BACKGROUND The sphericity of the femoral head is a metric used to evaluate hip pathologies and is associated with the development of osteoarthritis and femoral-acetabular impingement.AIM To analyze the three-dimension...BACKGROUND The sphericity of the femoral head is a metric used to evaluate hip pathologies and is associated with the development of osteoarthritis and femoral-acetabular impingement.AIM To analyze the three-dimensional asphericity of the femoral head of asymptomatic pediatric hips.We hypothesized that femoral head asphericity will vary significantly between male and female pediatric hips and increase with age in both sexes.METHODS Computed tomography scans were obtained on 158 children and adolescents from a single institution in the United States(8-18 years;50%male)without hip pain.Proximal femoral measurements including the femoral head diameter,femoral head volume,residual volume,asphericity index,and local diameter difference were used to evaluate femoral head sphericity.RESULTS In both sexes,the residual volume increased by age(P<0.05).Despite significantly smaller femoral head size in older ages(>13 years)in females,there were no sex-differences in residual volume and aspherity index.There were no age-related changes in mean diameter difference in both sexes(P=0.07)with no significant sex-differences across different age groups(P=0.06).In contrast,there were significant increases in local aspherity(maximum diameter difference)across whole surface of the femoral head and all quadrants except the inferior regions in males(P=0.03).There were no sex-differences in maximum diameter difference at any regions and age group(P>0.05).Increased alpha angle was only correlated to increased mean diameter difference across overall surface of the femoral head(P=0.024).CONCLUSION There is a substantial localized asphericity in asymptomatic hips which increases with age in.While 2D measured alpha angle can capture overall asphericity of the femoral head,it may not be sensitive enough to represent regional asphericity patterns.展开更多
Bone and joint-related diseases,including osteoarthritis(OA),rheumatoid arthritis(RA),and bone tumors,pose significant health challenges due to their debilitating effects on the musculoskeletal system.14-3-3 proteins,...Bone and joint-related diseases,including osteoarthritis(OA),rheumatoid arthritis(RA),and bone tumors,pose significant health challenges due to their debilitating effects on the musculoskeletal system.14-3-3 proteins,a family of conserved regulatory molecules,play a critical role in the pathology of these diseases.This review discusses the intricate structure and multifunctionality of 14-3-3 proteins,their regulation of signaling pathways,and their interactions with other proteins.We underscore the significance of 14-3-3 proteins in the regulation of osteoblasts,osteoclasts,chondrocytes,and bone remodeling,all key factors in the maintenance and dysfunction of bone and joint systems.Specific focus is directed toward elucidating the contribution of 14-3-3proteins in the pathology of OA,RA,and bone malignancies,where dysregulated 14-3-3-mediated signaling cascades have been implicated in the disease processes.This review illuminates how the perturbation of 14-3-3 protein interactions can lead to the pathological manifestations observed in these disorders,including joint destruction and osteolytic activity.We highlight cuttingedge research that positions 14-3-3 proteins as potential biomarkers for disease progression and as innovative therapeutic targets,offering new avenues for disease intervention and management.展开更多
Spinal nerve roots have a peculiar structure, different from the arrangements in the peripheral nerve. The nerve roots are devoid of lymphatic vessels but are immersed in the cerebrospinal fluid(CSF) within the subara...Spinal nerve roots have a peculiar structure, different from the arrangements in the peripheral nerve. The nerve roots are devoid of lymphatic vessels but are immersed in the cerebrospinal fluid(CSF) within the subarachnoid space. The blood supply of nerve roots depends on the blood flow from both and peripheral direction(ascending) and the spinal cord direction(descending). There is no hypovascular region in the nerve root, although there exists a so-called water-shed of the bloodstream in the radicular artery itself. Increased mechanical compression promotes the disturbance of CSF flow, circulatory disturbance starting from the venous congestion and intraradicular edema formation resulting from the breakdown of the blood-nerve barrier. Although this edema may diffuse into CSF when the subarachnoid space is preserved, the endoneurial fluid pressure may increase when the area is closed by increased compression. On the other hand, the nerve root tissue has already degenerated under the compression and the numerous macrophages releasing various chemical mediators, aggravating radicular symptomsthat appear in the area of Wallerian degeneration. Prostaglandin E1(PGE1) is a potent vasodilator as well as an inhibitor of platelet aggregation and has therefore attracted interest as a therapeutic drug for lumbar canal stenosis. However, investigations in the clinical setting have shown that PGE1 is effective in some patients but not in others, although the reason for this is unclear.展开更多
