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Background: The purpose of the present study was to compare the degree of sesamoid reduction after hallux valgus correction between distal chevron metatarsal osteotomy (DCMO) and S.E.R.I. (simple, effective, rapid, and inexpensive) osteotomy, and to analyze the effects on the recurrence of hallux valgus. Methods: We retrospectively analyzed the foot radiographs of 60 feet (30 DCMO and 30 SERI) treated for hallux valgus from August 2013 to July 2017. Radiographic assessments were performed preoperatively, at early follow-up (at a mean of 3.1 months) and at the most recent follow-up (at a mean of 16.7 months). The location of the medial sesamoid was classified into seven stages, in accordance with the method described by Hardy and Clapham; stage IV or less was defined as the normal position for the medial sesamoid, and stage V or greater was defined as lateral displacement of the sesamoid. The pre- and post-operative hallux valgus angle, 1–2 intermetatarsal angle, and sesamoid position were compared between the two groups. Results: The mean follow-up period was 18.4 (12–36) months in the DCMO group and 15.0 (12–36) months in the S.E.R.I. group (p = 0.108). The radiologic results showed that the hallux valgus angles were not significantly different between the two groups preoperatively and at the early follow-up: preoperatively, they were 28.8 ± 7.7 in the DCMO group and 32.6 ± 9.5 in the S.E.R.I. group (p = 0.101), and they were 10.4 ± 4.0 and 8.7 ± 5.0 (p = 0.148) at the early follow-up, respectively. However, at the most recent follow-up, the DCMO group (13.9 ± 5.6) showed significantly higher hallux valgus angles than the S.E.R.I. group (10.4 ± 6.4, p = 0.030), and there were no differences between the recurrence of hallux valgus in the DCMO group (13%)and that in the S.E.R.I. group (10%) (p = 0.553). There were no significant differences in the 1–2 intermetatarsal angles between the two groups at the early follow-up (6.1 ± 2.5 vs. 4.8 ± 3.1, p = 0.082) and at the most recent follow-up (7.3 ± 2.9 vs. 6.6 ± 3.5, p = 0.408). After hallux-valgus-correction surgery, the stage change of the tibia sesamoid position from the preoperative stage to the initial follow-up was significantly larger in the S.E.R.I. group (−4.4 ± 1.4) than in the DCMO group (−3.4 ± 1.1) (p = 0.003); the changes from the preoperative stage to the last follow-up were also significantly larger in the SERI group (−3.3 ± 1.7) than in the DCMO group (−2.4 ± 1.5) (p = 0.028); however, the changes from the initial follow-up to the last follow-up showed no significant differences between the two groups (+1.0 ± 1.1 in the DCMO group vs. +1.1 ± 1.2 in the S.E.R.I. group) (p = 0.822). The medial sesamoid was laterally subluxated in all the preoperative cases in the DCMO and S.E.R.I. groups. The lateral subluxation of the tibia sesamoid was more frequently observed in the DCMO group (four cases, 13%) than in the S.E.R.I. group (0 cases, 0%) (p = 0.038) at the early follow-up. Conclusion: In conclusion, our results demonstrated that the S.E.R.I. procedure is superior to DCMO in decreasing the hallux valgus angle and showed that the early post-operative reduction in the sesamoids can be a risk factor for the recurrence of hallux valgus. [ABSTRACT FROM AUTHOR]

