does not predict cardiac, infectious, and surgical complications or perioperative function.

Background The treatment of established orthopaedic infection is challenging. While the main focus of treatment is wide surgical debridement, systemic and local antibiotic administration are important adjuvant therapies. Several reports have described the clinical use of antibiotic-impregnated calcium phosphate cement (CPC) to provide local antibiotic therapy for bone infections. However, these were all individual case reports, and no case series have been reported. We report a case series treated by a single surgeon using antibiotic-impregnated CPC as part of a comprehensive treatment plan in patients with established orthopaedic infection. Methods We enrolled 13 consecutive patients with osteomyelitis ( n = 6) or infected non-union ( n = 7). Implantation of antibiotic-impregnated CPC was performed to provide local antibiotic therapy as part of a comprehensive treatment plan that also included wide surgical debridement, systemic antibiotic therapy, and subsequent second-stage reconstruction surgery. We investigated the rate of successful infection eradication and systemic/local complications. The concentration of antibiotics in the surgical drainage fluids, blood, and recovered CPC (via elution into a phosphate-buffered saline bath) were measured. Results The mean follow-up period after surgery was 50.4 (range, 27–73) months. There were no cases of infection recurrence during follow-up. No systemic toxicity or local complications from the implantation of antibiotic-impregnated CPC were observed. The vancomycin concentration in the fluid from surgical drainage ( n = 6) was 527.1 ± 363.9 μg/mL on postoperative day 1 and 224.5 ± 198.4 μg/mL on postoperative day 2. In patients who did not receive systemic vancomycin therapy ( n = 3), the maximum serum vancomycin level was In vitro vancomycin elution was observed from the CPC that was surgically retrieved ( n = 2). Conclusions Implantation of antibiotic-impregnated CPC is an option to provide local antibiotic therapy as part of a comprehensive treatment plan.

Oral squamous cell carcinoma (OSCC) is the most common form of oral cancers. Recent studies have shown that the malignant transformation of various carcinomas, including OSCC, is associated with epithelial-mesenchymal transition (EMT), and that expression of the EMT factors are significantly associated with tumor invasion, tumor metastasis, and survival rates in OSCC patients. Hence, there is a possibility that EMT suppression may improve the prognosis of OSCC patients. Hypoxia inducible factor-1α (HIF-1α) is a crucial microenvironmental factor in tumor progression, which induces the expression of EMT factors. We previously reported that transcutaneous CO2 suppresses both human OSCC tumor growth and metastasis to the regional lymph nodes by improving hypoxia in treated tissue. According to this background, we hypothesized that increased EMT with HIF-1α expression may increase the progression and the metastatic potential of OSCC, and that decreased hypoxia by transcutaneous CO2 could suppress EMT. In the present study, in vitro studies showed that hypoxic conditions increased the expression of HIF-1α and EMT factors in OSCC cells. In addition, in vivo studies revealed that transcutaneous CO2 increased E-cadherin expression with the decreased expression of HIF-1α, Snail, Slug, N-cadherin, and Vimentin in tumor treatment. These results suggest that transcutaneous CO2 could suppress EMT by improving hypoxia, resulting in the reduction of metastatic potential of OSCC. The findings indicate that transcutaneous CO2 may be able to improve the prognosis of OSCC patients through the suppression of EMT.

Preoperative nutritional status and physical function are important predictors of mortality and morbidity after cardiac surgery. However, the influence of nutritional status before cardiac surgery on physical function and the progress of postoperative rehabilitation requires clarification. To determine the effect of preoperative nutritional status on preoperative physical function and progress of rehabilitation after elective cardiac surgery. We enrolled 131 elderly patients with mean age of 73.7 ± 5.8 years undergoing cardiac surgery. We divided them into two groups by nutritional status as measured by the Geriatric Nutritional Risk Index (GNRI): high GNRI group (GNRI ≥ 92, n = 106) and low GNRI group (GNRI

IntroductionDiabetes mellitus (DM) negatively affects fracture repair by inhibiting endochondral ossification, chondrogenesis, callus formation, and angiogenesis. We previously reported that transcutaneous CO2application accelerates fracture repair by promoting endochondral ossification and angiogenesis. The present study aimed to determine whether CO2treatment would promote fracture repair in cases with type I DM.Research design and methodsA closed femoral shaft fracture was induced in female rats with streptozotocin-induced type I DM. CO2treatment was performed five times a week for the CO2group. Sham treatment, where CO2was replaced with air, was performed for the control group. Radiographic, histologic, genetic, and biomechanical measurements were taken at several time points.ResultsRadiographic assessment demonstrated that fracture repair was induced in the CO2group. Histologically, accelerated endochondral ossification and capillary formation were observed in the CO2group. Immunohistochemical assessment indicated that early postfracture proliferation of chondrocytes in callus was enhanced in the CO2group. Genetic assessment results suggested that cartilage and bone formation, angiogenesis, and vasodilation were upregulated in the CO2group. Biomechanical assessment revealed enhanced mechanical strength in the CO2group.ConclusionsOur findings suggest that CO2treatment accelerates fracture repair in type I DM rats. CO2treatment could be an effective strategy for delayed fracture repair due to DM.