Osteoarthritis （OA） is a common joint degenerative disease affecting the whole joint structure, including articular cartilage, subchondral bone and synovial tissue. Although extensive work has been done in recent ye...Osteoarthritis （OA） is a common joint degenerative disease affecting the whole joint structure, including articular cartilage, subchondral bone and synovial tissue. Although extensive work has been done in recent years to explore the molecular mechanism underlying this disease, the pathogenesis of OA is still poorly understood and currently, there is no effective disease-modifying treatment for OA. Recently, both in vitro an, in vivo studies suggest that confirmed （TGF-β）/SMAD pathway plays a critical role during OA development This short review will focus on the function and signaling mechanisms of TGF-β/SMAD pathway in articula chondrocytes, mesenchymal progenitor cells of subchondral bone and synovial lining cells during OA development.展开更多
This review presents a conceptual framework and supporting evidence that links impaired motor control after sport-related concussion(SRC)to increased risk for musculoskeletal injury.Multiple studies have found that at...This review presents a conceptual framework and supporting evidence that links impaired motor control after sport-related concussion(SRC)to increased risk for musculoskeletal injury.Multiple studies have found that athletes who are post-SRC have higher risk for musculoskeletal injury compared to their counterparts.A small body of research suggests that impairments in motor control are associated with musculoskeletal injury risk.Motor control involves the perception and processing of sensory information and subsequent coordination of motor output within the central nervous system to perform a motor task.Motor control is inclusive of motor planning and motor learning.If sensory information is not accurately perceived or there is interference with sensory information processing and cognition,motor function will be altered,and an athlete may become vulnerable to injury during sport participation.Athletes with SRC show neuroanatomic and neurophysiological changes relevant to motor control even after meeting return to sport criteria,including a normal neurological examination,resolution of symptoms,and return to baseline function on traditional concussion testing.In conjunction,altered motor function is demonstrated after SRC in muscle activation and force production,movement patterns,balance/postural stability,and motor task performance,especially performance of a motor task paired with a cognitive task(i.e.,dual-task condition).The clinical implications of this conceptual framework include a need to intentionally address motor control impairments after SRC to mitigate musculoskeletal injury risk and to monitor motor control as the athlete progresses through the return to sport continuum.展开更多
We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect ...We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect of 4-AP is unknown in nerve transection,gap,and grafting models.To evaluate and compare the functional recovery,nerve morphology,and muscle atrophy,we used a novel stepwise nerve transection with gluing(STG),as well as 7-mm irreparable nerve gap(G-7/0)and 7-mm isografting in 5-mm gap(G-5/7)models in the absence and presence of 4-AP treatment.Following surgery,sciatic functional index was determined wee kly to evaluate the direct in vivo global motor functional recovery.After 12 weeks,nerves were processed for whole-mount immunofluorescence imaging,and tibialis anterior muscles were harvested for wet weight and quantitative histomorphological analyses for muscle fiber crosssectional area and minimal Feret's diameter.Average post-injury sciatic functional index values in STG and G-5/7 models were significantly greater than those in the G-7/0 model.4-AP did not affect the sciatic functional index recovery in any model.Compared to STG,nerve imaging revealed more misdirected axons and distorted nerve architecture with isografting.While muscle weight,cross-sectional area,and minimal Feret's diameter were significantly smaller in G-7/0 model compared with STG and G-5/7,4-AP treatment significantly increased right TA muscle mass,cross-sectional area,and minimal Feret's diameter in G-7/0 model.These findings demonstrate that functional recovery and muscle atrophy after peripheral nerve injury are directly related to the intervening nerve gap,and 4-AP exerts diffe rential effects on functional recove ry and muscle atrophy.展开更多
BACKGROUND Injuries to multiple fingertips pose a significant treatment dilemma.Numerous reconstructive options exist,all with the ultimate goal of restoring function and sensibility to the injured fingertips.CASE SUM...BACKGROUND Injuries to multiple fingertips pose a significant treatment dilemma.Numerous reconstructive options exist,all with the ultimate goal of restoring function and sensibility to the injured fingertips.CASE SUMMARY A 24-year-old male suffered injury to multiple fingertips of the right hand,resulting in exposed distal phalanges of the middle,ring,and small fingers.The amputated distal stumps were not possible for replantation.Free flap coverage was selected in order to achieve better functional outcome.The fingertip defects were covered by performing a right second toe split tibial flap using local anesthesia at the harvest site and brachial plexus nerve block for the right upper extremity.At 6-month follow-up,all three of the reconstructed fingertips had some preserved nail growth,Semmes-Weinstein Monofilaments testing was equal to the contralateral side and the Static Two-Point Discrimination were comparable to the contralateral side.CONCLUSION This report provides a novel reconstructive option for the management of multiple fingertip injuries and demonstrates the utility of supermicrosurgery in management of these injuries.展开更多
RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling c...RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling can regulate Sox9 transcription, although how this occurs at the molecular level in chondrocytes and whether this transcriptional regulation mediates Notch control of chondrocyte hypertrophy and cartilage development is unknown or controversial. Here we have provided conclusive genetic evidence linking RBPjk-dependent Notch signaling to the regulation of Sox9 expression and chondrocyte hypertrophy by examining tissuespecific Rbpjk mutant（Prx1Cre;Rbpjkf/f）, Rbpjk mutant/Sox9 haploinsufficient（Prx1Cre;Rbpjkf/f;Sox9f/1）,and control embryos for alterations in SOX9 expression and chondrocyte hypertrophy during cartilage development. These studies demonstrate that Notch signaling regulates the onset of chondrocyte maturation in a SOX9-dependent manner, while Notch-mediated regulation of terminal chondrocyte maturation likely functions independently of SOX9. Furthermore, our in vitro molecular analyses of the Sox9 promoter and Notch-mediated regulation of Sox9 gene expression in chondrogenic cells identified the ability of Notch to induce Sox9 expression directly in the acute setting, but suppresses Sox9 transcription with prolonged Notch signaling that requires protein synthesis of secondary effectors.展开更多
Background:Recognizing sport-related concussion(SRC)is challenging and relies heavily on subjective symptom reports.An objective,biological marker could improve recognition and understanding of SRC.There is emerging e...Background:Recognizing sport-related concussion(SRC)is challenging and relies heavily on subjective symptom reports.An objective,biological marker could improve recognition and understanding of SRC.There is emerging evidence that salivary micro-ribonucleic acids(miRNAs)may serve as biomarkers of concussion;however,it remains unclear whether concussion-related miRNAs are impacted by exercise.We sought to determine whether40 miRNAs previously implicated in concussion pathophysiology were affected by participation in a variety of contact and non-contact sports.Our goal was to refine a miRNA-based tool capable of identifying athletes with SRC without the confounding effects of exercise.Methods:This case-control study harmonized data from concussed and non-concussed athletes recruited across 10 sites.Levels of salivary miRNAs within 455 samples from 314 individuals were measured with RNA sequencing.Within-subjects testing was used to identify and exclude miRNAs that changed with either(a)a single episode of exercise(166 samples from 83 individuals)or(b)season-long participation in contact sports(212 samples from 106 individuals).The miRNAs that were not impacted by exercise were interrogated for SRC diagnostic utility using logistic regression(172 samples from 75 concussed and 97 non-concussed individuals).Results:Two miRNAs(miR-532-5p and miR-182-5p)decreased(adjusted p<0.05)after a single episode of exercise,and 1 miRNA(miR-4510)increased only after contact sports participation.Twenty-three miRNAs changed at the end of a contact sports season.Two of these miRNAs(miR-26b-3p and miR-29c-3p)were associated(R>0.50;adjusted p<0.05)with the number of head impacts sustained in a single football practice.Among the 15 miRNAs not confounded by exercise or season-long contact sports participation,11 demonstrated a significant difference(adjusted p<0.05)between concussed and non-concussed participants,and 6 displayed moderate ability(area under curve>0.70)to identify concussion.A single ratio(miR-27a-5p/miR-30a-3p)displayed the highest accuracy(AUC=0.810,sensitivity=82.4%,specificity=73.3%)for differentiating concussed and non-concussed participants.Accuracy did not differ between participants with SRC and non-SRC(z=0.5,p=0.60).Conclusion:Salivary miRNA levels may accurately identify SRC when not confounded by exercise.Refinement of this approach in a large cohort of athletes could eventually lead to a non-invasive,sideline adjunct for SRC assessment.展开更多
BACKGROUND Despite over 150000 amputations of lower limbs annually,there remains a wide variation in tourniquet practice patterns and no consensus on their necessity,especially among orthopedic patient populations.The...BACKGROUND Despite over 150000 amputations of lower limbs annually,there remains a wide variation in tourniquet practice patterns and no consensus on their necessity,especially among orthopedic patient populations.The purpose of this study was to determine whether tourniquet use in orthopedic patients undergoing below knee amputation(BKA) was associated with a difference in calculated blood loss relative to no tourniquet use.AIM To determine if tourniquet use in orthopedic patients undergoing BKA was associated with a difference in calculated blood loss relative to no tourniquet use.METHODS We performed a retrospective review of consecutive patients undergoing BKA by orthopedic surgeons at a tertiary care hospital from 2008 through 2018.Blood loss was calculated using a combination of the Nadler equation for preoperative blood volume and a novel formula utilizing preoperative and postoperative hemoglobin levels and transfusions.Univariate and forwards step-wise multivariate linear