Background: Few studies have investigated long-term clinical outcomes of a mobile-bearing total ankle arthroplasty (TAA) system. This study analyzed long-term outcomes of TAA using the HINTEGRA prosthesis at a single, non-developer center.Methods: Primary TAAs were performed on 213 ankles in 194 patients, and 151 consecutive ankles [71%] in 136 patients with a minimum follow-up of 10 years after the primary TAA were included in this study. Clinical results were assessed using a visual analog scale (VAS) pain score, the American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot Scale score, the Ankle Osteoarthritis Scale (AOS) pain and disability subscores, and ankle range of motion. Prosthesis survivorship, reoperations, and risk factors were also evaluated.Results: The mean follow-up was 135.5 months (range, 120.0 to 204.0 months). All clinical scores and ankle range of motion improved significantly from preoperatively to 2 years, 4 to 6 years, and ≥10 years after TAA (p < 0.001). A total of 43 ankles (28.5%) required revision procedures, with the most common reason being periprosthetic osteolysis (32 ankles [21.2%]). The overall implant survivorship was 93.5% in Kaplan-Meier survival analysis at the mean follow-up of 11.3 years after the TAA.Conclusions: TAA using the HINTEGRA prosthesis with careful follow-up observation and appropriate adjunct procedures for the treatment of end-stage ankle arthritis produced satisfactory clinical results, which were maintained at a follow-up of ≥10 years, and resulted in 93.5% of implant survivorship.Level Of Evidence: Prognostic Level IV . See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Ubiquitin-specific protease 7 (USP7) is highly expressed in a variety of malignant tumors. However, the role of USP7 in regulating self-renewal and differentiation of human bone marrow derived mesenchymal stromal cells (hBMSCs) remains unknown. Herein, we report that USP7 regulates self-renewal of hBMSCs and is required during the early stages of osteogenic, adipogenic, and chondrogenic differentiation of hBMSCs. USP7, a deubiquitinating enzyme (DUB), was found to be downregulated during hBMSC differentiation. Furthermore, USP7 is an upstream regulator of the self-renewal regulating proteins SOX2 and NANOG in hBMSCs. Moreover, we observed that SOX2 and NANOG are poly-ubiquitinated and their expression is downregulated in USP7-deficient hBMSCs. Overall, this study showed that USP7 is required for maintaining self-renewal and multipotency in cultured hBMSCs. Targeting USP7 might be a novel strategy to preserve the self-renewal capacity of hBMSCs intended for stem cell therapy. [ABSTRACT FROM AUTHOR]

Background: Although high talar tilt and ankle mortise incongruence are risk factors for supramalleolar osteotomy (SMO), no study on lateral talofibular joint congruence exists. We aimed to evaluate the outcomes of oblique SMO without fibular osteotomy for medial ankle arthritis and compare them according to the lateral talofibular joint congruity.Methods: Forty-eight ankles were retrospectively reviewed and divided according to preoperative talofibular joint congruity (congruent, 22 [45.8%] vs. incongruent, 26 [54.2%]).Results: The mean VAS score, AOFAS score, and modified Takakura stage were significantly improved. No significant differences were noted in clinical outcomes, but the mean postoperative tibiotalar angle and difference between the upper and lower talofibular gaps were significantly different in both groups (p = 0.004 and p = 0.009, respectively). The mean Takakura stage at 1 and 2 years after surgery was higher in the incongruent group (p = 0.013, p = 0.012).Conclusion: This procedure was effective against early- to mid-stage medial ankle arthritis. Radiographic arthritic grade changed according to the talofibular joint congruity. [ABSTRACT FROM AUTHOR]

The incidence of achilles tendon rupture varies by gender, age, and seasonal variation. However, there has been no study as yet linking achilles tendon rupture to daily fluctuations in outdoor temperature. The purpose of this study was to investigate the association between outdoor temperature and achilles tendon rupture using a Korea Meteorological Administration database and a Korean National Health Insurance Service-National Sample Cohort database. Between 2002 and 2015, all instances of achilles tendon repair were retrieved from the National Health Insurance Service-National Sample Cohort database to examine sociodemographic factors, specifically sex, age, residential area, and income level. Minimum age requirement was 20 years. Outdoor temperatures recorded at 16 observation points in South Korea were also acquired from the Korea Meteorological Administration data center for analysis. Overall, 850 (0.119%) of 713,456 individuals in the National Health Insurance Service-National Sample Cohort database underwent achilles tendon repair between 2002 and 2015. Yearly procedural totals increased with advancing age, peaking at ages 30–39 years (14.6 per 100,000 persons) and declining thereafter. Minimum, median, and maximum outdoor temperatures were associated with achilles tendon repair (p<0.05), as did household income. In multivariate logistic regression analysis, outdoor temperatures, sex, age, and household income emerged as factors significantly associated with achilles tendon repair. Outcomes of this study confirm an association between incidence of achilles tendon repair and outdoor temperature, the latter denoting a novel index and likely surrogate measure of vigorous physical activity afforded by warmer weather. [ABSTRACT FROM AUTHOR]