Objective Diurnal variation of symptoms are observed in rheumatoid arthritis, especially in productions of cytokines that show peak concentrations during mid night. In contrast, cytokines of collagen-induced arthritis (CIA) mice increase in daytimes under Mid-light condition. By using chronotherapy, differences in drug efficacies according to administration time of Baricitinib, a wide ranged cytokine blocker, were examined in CIA mice. Methods CIA mice were administered a dose of 3 mg/kg of Baricitinib once a day at zeitgeber time (ZT) 0 or ZT12 for 21 days. Arthritis scores, histopathology and factors related to joint destruction in sera were examined. Phosphorylation of STAT3 in liver, expressions of cytokines in spleen, and Interleukin (IL)-6 and tumor necrosis factor (TNF)-α in sera were measured. Results In CIA mice, diurnal variations were observed both in expressions of cytokines and phosphorylation of STAT3. Arthritis scores of ZT0/12 group decreased from day3 as compared to untreated mice, and those of ZT0 group significantly decreased as compared to ZT12 group from day12. Pathological findings, immunohistochemistry of cytokines and Receptor activator of nuclear factor kappa-Β ligand (RANKL)/osteoprotegerin ratio in sera well reflected results of arthritis scores. Diurnal variation of STAT3 phosphorylation was suppressed in ZT0 group. At ZT2, expressions of IL-6/Interferon-γ/TNF/granulocyte–macrophage colony-stimulating factor in ZT0 group were significantly decreased as compared to untreated mice, though not in ZT12 group. In ZT0 group, IL-6 and TNF-α in sera were decreased for longer time than that in ZT12 group. Conclusion Chronotherapy using Baricitinib targeting cytokine secretions is effective in CIA mice. Clinical applications of chronotherapy can be expected to enhance the drug efficacy.

Backgroud Tibial fracture after cementless Oxford unicompartmental knee arthroplasty (OUKA) is a rare but serious complication. It is reported more frequently in Asian countries. The aim of this retrospective study was to assess the morphological characteristics of the tibia by using a simple novel measurement method in patients with tibial fractures after OUKA. Methods Six knees (all women) with tibial fractures after cementless OUKA (fracture group) and 150 knees without an obvious complication after cementless OUKA (control group) were examined retrospectively at our institution between January 2016 and April 2017. We drew a medial eminence line (ME line) defined as a line extending from the tip of the medial intercondylar eminence parallel to the tibial axis. The ME line was classified into two types (intramedullary type [type I] and extramedullary type [type E]), and the proportion of each type was compared between fracture patients and controls. Results In the fracture group, there were four (66.7%) type E cases and two (33.3%) type I cases; in the control group, there were 18 (12%) type E cases and 132 (88%) type I cases. Fisher exact tests showed that the proportion of type E was higher in the fracture group than in the control group (p < 0.01). Conclusions Measurement of the ME line can be recommended as a useful method to assess the risk of postoperative fracture after cementless OUKA.

The purpose of the present study was to determine the effects of transcutaneous CO2 application on the blood flow and capillary architecture of the soleus muscle in rats with streptozotocin (STZ)-induced hyperglycemia. Wistar rats were randomly divided into four groups: control, control + CO2-treated, STZ-induced hyperglycemia, and STZ-induced hyperglycemia + CO2-treated groups. Blood flow in soleus muscle increased during the transcutaneous CO2 exposure, and continued to increase for 30 min after the treatment. In addition, the transcutaneous CO2 attenuated a decrease in capillary and the expression level of eNOS and VEGF protein, and an increase in the expression level of MDM-2 and TSP-1 protein of soleus muscle due to STZ-induced hyperglycemia. These results indicate that the application of transcutaneous CO2 could improve capillary regression via the change of pro- and anti-angiogenesis factors, which might be induced by an increase in blood flow.

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.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.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) age23 years with a preoperative QSI ≥78.8%, (2) age ≥29 years with a preoperative QSI ≥98.0%, or (3) age16 years with a preoperative QSI58.5% and pre-injury Tegner activity scale ≥9. By contrast, patients ≥29 years with a preoperative QSI98.0% were likely to achieve a quadriceps strength index70% at 6 months after surgery.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.