regressions were performed to determine the association between tourniquet use and blood loss.A Wilcoxon was used to determine the univariate relationship between tourniquet use and blood loss for in the restricted subgroups of patients who underwent BKA for trauma,tumor,and infection.RESULTS Of 97 eligible patients identified,67 underwent surgery with a tourniquet and 30 did not.In multivariate regression,tourniquet use was associated with a 488 mL decrease in calculated blood loss(CI 119-857,P = 0.01).In subgroup analysis,no individual group showed a statistically significant decrease in blood loss with tourniquet use.There was no significant association between tourniquet use and either postoperative transfusions or reoperation at one year.CONCLUSION We found that tourniquet use during BKA is associated with decreased calculated intraoperative blood loss.We recommend that surgeons performing this procedure use a tourniquet to minimize blood loss.展开更多
BACKGROUND Direct anterior approach(DAA)total hip arthroplasty(THA)in a supine position provides a unique opportunity to assess leg length discrepancy(LLD)intraoperatively with fluoroscopy.Reported fluoroscopic techni...BACKGROUND Direct anterior approach(DAA)total hip arthroplasty(THA)in a supine position provides a unique opportunity to assess leg length discrepancy(LLD)intraoperatively with fluoroscopy.Reported fluoroscopic techniques are useful but are generally complicated or costly.Despite the use of multiple techniques for leg length assessment,LLD continues to be a major post-operative source of patient dissatisfaction further emphasizing the importance of near-anatomic restoration.The utility of an alternative direct measurement of LLD on an intra-operative fluoroscopic pelvic image during DAA THA has not been reported.AIM To determine the reliability of a novel simple intra-operative measurement of LLD using a parallel line technique on a single fluoroscopic digital image of the pelvis.METHODS One hundred and seventy-one patients who underwent DAA THA were included for analysis.Intra-operative fluoroscopic and post-operative anterior-posterior radiographs were imported to TraumaCad and calibrated for LLD measurement.LLD was measured on each image using the right-left hip differences in lesser trochanter to pelvic reference line distances.Pelvic reference points included the teardrops and ischia.Fluoroscopic LLD was compared to the gold-standard measurement of LLD measured on a post-operative radiograph.RESULTS Mean absolute difference in teardrop referenced LLD between fluoroscopic and post-operative radiographs was 2.17 mm and based on the ischia mean absolute difference was 2.63 mm.Linear regression of fluoroscopic and post-operative radiograph LLD based on teardrop and ischia LLD found r2 values of 0.57 and 0.84,respectively.Mean absolute difference between fluoroscopic and postoperative x-ray LLD was within 5 mm in 95%of cases regardless of pelvic reference.CONCLUSION This study demonstrates that a single fluoroscopic view obtained during DAA THA for leg length assessment is clinically useful.展开更多
Estrogen deficiency is considered the most important cause of postmenopausal osteoporosis.However,the underlying mechanism is still not completely understood.In this study,progranulin(PGRN)was isolated as a key regula...Estrogen deficiency is considered the most important cause of postmenopausal osteoporosis.However,the underlying mechanism is still not completely understood.In this study,progranulin(PGRN)was isolated as a key regulator of bone mineral density in postmenopausal women through high throughput proteomics screening.In addition,PGRN-deficient mice exhibited significantly lower bone mass than their littermates in an ovariectomy-induced osteoporosis model.Furthermore,estrogen-mediated inhibition of osteoclastogenesis and bone resorption as well as its protection against ovariectomy-induced bone loss largely depended on PGRN.Mechanistic studies revealed the existence of a positive feedback regulatory loop between PGRN and estrogen signaling.In addition,loss of PGRN led to the reduction of estrogen receptorα,the important estrogen receptor involved in estrogen regulation of osteoporosis,through enhancing its degradation via K48-linked ubiquitination.These findings not only provide a previously unrecognized interplay between PGRN and estrogen signaling in regulating osteoclastogenesis and osteoporosis but may also present a new therapeutic approach for the prevention and treatment of postmenopausal osteoporosis by targeting PGRN/estrogen receptorα.展开更多
Background:Osteosarcoma is the most common bone malignancy in children and adolescents,and 20%-30%of the patients suffer from poor prognosis because of individual chemoresistance.The Hippo/yes-associated protein(YAP) ...Background:Osteosarcoma is the most common bone malignancy in children and adolescents,and 20%-30%of the patients suffer from poor prognosis because of individual chemoresistance.The Hippo/yes-associated protein(YAP) signaling pathway has been shown to play a role in tumor chemoresistance,but no previous report has focused on its involvement in osteosarcoma chemoresistance.This study aimed to investigate the role of the Hippo/YAP signaling pathway in osteosarcoma chemoresistance and to determine potential treatment targets.Methods:Using the Cell Titer-Glo Luminescent cell viability assay and flow cytometry analysis,we determined the proliferation and chemosensitivity of YAP-overexpressing and YAP-knockdown osteosarcoma cells.In addition,using western blotting and the real-time polymerase chain reaction technique,we investigated the alteration of the Hippo/YAP signaling pathway in osteosarcoma cells treated with chemotherapeutic agents.Results:Mammalian sterile 20-like kinase 1(MST1) degradation was increased,and large tumor suppressor kinase1/2(LAT51/2) total protein levels were decreased by methotrexate and doxorubicin,which increased activation and nuclear translocation of YAP.Moreover,YAP increased the proliferation and chemoresistance of MG63 cells.Conclusions:The Hippo/YAP signaling pathway plays a role in osteosarcoma chemoresistance,and YAP is a potential target for reducing chemoresistance.展开更多