Background: Arthroscopic bone marrow stimulation (BMS) is considered the first-line treatment for osteochondral lesions of the talus (OLTs). However, the long-term stability of the clinical success of BMS remains unclear. Purpose: To investigate the long-term clinical outcomes among patients who underwent BMS for OLT and to identify prognostic factors for the need for revision surgery. Study Design: Case series; Level of evidence, 4. Methods: A retrospective analysis was performed on 202 ankles (189 patients) that were treated with BMS for OLT and had a minimum follow-up of 10 years. The visual analog scale for pain, American Orthopaedic Foot & Ankle Society ankle-hindfoot score, and the Foot and Ankle Outcome Score (FAOS) were assessed by repeated measures analysis of variance. Prognostic factors associated with revision surgery were evaluated with Cox proportional hazard regression models and log-rank tests. Results: The mean lesion size was 105.32 mm2 (range, 19.75-322.79); 42 ankles (20.8%) had large lesions (≥150 mm2). The mean visual analog scale for pain improved from 7.11 ± 1.73 (mean ± SD) preoperatively to 1.44 ± 1.52, 1.46 ± 1.57, and 1.99 ± 1.67 at 1, 3 to 6, and ≥10 years, respectively, after BMS (P <.001). The mean ankle-hindfoot score also improved, from 58.22 ± 13.57 preoperatively to 86.88 ± 10.61, 86.17 ± 10.23, and 82.76 ± 11.65 at 1, 3 to 6, and ≥10 years after BMS (P <.001). The FAOS at the final follow-up was 82.97 ± 13.95 for pain, 81.81 ± 14.64 for symptoms, 83.49 ± 11.04 for activities of daily living, 79.34 ± 11.61 for sports, and 78.71 ± 12.42 for quality of life. Twelve ankles underwent revision surgery after a mean 53.5 months. Significant prognostic factors associated with revision surgery were the size of the lesion (preoperative magnetic resonance imaging measurement ≥150 mm2; P =.014) and obesity (body mass index ≥25; P =.009). Conclusion: BMS for OLT yields satisfactory clinical outcomes at a mean follow-up of 13.9 years. The success of the surgery may depend on the lesion size and body mass index of the patient. [ABSTRACT FROM AUTHOR]

The crucial trace element zinc stimulates osteogenesis in vitro and in vivo. However, the pathways mediating these effects remain poorly understood. This study aimed to investigate the effects of zinc on osteoblast differentiation in human bone marrow-derived mesenchymal stem cells (hBMSCs) and to identify the molecular mechanisms of these effects. In hBMSCs, zinc exposure resulted in a dose-dependent increase in osteogenesis and increased mRNA and protein levels of the master transcriptional factor RUNX2. Analyzing the upstream signaling pathways of RUNX2, we found that protein kinase A (PKA) signaling inhibition blocked zinc-induced osteogenic effects. Zinc exposure increased transcriptional activity and protein levels of phospho-CREB and enhanced translocation of phospho-CREB into the nucleus. These effects were reversed by H-89, a potent inhibitor of PKA. Moreover, zinc exposure led to dose-dependent increases in levels of intracellular cyclic adenosine monophosphate (cAMP). These findings indicate that zinc activates the PKA signaling pathway by triggering an increase in intracellular cAMP, leading to enhanced osteogenic differentiation in hBMSCs. Our results suggest that zinc exerts osteogenic effects in hBMSCs by activation of RUNX2 via the cAMP-PKA-CREB signaling pathway. Zinc supplementation may offer a promise as a potential pharmaceutical therapy for osteoporosis and other bone loss conditions. [ABSTRACT FROM AUTHOR]