Introduction: Analysis of predictive factors for the improvement of bone mineral density (BMD) in response to osteoporosis treatment is critical. Several studies reported on the analysis of bone turnover markers as a predictive factor for the improvement of BMD; however, few studies reported on predictive factors other than bone turnover markers. Thus, this study aimed to analyze other predictive factors for distal radial BMD improvement in response to denosumab treatment among patients with osteoporosis.Methods: We evaluated 133 patients with osteoporosis over a 24 month period. All patients received denosumab (60 mg) subcutaneously every 6 months. The BMD of the distal radius was assessed in all patients and serum concentrations of PINP and TRACP5b determined.Results: Denosumab treatment resulted in a 3.3% increase, from baseline, in distal radius BMD at 24 months. The average BMD change at 24 months was not significantly changed in relation to gender or prevalent medication. The average BMD change at 24 months was negatively correlated with patient’s age. Almost all the points of PINP and TRACP5b were not correlated with BMD except TRACP5b value at 24 months.Conclusions: We found that improvement of bone mineral density with denosumab treatment for osteoporosis is associated with young age of the patients. We recommend denosumab treatment for younger patients with osteoporosis.

Radiotherapy (RT) is one of the main treatment modalities for oral squamous cell carcinoma (OSCC), however, radioresistance is a major impediment to its clinical success and poses as a concern that needs to be addressed. Tumor hypoxia is known to be significantly associated with radioresistance in various malignancies, hence, resolving the hypoxic state of a tumor may improve the antitumor effect of RT on OSCC. We have previously revealed that transcutaneous CO2 induced mitochondrial apoptosis and suppressed tumor growth in OSCC by resolving hypoxia. Considering the previous study, we hypothesized that transcutaneous CO2 may enhance the antitumor effect of RT on OSCC by improving intratumoral hypoxia, thereby overcoming radioresistance. In the present study, the combination of transcutaneous CO2 and RT significantly inhibited tumor growth compared with other treatments. This combination therapy also led to decreased expression of HIF-1α in parallel with increased expression of the cleaved forms of caspase-3-8-9 and PARP, which play essential roles in mitochondrial apoptosis. Additionally, the combination therapy increased the expression of ROS modulator 1 and subsequent mitochondrial ROS production, compared to RT alone. These results indicated that transcutaneous CO2 could potentially improve the antitumor effect of RT by decreasing the intratumoral hypoxia and increasing the mitochondrial apoptosis. Our findings indicated that CO2 therapy may be a novel adjuvant therapy in combination with RT for OSCC.

Background Methotrexate inhibits the proliferation of RA fibroblast-like synovial cells (RA-FLS) by folate anti-metabolism. We previously reported that disruptions of circadian clock genes were involved in the pathogenesis of inflammatory arthritis (1,2). Objectives To explore pharmacological effects of MTX on circadian clock genes of RA-FLS. Methods Under treatments of MTX on RA-FLS, cell viabilities were determined by WST-8 assay, expressions of circadian clock genes (Clock, Bmal1, Cry1 and Per2), circadian transcriptional factor PAR bZip (Dbp, Tef and Hlf), and pro-apoptotic Bcl-2 interacting killer (BIK) were examined by real time PCR, and expressions of PER2 and CYTOCHROME C were examined by western blotting. The expressions of PER2, BIK, CYTOCHROME C and morphological changes of the nucleus were observed by fluorescent immunostaining. RA-FLS were transfected with Per2 and BIK siRNAs and successively treated with MTX to determine cell viabilities by WST-8 assay. Results MTX (1,10 nM) treatment significantly decreased the cell viabilities. MTX (10nM) have increased mRNA expression of Per2, Dbp, Tef, Hlf, and BIK, and protein expressions of PER2 and CYTOCHROME C, as well. In fluorescent observations, PER2, BIK, and CYTOCHROME C were increased in apoptotic cells. Cytotoxicity of MTX was attenuated by knockdowns of Per2 or BIK in RA-FLS. Conclusions The transcriptional factor PAR bZip binds to the D-box elements of Per2 and BIK promoters (3,4). Here, we propose a novel action of MTX that up-regulates the expressions of Per2 and BIK via PAR bZip to induce apoptosis in RA-FLS. References Hashiramoto A, J Immunol. 2010 Feb 1;184(3):1560–5. Hand LE, FASEB J. 2016 Nov;30(11):3759–3770. Yoshida K, Scand J Rheumatol. 2013;42(4):276–80. Ritchie A, Cell Death Differ. 2009 Jun;16(6):838–46. Disclosure of Interest None declared