Purpose: Failure after radial head arthroplasty is uncommon, but clinically significant. Treatment for failure may involve implant removal. We describe fourteen patients who underwent implant removal after failed radi...Purpose: Failure after radial head arthroplasty is uncommon, but clinically significant. Treatment for failure may involve implant removal. We describe fourteen patients who underwent implant removal after failed radial head arthroplasty. Methods: A retrospective review was performed to determine the cause of failure and clinical data were prospectively collected. Results: At mean follow up of 38 months the mean VAS for pain score was 3.0 and the mean DASH score was 40.5. The mean MEPS was 69. All patients demonstrated improved elbow range of motion. Mean elbow flexion at final follow up was 124°to an average extension deficit of 25°. Fifty percent of patients exhibited clinical symptoms of cubital tunnel syndrome. Three patients required additional surgery after implant removal. Conclusions: Implant removal for failed radial head arthroplasty improves range of motion and demonstrates acceptable outcomes at intermediate-term follow up. However, 50% of patients developed cubital tunnel syndrome and 21% required revision surgery.展开更多
Maturation of the 3′end of almost all eukaryotic messenger RNAs(m RNAs)requires cleavage and polyadenylation.Most mammalian m RNAs are polyadenylated at different sites within the last exon,generating alternative pol...Maturation of the 3′end of almost all eukaryotic messenger RNAs(m RNAs)requires cleavage and polyadenylation.Most mammalian m RNAs are polyadenylated at different sites within the last exon,generating alternative polyadenylation(APA)isoforms that have the same coding region but distinct 3′untranslated regions(UTRs).The 3′UTR contains motifs that regulate m RNA metabolism;thus,changing the 3′UTR length via APA can significantly affect gene expression.Endochondral ossification is a central process in bone healing,but the impact of APA on gene expression during this process is unknown.Here,we report the widespread occurrence of APA,which impacts multiple pathways that are known to participate in bone healing.Importantly,the progression of endochondral ossification involves global 3′UTR shortening,which is coupled with an increased abundance of shortened transcripts relative to other transcripts;these results highlight the role of APA in promoting gene expression during endochondral bone formation.Our mechanistic studies of transcripts that undergo APA in the fracture callus revealed an intricate regulatory network in which APA enhances the expression of the collagen,type I,alpha 1(Col1a1)and Col1a2 genes,which encode the 2 subunits of the abundantly expressed protein collagen 1.APA exerts this effect by shortening the 3′UTRs of the Col1a1 and Col1a2 m RNAs,thus removing the binding sites of mi R-29a-3p,which would otherwise strongly promote the degradation of both transcripts.Taken together,our study is the first to characterize the crucial roles of APA in regulating the 3′UTR landscape and modulating gene expression during fracture healing.展开更多
OBJECTIVE： In the present study, we systemically evaluated the ability of two bioactive compounds from traditional Chinese medicine, celastrol and pristimerin, to enhance recombinant adeno-associated virus （rAAV） s...OBJECTIVE： In the present study, we systemically evaluated the ability of two bioactive compounds from traditional Chinese medicine, celastrol and pristimerin, to enhance recombinant adeno-associated virus （rAAV） serotype vector-mediated transgene expression both in human cell lines in vitro, and in murine hepatocytes in vivo. METHODS： Human cell lines were infected with rAAV vectors with either mock treatment or treatment with celastrol or pristimerin. The transgene expression, percentage of nuclear translocated viral genomes and the ubiquitination of intracellular proteins were investigated post-treatment. In addition, nonobese diabetic/severe combined immunodeficient gamma （NSG） mice were tail vain-injected with rAAV vectors and co-administered with either dimethyl sulfoxide, celastrol, pristimerin or a positive control, bortezomib. The transgene expression in liver was detected and compared over time. RESULTS： We observed that treatment with pristimerin, at as low as 1 IJmol/L concentration, significantly enhanced rAAV2 vector-mediated transgene expression in vitro, and intraperitoneal co- administration with pristimerin at 4 mg/（kg.d） for 3 d dramatically facilitated viral transduction in murine hepatocytes in vivo. The transduction efficiency of the tyrosine-mutant rAAV2 vectors as well as that of rAAV8 vectors carrying oversized transgene cassette was also augmented significantly by pristimerin. The underlying molecular mechanisms by which pristimerin mediated the observed increase in the transduction efficiency of rAAV vectors include both inhibition of proteasomal degradation of the intracellular proteins and enhanced nuclear translocation of the vector genomes. CONCLUSION： These studies suggest the potential beneficial use of pristimerin and pristimerincontaining herb extract in future liver-targeted gene therapy with rAAV vectors.展开更多