Aims: This study was conducted to evaluate the efficacy and safety of a novel spray-applied growth factor therapy containing recombinant human epidermal growth factor (rhEGF) for the treatment of chronic diabetic foot ulcers (DFU).Methods: This study was a phase III double-blind, randomized, placebo-controlled trial. 167 adult patients at six medical centers were randomized to receive routine wound care plus either topical spray treatment with 0.005% rhEGF (n = 82) or an equivalent volume of saline spray (n = 85) twice a day until ulcer healing or for up to 12 weeks.Results: Demographics, medical status, and wound characteristics were comparable between rhEGF and placebo groups. More patients in the rhEGF group significantly had complete wound healing compared to placebo (73.2% versus 50.6%, respectively; P = .001). Wound healing velocity was faster in the rhEGF group (P = .029) regardless of HbA1c levels. The rhEGF group had a shorter median time to 50% ulcer size reduction (21 versus 35 days; hazard ratio = 3.13, P < .001) and shorter time to complete ulcer healing (56 versus 84 days; hazard ratio = 2.13, P < .001).Conclusions: This study confirms that application of spray-applied rhEGF in DFU patients results in faster healing velocity and higher complete healing rate regardless of HbA1c levels. [ABSTRACT FROM AUTHOR]

Background: The modified Broström procedure for chronic lateral ankle instability (CLAI) has presented outstanding clinical results. However, after the procedure, some patients with generalized ligamentous laxity have experienced a recurrence of ankle instability. Purpose: To understand the effect of generalized ligamentous laxity on prognosis and risk of recurrence in a cohort of patients with CLAI after the modified Broström procedure. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 199 ankles from 188 patients underwent the modified Broström procedure for CLAI with a mean follow-up of 60.1 months (range, 48-108 months). Generalized ligamentous laxity was assessed in all patients. The Karlsson-Peterson ankle score (Karlsson score), talar tilt angle, and anterior displacement of the talus were used to evaluate clinical and radiological outcomes. Risk factors associated with clinical outcomes were evaluated using bivariate analysis and logistic regression analysis. Survival outcomes were compared using Kaplan-Meier analysis. Results: Generalized ligamentous laxity was evident in 42 cases (21.1%). The average Karlsson score improved from 54.6 ± 7.1 preoperatively to 87.9 ± 7.2 at last follow-up (P < .001). The presence of generalized ligamentous laxity was significantly associated with poor clinical and radiological outcomes. The rates of clinical failure were 10.8% and 45.2% in the nonlaxity group and the laxity group, respectively (P < .001). According to bivariate analysis, generalized ligamentous laxity, syndesmosis widening, osteochondral lesion of the talus, high preoperative talar tilt angle (>15°), and high preoperative anterior displacement of the talus (>10 mm) were significantly associated with clinical failure. Multivariate logistic regression analysis revealed that generalized ligamentous laxity was the most important independent predictor of clinical failure after the modified Broström procedure. The cumulative success rates for the nonlaxity group were significantly superior to those for the laxity group in Kaplan-Meier curves (P < .001). Conclusion: Generalized ligamentous laxity is an independent predictor of poor outcomes and a risk factor of recurrent instability following the modified Broström procedure for CLAI. [ABSTRACT FROM AUTHOR]

Background: Recent reports revealed that outcomes of anterior cruciate ligament (ACL) reconstruction in middle- or old-age patients are comparable with those of young patients. However, in case of concomitant arthrosis in the affected knee, there has been a paucity of literature regarding the outcomes of ACL reconstruction. We studied the level of improvement in pain originating from significant cartilage degeneration in middle-aged ACL-deficient patients after ACL reconstruction. We divided the pain into pain at rest and activity-induced pain. Hypothesis: The activity-induced pain would be more improved by ACL reconstruction than the pain at rest. Study Design: Case series; Level of evidence, 4. Methods: We studied 36 patients who had undergone arthroscopic isolated ACL reconstruction for functional instability with significant cartilage degeneration grade III or IV without mensical injury. All patients had activity-induced pain; 20 of these patients also had pain at rest. To assess the pain level, the visual analog scale (VAS) was employed, in addition to radiologic and clinical evaluations such as the Lachman test, KT-2000 arthrometer, and pivot shift test. The mean age of the patients was 48.6 years (range, 41-61 years); mean follow-up was 46.7 months (range, 27-74 months). Results: The preoperative mean VAS of the activity-induced pain (4.1 ± 1.0; range, 2-6) showed significant improvement at the most recent follow-up (2.0 ± 1.0; range, 0-4; P < .0001). However, the preoperative mean VAS of the pain at rest (2.9 ± 0.9; range, 2-5) did not improve significantly at the most recent follow-up (2.5 ± 0.8; range, 1-4; P = .149). The Lachman test, KT-2000 arthrometer, andpivot shift test showed significant improvement compared with preoperative outcomes (P < .0001). There was no significant difference in radiologic assessment between preoperative and postoperative outcomes (P = .082). Conclusion: Anterior cruciate ligament reconstruction in middle-aged patients with significant cartilage degeneration is effective in reducing activity-induced pain and instability. Even though all patients had less than severe arthritic changes on preoperative radiographs, the pain at rest did not improve after ACL reconstruction. [ABSTRACT FROM AUTHOR]