Xeroderma pigmentosum (XP) is a genetic photosensitive disorder in which patients are highly susceptibe to skin cancers on the sun-exposed body sites. In Japan, more than half of patients (30% worldwide) with XP show complications of idiopathic progressive, intractable neurological symptoms with poor prognoses. Therefore, this disease does not merely present with dermatological symptoms, such as photosensitivity, pigmentary change and skin cancers, but is "an intractable neurological and dermatological disease". For this reason, in March 2007, the Japanese Ministry of Health, Labor and Welfare added XP to the neurocutaneous syndromes that are subject to government research initiatives for overcoming intractable diseases. XP is one of the extremely serious photosensitive disorders in which patients easily develop multiple skin cancers if they are not completely protected from ultraviolet radiation. XP patients thus need to be strictly shielded from sunlight throughout their lives, and they often experience idiopathic neurodegenerative complications that markedly reduce the quality of life for both the patients and their families. Hospitals in Japan often see cases of XP as severely photosensitive in children, and as advanced pigmentary disorders of the sun-exposed area with multiple skin cancers in adults (aged in their 20-40s), making XP an important disease to differentiate in everyday clinical practice. It was thus decided that there was a strong need for clinical practice guidelines dedicated to XP. This process led to the creation of new clinical practice guidelines for XP.

The present study aimed to evaluate the efficacy of an intra-arterially infused carbon dioxide (CO2)-saturated solution in sensitizing the anticancer effect of cisplatin in a rabbit VX2 liver tumor model. Forty VX2 liver tumor-bearing Japanese white rabbits were randomly divided into four groups and infused via the proper hepatic artery with a saline solution (control group), CO2-saturated solution (CO2 group), cisplatin solution (cisplatin group), or CO2-saturated solution and cisplatin solution (combined group). The tumor volume (TV) and the relative tumor volume (RTV), RTV = (TV on day 3 or 7)/(TV on day 0) x 100, were calculated using contrast-enhanced computed tomography. Hypoxia-inducible factor-1α (HIF‑1α) and carbonic anhydrase IX (CA IX) staining were used to evaluate cellular hypoxia. Cleaved caspase-3 and cleaved caspase-9 were analyzed to assess tumor apoptosis. The mean RTV on days 3 and 7 were 202.6±23.7 and 429.2±94.8%, respectively, in the control group; 172.2±38.1 and 376.5±61.1% in the CO2 group; 156.1±15.1 and 269.6±45.2% in the cisplatin group; and 118.3±28.1 and 210.3±55.1% in the combined group. RTV was significantly lower in the CO2 group than in the control group (day 3; P

Background/aim Cancer stem cells are suspected to contribute to malignancy in tumors. Hypoxia affects cell differentiation and induces stem-cell-like characteristics in malignancies. Induced pluripotency was demonstrated in mouse fibroblasts by reprogramming with four transcriptional factors: Oct3/4, Sox2, c-Myc, and Klf4. Conversely, oncogenic transformations frequently express transcriptional factors and Nanog. Therefore, cancer cells present some similarities with induced pluripotent stem (iPS) cells. Materials and methods We investigated the expression of iPS-related genes in vitro and in clinical samples to identify their relationships with hypoxia and tumorigenesis. Results Oral squamous cell carcinoma (SCC) cells were used to show that expression levels of Oct3/4, Sox2, and Nanog were significantly increased in hypoxic condition in vitro and in moderately- and poorly-differentiated samples. Conclusion We propose that Oct3/4, Sox2 and Nanog are associated with tumor hypoxia characterized in oral SCC and that these factors may also contribute to the undifferentiated potency observed in oral SCC clinically.

Endurance exercise generates CO2 via aerobic metabolism; however, its role remains unclear. Exogenous CO2 by transcutaneous delivery promotes muscle fibre-type switching to increase endurance power in skeletal muscles. Here we determined the performance of rats running in activity wheels with/without transcutaneous CO2 exposure to clarify its effect on endurance exercise and recovery from muscle fatigue. Rats were randomised to control, training and CO2 groups. Endurance exercise included activity-wheel running with/without transcutaneous CO2 delivery. Running performance was measured after exercise initiation. We also analysed changes in muscle weight and muscle fibres in the tibialis anterior muscle. Running performance improved over the treatment period in the CO2 group, with a concomitant switch in muscle fibres to slow-type. The mitochondrial DNA content and capillary density in the CO2 group increased. CO2 was beneficial for performance and muscle development during endurance exercise: it may enhance recovery from fatigue and support anabolic metabolism in skeletal muscles.

Postoperative delirium (POD) is a critical complication that is closely associated with mortality and major morbidity in elective cardiac surgery. The identification of patients at risk for POD is crucial but has not been fully explored. The aim of this study was to determine the predictive value of the assessment of preoperative exercise capacity for POD. We enrolled 313 consecutive patients (mean age, 68.6 ± 14.8 years) undergoing elective cardiac surgery. We measured physical functions such as the 6-minute walking distance (6MWD) and Timed Up-and-Go test (TUG) before surgery. The assessment of delirium was conducted every 8 h from the day of surgery to 5 days after surgery using the Intensive Care Delirium Screening Checklist. POD occurred in 46 patients (14.6%). Age, 6MWD, TUG, serum hemoglobin, estimated glomerular filtration rate, and length of intensive care unit stay were significantly different based on the presence or absence of POD (p