Background： Resection of sacral chordomas is challenging. The anatomy is complex, and there are often no bony landmarks to guide the resection. Achieving adequate surgical margins is, therefore, difficult, and the re...Background： Resection of sacral chordomas is challenging. The anatomy is complex, and there are often no bony landmarks to guide the resection. Achieving adequate surgical margins is, therefore, difficult, and the recurrence rate is high. Use of computer navigation may allow optimal preoperative planning and improve precision in tumor resection. The purpose of this study was to evaluate the safety and feasibility of computer navigation-aided resection of sacral chordomas. Methods： Between 2007 and 2013, a total of 26 patients with sacral chordoma underwent computer navigation-aided surgery were included and followed for a minimum of 18 months. There were 21 primary cases and 5 recurrent cases, with a mean age of 55.8 years old （range： 35 84 years old）. Tumors were located above the level of the $3 neural foramen in 23 patients and below the level of the $3 neural foramen in 3 patients. Three-dimensional images were reconstructed with a computed tomography-based navigation system combined with the magnetic resonance images using the navigation software. Tumors were resected via a posterior approach assisted by the computer navigation. Mean follow-up was 38.6 months （range： 18-84 months）. Results： Mean operative time was 307 min. Mean intraoperative blood loss was 3065 ml. For computer navigation, the mean registration deviation during surgery was 1.7 ram. There were 18 wide resections, 4 marginal resections, and 4 intralesional resections. All patients were alive at the final follow-up, with 2 （7.7%） exhibiting tumor recurrence. The other 24 patients were tumor-free. The mean Musculoskeletal Tumor Society Score was 27.3 （range： 19-30）. Conclusions： Computer-assisted navigation can be safely applied to the resection of the sacral chordomas, allowing execution of preoperative plans, and achieving good oncological outcomes. Nevertheless, this needs to be accomplished by surgeons with adequate experience and skill.展开更多
Citrate based polymer poly(octamethylene citrate)(POC)has shown promise when formulated into composite material containing up to 65 wt%hydroxylapatite(HA)for orthopedic applications.Despite significant research into P...Citrate based polymer poly(octamethylene citrate)(POC)has shown promise when formulated into composite material containing up to 65 wt%hydroxylapatite(HA)for orthopedic applications.Despite significant research into POC,insufficient information about the biocompatibility of the monomers 1,8-Octanediol and Citrate used in its synthesis is available.Herein,we investigated the acute cytotoxicity,immune response,and long-term functionality of both monomers.Our results showed a cell-type dependent cytotoxicity of the two monomers:1,8-Octanediol induced less acute toxicity to 3T3 fibroblasts than Citrate while presenting comparable cytotoxicity to MG63 osteoblast-like cells;however,Citrate demonstrated enhanced compatibility with hMSCs compared to 1,8-Octanediol.The critical cytotoxic concentration values EC30 and EC50,standard for comparing cytotoxicity of chemicals,were also provided.Additionally,Citrate showed slower and less inhibitory effects on long-term hMSC cell proliferation compared with 1,8-Octanediol.Furthermore,osteogenic differentiation of hMSCs exposure to Citrate resulted in less inhibitory effect on alkaline phosphatase(ALP)production.Neither monomer triggered undesired pro-inflammatory responses.In combination with diffusion model analysis of monomer release from cylindrical implants,based on which the maximum concentration of monomers in contact with bone tissue was estimated to be 2.2104 mmol/L,far lower than the critical cytotoxic concentrations as well as the 1,8-Octanediol concentration(0.4 mg/mL or 2.7 mmol/L)affecting hMSCs differentiation,we provide strong evidence for the cytocompatibility of the two monomers degraded from citrate-based composites in the orthopedic setting.展开更多
background Although less common in adults,venous thromboembolism(VTE)in children is a highly morbid,preventable adverse event.While VTE has been well studied among pediatric hospitalized and trauma patients,limited wo...background Although less common in adults,venous thromboembolism(VTE)in children is a highly morbid,preventable adverse event.While VTE has been well studied among pediatric hospitalized and trauma patients,limited work has been done to examine postoperative VTE in children undergoing surgery.Methods Using data from National Surgical Quality Improvement Project Pediatric database(NSQIP-P)from 2012 to 2016,a retrospective cohort analysis was performed to determine the incidence of,and risk factors for,VTE in children undergoing surgery.Additionally,the relationships between VTE and other postoperative adverse outcomes were evaluated.results Of 361384 pediatric surgical patients,378(0.10%)were identified as experiencing postoperative VTE.After controlling for patient and surgical factors,we found that American Society of Anesthesiologists(ASA)class of II or greater,aged 16-18 years,non-elective surgery,general surgery(compared with several other surgical specialties),cardiothoracic surgery(compared with general surgery)and longer operative time were significantly associated with VTE in pediatric patients(p<0.001 for each comparison).Furthermore,a majority of adverse events were found to be associated with increased risk of subsequent VTE(p<0.001).Conclusion In a large pediatric surgical population,an incidence of postoperative VTE of 0.10%was observed.Defined patient and surgical factors,and perioperative adverse events were found to be associated with such VTE events.展开更多