Aims: Because collagen is fundamental to wound healing and skin formation, collagen-containing dressing materials might be beneficial in treating diabetic foot ulcers (DFU), but supporting evidence is needed. Here, we examined the effectiveness and safety of collagen dressing material in DFU treatment.Methods: This prospective, randomized, placebo-controlled, single-center study included patients with type 1 or 2 diabetes and palpable foot pulse who had Wagner grade 1 or 2 ulcers ≥1.0 cm2 with no signs of healing for ≥6 weeks. Patients were treated with foam dressing alone (control group) or with a porcine type I collagen dressing material (collagen group). Complete ulcer healing rate was the primary endpoint, and healing velocity and time to 50% size reduction were secondary endpoints.Results: Thirty patients were included (collagen group: 17, control group: 13). There were no significant differences in demographic factors or baseline DFU characteristics. Compared to the control group, the collagen group presented a higher rate of complete healing [82.4% vs. 38.5%, P = .022], faster healing velocity (P < .05), and shorter median time to 50% size reduction (21 versus 42 days; hazard ratio = 1.94, P < .05).Conclusions: Wound management using collagen materials in DFUs showed faster and complete healing rate. [ABSTRACT FROM AUTHOR]

Decreased angiogenesis contributes to delayed wound healing in diabetic patients. Recombinant human bone morphogenetic protein-2 (rhBMP2) has also been demonstrated to promote angiogenesis. However, the short half-lives of soluble growth factors, including rhBMP2, limit their use in wound-healing applications. To address this limitation, we propose a novel delivery model using a protein transduction domain (PTD) formulated in a lipid nanoparticle (LNP). We aimed to determine whether a gelatin hydrogel dressing loaded with LNP-formulated PTD-BMP2 (LNP-PTD-BMP2) could enhance the angiogenic function of BMP2 and improve diabetic wound healing. In vitro, compared to the control and rhBMP2, LNP-PTD-BMP2 induced greater tube formation in human umbilical vein endothelial cells and increased the cell recruitment capacity of HaCaT cells. We inflicted large, full-thickness back skin wounds on streptozotocin-induced diabetic mice and applied gelatin hydrogel (GH) cross-linked by microbial transglutaminase containing rhBMP2, LNP-PTD-BMP2, or a control to these wounds. Wounds treated with LNP-PTD-BMP2-loaded GH exhibited enhanced wound closure, increased re-epithelialization rates, and higher collagen deposition than those with other treatments. Moreover, LNP-PTD-BMP2-loaded GH treatment resulted in more CD31- and α-SMA-positive cells, indicating greater neovascularization capacity than rhBMP2-loaded GH or GH treatments alone. Furthermore, in vivo near-infrared fluorescence revealed that LNP-PTD-BMP2 has a longer half-life than rhBMP2 and that BMP2 localizes around wounds. In conclusion, LNP-PTD-BMP2-loaded GH is a viable treatment option for diabetic wounds. [ABSTRACT FROM AUTHOR]