Neurofibroma cell lines derived from mice transgenic for HTLV-I LTR tax express high levels of HTLV-I tax mRNA and protein and exhibit a transformed phenotype. A retrovirus vector carrying HTLV-I tax cDNA in reversed ...Neurofibroma cell lines derived from mice transgenic for HTLV-I LTR tax express high levels of HTLV-I tax mRNA and protein and exhibit a transformed phenotype. A retrovirus vector carrying HTLV-I tax cDNA in reversed transcriptional orientation was stably transfected into the neurofibroma cells. Antisense RNA inhibited expression of the tax gene with a decrease of more than 40 % in both tax mRNA and protein. Tax antisense RNA reversed the transformed phenotype as exhibited by dramatic changes in cell morphology and growth characteristics. Expression of several cellular genes which are activated by Tax protein including GM-CSF, IL-6, LT/TNF, c-myc and LIF was down-regulated, while M-CSF and c-src proto-oncogene expressions were up-regulated. Accumulation of β-actin mRNA was not affected. The changes that occurred in the tax antisense expressing neurofibroma cells could be the consequence of the decreased concentration of Tax protein. These results also indicate that HTLV-I Tax protein is crucial for maintaining the transformed cell morphology, growth and proliferation of murine neurofibroma cells and suggest that deregulation of endogenous cellular genes by Tax protein is the mechanism through which neurofibromas occur in tax mice.展开更多
文摘BACKGROUND The sphericity of the femoral head is a metric used to evaluate hip pathologies and is associated with the development of osteoarthritis and femoral-acetabular impingement.AIM To analyze the three-dimensional asphericity of the femoral head of asymptomatic pediatric hips.We hypothesized that femoral head asphericity will vary significantly between male and female pediatric hips and increase with age in both sexes.METHODS Computed tomography scans were obtained on 158 children and adolescents from a single institution in the United States(8-18 years;50%male)without hip pain.Proximal femoral measurements including the femoral head diameter,femoral head volume,residual volume,asphericity index,and local diameter difference were used to evaluate femoral head sphericity.RESULTS In both sexes,the residual volume increased by age(P<0.05).Despite significantly smaller femoral head size in older ages(>13 years)in females,there were no sex-differences in residual volume and aspherity index.There were no age-related changes in mean diameter difference in both sexes(P=0.07)with no significant sex-differences across different age groups(P=0.06).In contrast,there were significant increases in local aspherity(maximum diameter difference)across whole surface of the femoral head and all quadrants except the inferior regions in males(P=0.03).There were no sex-differences in maximum diameter difference at any regions and age group(P>0.05).Increased alpha angle was only correlated to increased mean diameter difference across overall surface of the femoral head(P=0.024).CONCLUSION There is a substantial localized asphericity in asymptomatic hips which increases with age in.While 2D measured alpha angle can capture overall asphericity of the femoral head,it may not be sensitive enough to represent regional asphericity patterns.
基金supported by NIH research grants R01AR062207,R01AR061484,R01AR076900,R01AR078035,and R01NS070328。
文摘Bone and joint-related diseases,including osteoarthritis(OA),rheumatoid arthritis(RA),and bone tumors,pose significant health challenges due to their debilitating effects on the musculoskeletal system.14-3-3 proteins,a family of conserved regulatory molecules,play a critical role in the pathology of these diseases.This review discusses the intricate structure and multifunctionality of 14-3-3 proteins,their regulation of signaling pathways,and their interactions with other proteins.We underscore the significance of 14-3-3 proteins in the regulation of osteoblasts,osteoclasts,chondrocytes,and bone remodeling,all key factors in the maintenance and dysfunction of bone and joint systems.Specific focus is directed toward elucidating the contribution of 14-3-3proteins in the pathology of OA,RA,and bone malignancies,where dysregulated 14-3-3-mediated signaling cascades have been implicated in the disease processes.This review illuminates how the perturbation of 14-3-3 protein interactions can lead to the pathological manifestations observed in these disorders,including joint destruction and osteolytic activity.We highlight cuttingedge research that positions 14-3-3 proteins as potential biomarkers for disease progression and as innovative therapeutic targets,offering new avenues for disease intervention and management.