Background: Although mRNA dysregulation can induce changes in mesenchymal stem cell (MSC) homeostasis, the mechanisms by which post-transcriptional regulation influences MSC differentiation potential remain understudied. PUMILIO2 (PUM2) represses translation by binding target mRNAs in a sequence-specific manner. Methods: In vitro osteogenic differentiation assays were conducted using human bone marrow-derived MSCs. Alkaline phosphatase and alizarin red S staining were used to evaluate the osteogenic potential of MSCs. A rat xenograft model featuring a calvarial defect to examine effects of MSC-driven bone regeneration. RNA-immunoprecipitation (RNA-IP) assay was used to determine the interaction between PUM2 protein and Distal-Less Homeobox 5 (DLX5) mRNA. Ovariectomized (OVX) mice were employed to evaluate the effect of gene therapy for postmenopausal osteoporosis. Results: Here, we elucidated the molecular mechanism of PUM2 in MSC osteogenesis and evaluated the applicability of PUM2 knockdown (KD) as a potential cell-based or gene therapy. PUM2 level was downregulated during MSC osteogenic differentiation, and PUM2 KD enhanced MSC osteogenic potential. Following PUM2 KD, MSCs were transplanted onto calvarial defects in 12-week-old rats; after 8 weeks, transplanted MSCs promoted bone regeneration. PUM2 KD upregulated the expression of DLX5 mRNA and protein and the reporter activity of its 3'-untranslated region. RNA-IP revealed direct binding of PUM2 to DLX5 mRNA. We then evaluated the potential of adeno-associated virus serotype 9 (AAV9)-siPum2 as a gene therapy for osteoporosis in OVX mice. Conclusion: Our findings suggest a novel role for PUM2 in MSC osteogenesis and highlight the potential of PUM2 KD-MSCs in bone regeneration. Additionally, we showed that AAV9-siPum2 is a potential gene therapy for osteoporosis. [ABSTRACT FROM AUTHOR]

Fractures and related complications are a common challenge in the field of skeletal tissue engineering. Vitamin D and calcium are the only broadly available medications for fracture healing, while zinc has been recognized as a nutritional supplement for healthy bones. Here, we aimed to use polaprezinc, an anti-ulcer drug and a chelate form of zinc and L-carnosine, as a supplement for fracture healing. Polaprezinc induced upregulation of osteogenesis-related genes and enhanced the osteogenic potential of human bone marrow-derived mesenchymal stem cells and osteoclast differentiation potential of mouse bone marrow-derived monocytes. In mouse experimental models with bone fractures, oral administration of polaprezinc accelerated fracture healing and maintained a high number of both osteoblasts and osteoclasts in the fracture areas. Collectively, polaprezinc promotes the fracture healing process efficiently by enhancing the activity of both osteoblasts and osteoclasts. Therefore, we suggest that drug repositioning of polaprezinc would be helpful for patients with fractures. Polaprezinc promoted both osteoblast and osteoclast differentiation and altered YAP protein expression in vitro, and animals treated with polaprezinc showed greater bone formation in their fracture calluses after 21 days. [ABSTRACT FROM AUTHOR]

Patients with diabetes experience impaired growth factor production such as epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), and they are reportedly involved in wound healing processes. Here, we report dual growth factor-loaded hyaluronate collagen dressing (Dual-HCD) matrix, using different ratios of the concentration of stabilized growth factors—stabilized-EGF (S-EGF) and stabilized-bFGF (S-bFGF). At first, the optimal concentration ratio of S-EGF to S-bFGF in the Dual-HCD matrix is determined to be 1:2 in type I diabetic mice. This Dual-HCD matrix does not cause cytotoxicity and can be used in vivo. The wound-healing effect of this matrix is confirmed in type II diabetic mice. Dual HCD enhances angiogenesis which promotes wound healing and thus, it shows a significantly greater synergistic effect than the HCD matrix loaded with a single growth factor. Overall, we conclude that the Dual-HCD matrix represents an effective therapeutic agent for impaired diabetic wound healing. [ABSTRACT FROM AUTHOR]

Patients with diabetes experience impaired growth factor production such as epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), and they are reportedly involved in wound healing processes. Here, we report dual growth factor-loaded hyaluronate collagen dressing (Dual-HCD) matrix, using different ratios of the concentration of stabilized growth factors—stabilized-EGF (S-EGF) and stabilized-bFGF (S-bFGF). At first, the optimal concentration ratio of S-EGF to S-bFGF in the Dual-HCD matrix is determined to be 1:2 in type I diabetic mice. This Dual-HCD matrix does not cause cytotoxicity and can be used in vivo. The wound-healing effect of this matrix is confirmed in type II diabetic mice. Dual HCD enhances angiogenesis which promotes wound healing and thus, it shows a significantly greater synergistic effect than the HCD matrix loaded with a single growth factor. Overall, we conclude that the Dual-HCD matrix represents an effective therapeutic agent for impaired diabetic wound healing. [ABSTRACT FROM AUTHOR]

Purpose: Lower extremity amputation (LEA) is associated with a high risk of postoperative mortality. The effect of type of anesthesia on postoperative mortality has been studied in various surgeries. However, data for guiding the selection of optimal anesthesia for LEA are limited. This study aimed to determine the effect of anesthesia type on perioperative outcomes in patients with diabetes and/or peripheral vascular disease undergoing LEA.Patients and Methods: We reviewed the medical records of patients who underwent LEA at our center between September 2007 and August 2017, who were grouped according to use of general anesthesia (GA) or regional anesthesia (RA). Primary outcomes were 30-day and 90-day mortality. Secondary outcomes were postoperative morbidity, intraoperative events, postoperative intensive care unit admission, and postoperative length of stay. Propensity score-matched cohort design was used to control for potentially confounding factors, including patient demographics, comorbidities, medications, and type of surgery.Results: Five hundred and nineteen patients (75% male, mean age 65 years) were identified to have received GA (n=227) or RA (n=292) for above-knee amputation (1.5%), below-knee amputation (16%), or more minor amputation (82.5%). Before propensity score matching, there was an association of GA with coronary artery disease (44% [GA] vs 34.5% [RA], p=0.028), peripheral arterial disease (73.1% vs 60.2%, p=0.002), and preoperative treatment with aspirin and clopidogrel (68.7% vs 55.1%, p=0.001; 63% vs 41.8%, p<0.001, respectively). Propensity score matching produced a cohort of 342 patients equally divided between GA and RA. There was no significant between-group difference in 30-day (3.5% vs 2.9%, p=0.737) or 90-day (6.4% vs 4.6%, p=0.474) mortality or postoperative morbidity. However, postoperative ICU admission (14.6% vs 7%, p=0.032), intraoperative hypotension (61.4% vs 14.6%, p<0.001), and vasopressor use (52% vs 14%, p<0.001) were more common with GA than with RA.Conclusion: Type of anesthesia did not significantly affect mortality or morbidity after LEA. However, intraoperative hypotension, vasopressor use, and postoperative ICU admission rates were lower with RA. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that function as key signal transducers of a wide spectrum of extracellular stimuli, including growth factors and pro-inflammatory cytokines. Dysregulation of the extracellular signal-regulated kinase (ERK) MAPK pathway is associated with human skeletal abnormalities including Noonan syndrome, neurofibromatosis type 1, and cardiofaciocutaneous syndrome. Here, we demonstrate that ERK activation in osteoprogenitors is required for bone formation during skeletal development and homeostasis. Deletion of Mek1 and Mek2, kinases upstream of ERK MAPK, in osteoprogenitors (Mek1OsxMek2−/−), resulted in severe osteopenia and cleidocranial dysplasia (CCD), similar to that seen in humans and mice with impaired RUNX2 function. Additionally, tamoxifen-induced deletion of Mek1 and Mek2 in osteoprogenitors in adult mice (Mek1Osx-ERTMek2−/−) significantly reduced bone mass. Mechanistically, this corresponded to decreased activation of osteoblast master regulators, including RUNX2, ATF4, and β-catenin. Finally, we identified potential regulators of osteoblast differentiation in the ERK MAPK pathway using unbiased phospho-mass spectrometry. These observations demonstrate essential roles of ERK activation in osteogenesis and bone formation. [ABSTRACT FROM AUTHOR]

Resveratrol is a sirtuin 1 (SIRT1) activator and can function as an anti-inflammatory and antioxidant factor. In mesenchymal stem cells (MSCs), resveratrol enhances the proliferation and differentiation potential and has an anti-aging effect. However, contradictory effects of resveratrol on MSC cultures have been reported. In this study, we found that resveratrol had different effects on MSC cultures according to their cell passage and SIRT1 expression. Resveratrol enhanced the self-renewal potential and multipotency of early passage MSCs, but accelerated cellular senescence of late passage MSCs. In early passage MSCs expressing SIRT1, resveratrol decreased ERK and GSK-3β phosphorylation, suppressing β-catenin activity. In contrast, in late passage MSCs, which did not express SIRT1, resveratrol increased ERK and GSK-3β phosphorylation, activating β-catenin. We confirmed that SIRT1-deficient early passage MSCs treated with resveratrol lost their self-renewal potential and multipotency, and became senescent due to increased β-catenin activity. Sustained treatment with resveratrol at early passages maintained the self-renewal potential and multipotency of MSCs up to passage 10. Our findings suggest that resveratrol can be effectively applied to early passage MSC cultures, whereas parameters such as cell passage and SIRT1 expression must be taken into consideration before applying resveratrol to late passage MSCs. [ABSTRACT FROM AUTHOR]

• Phospholipid enzymatic assay was developed based on amperometry with a graphite electrode. • Electrochemical properties of graphite-electrodes were compared with Au-electrode. • Phospholipid enzymatic assay using amperometry was applied for the diagnosis of sepsis using patient sera. • Phospholipid quantification results were statistically compared with the conventional method based on OD measurement. In this work phospholipid quantification was carried out using an enzymatic assay based on cyclic voltammetry of the condensation product of N -ethyl- N -(2-hydroxy-3-sulfopropyl)-3,5-dimethoxyaniline sodium salt (DAOS) and 4-aminoantipyrine (4-AP) with a graphite electrode. For the optimization of electrochemical measurement for the product, electrochemical properties such as the electrochemical window, double layer capacitance (Cdl) and electron transfer rate (kapp) were analyzed for a graphite-electrode and Au-electrode. The phospholipid enzymatic assay based the on electrochemical measurement using the graphite electrode was applied to the diagnosis of sepsis for sera from healthy volunteers (n = 16), patients with systemic inflammatory response syndrome (SIRS, n = 16) and severe sepsis patients (n = 24). Finally, the phospholipid quantification results from the electrochemical measurement were statistically compared with the conventional method based on optical density measurement. [ABSTRACT FROM AUTHOR]

Tauroursodeoxycholic acid (TUDCA) is a US FDA-approved hydrophilic bile acid for the treatment of chronic cholestatic liver disease. In the present study, we investigate the effects of TUDCA on the proliferation and differentiation of osteoblasts and its therapeutic effect on a mice model of osteoporosis. Following treatment with different concentrations of TUDCA, cell viability, differentiation, and mineralization were measured. Three-month-old female C57BL/6 mice were randomly divided into three groups (n = 8 mice per group): (i) normal mice as the control group, (ii) ovariectomy (OVX) group (receiving phosphate-buffered saline (PBS) treatment every other day for 4 weeks), and (iii) OVX group with TUDCA (receiving TUDCA treatment every other day for 4 weeks starting 6 weeks after OVX). At 11 weeks post-surgery, serum levels of procollagen type I N-terminal propeptides (PINP) and type I collagen crosslinked C-telopeptides (CTX) were measured, and all mice were sacrificed to examine the distal femur by micro-computed tomography (CT) scans and histology. TUDCA (100 nM, 1 µM) significantly increased the proliferation and viability of osteoblasts and osteoblast differentiation and mineralization when used in vitro. Furthermore, TUDCA neutralized the detrimental effects of methylprednisolone (methylprednisolone-induced osteoblast apoptosis). In the TUDCA treatment group the PINP level was higher and the CTX level was lower, but these levels were not significantly different compared to the PBS treatment group. Micro-CT and histology showed that the TUDCA treatment group preserved more trabecular structures in the distal femur compared to the PBS treatment group. In addition, the TUDCA treatment group increased the percentage bone volume with respect to the total bone volume, bone mineral density, and mice distal femur trabeculae compared with the PBS treatment group. Taken together, our findings suggest that TUDCA may provide a favorable effect on bones and could be used for the prevention and treatment of osteoporosis. [ABSTRACT FROM AUTHOR]