基金Supported by Grant-in Aid from the Ministry of Education,Science and Culture of Japan,No,25460719
文摘Spinal nerve roots have a peculiar structure, different from the arrangements in the peripheral nerve. The nerve roots are devoid of lymphatic vessels but are immersed in the cerebrospinal fluid(CSF) within the subarachnoid space. The blood supply of nerve roots depends on the blood flow from both and peripheral direction(ascending) and the spinal cord direction(descending). There is no hypovascular region in the nerve root, although there exists a so-called water-shed of the bloodstream in the radicular artery itself. Increased mechanical compression promotes the disturbance of CSF flow, circulatory disturbance starting from the venous congestion and intraradicular edema formation resulting from the breakdown of the blood-nerve barrier. Although this edema may diffuse into CSF when the subarachnoid space is preserved, the endoneurial fluid pressure may increase when the area is closed by increased compression. On the other hand, the nerve root tissue has already degenerated under the compression and the numerous macrophages releasing various chemical mediators, aggravating radicular symptomsthat appear in the area of Wallerian degeneration. Prostaglandin E1(PGE1) is a potent vasodilator as well as an inhibitor of platelet aggregation and has therefore attracted interest as a therapeutic drug for lumbar canal stenosis. However, investigations in the clinical setting have shown that PGE1 is effective in some patients but not in others, although the reason for this is unclear.
基金supported by Grants R01 AR055915 and R01 AR054465 to DC from the National Institute of Health
文摘Osteoarthritis （OA） is a common joint degenerative disease affecting the whole joint structure, including articular cartilage, subchondral bone and synovial tissue. Although extensive work has been done in recent years to explore the molecular mechanism underlying this disease, the pathogenesis of OA is still poorly understood and currently, there is no effective disease-modifying treatment for OA. Recently, both in vitro an, in vivo studies suggest that confirmed （TGF-β）/SMAD pathway plays a critical role during OA development This short review will focus on the function and signaling mechanisms of TGF-β/SMAD pathway in articula chondrocytes, mesenchymal progenitor cells of subchondral bone and synovial lining cells during OA development.
文摘This review presents a conceptual framework and supporting evidence that links impaired motor control after sport-related concussion(SRC)to increased risk for musculoskeletal injury.Multiple studies have found that athletes who are post-SRC have higher risk for musculoskeletal injury compared to their counterparts.A small body of research suggests that impairments in motor control are associated with musculoskeletal injury risk.Motor control involves the perception and processing of sensory information and subsequent coordination of motor output within the central nervous system to perform a motor task.Motor control is inclusive of motor planning and motor learning.If sensory information is not accurately perceived or there is interference with sensory information processing and cognition,motor function will be altered,and an athlete may become vulnerable to injury during sport participation.Athletes with SRC show neuroanatomic and neurophysiological changes relevant to motor control even after meeting return to sport criteria,including a normal neurological examination,resolution of symptoms,and return to baseline function on traditional concussion testing.In conjunction,altered motor function is demonstrated after SRC in muscle activation and force production,movement patterns,balance/postural stability,and motor task performance,especially performance of a motor task paired with a cognitive task(i.e.,dual-task condition).The clinical implications of this conceptual framework include a need to intentionally address motor control impairments after SRC to mitigate musculoskeletal injury risk and to monitor motor control as the athlete progresses through the return to sport continuum.
基金supported by grants from the National Institutes of Health,USA(No.K08 AR060164-01A)Department of Defense,USA(Nos.W81XWH-16-1-0725 and W81XWH-19-1-0773)in addition to institutional support from the Pennsylvania State University College of Medicine。
文摘We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect of 4-AP is unknown in nerve transection,gap,and grafting models.To evaluate and compare the functional recovery,nerve morphology,and muscle atrophy,we used a novel stepwise nerve transection with gluing(STG),as well as 7-mm irreparable nerve gap(G-7/0)and 7-mm isografting in 5-mm gap(G-5/7)models in the absence and presence of 4-AP treatment.Following surgery,sciatic functional index was determined wee kly to evaluate the direct in vivo global motor functional recovery.After 12 weeks,nerves were processed for whole-mount immunofluorescence imaging,and tibialis anterior muscles were harvested for wet weight and quantitative histomorphological analyses for muscle fiber crosssectional area and minimal Feret's diameter.Average post-injury sciatic functional index values in STG and G-5/7 models were significantly greater than those in the G-7/0 model.4-AP did not affect the sciatic functional index recovery in any model.Compared to STG,nerve imaging revealed more misdirected axons and distorted nerve architecture with isografting.While muscle weight,cross-sectional area,and minimal Feret's diameter were significantly smaller in G-7/0 model compared with STG and G-5/7,4-AP treatment significantly increased right TA muscle mass,cross-sectional area,and minimal Feret's diameter in G-7/0 model.These findings demonstrate that functional recovery and muscle atrophy after peripheral nerve injury are directly related to the intervening nerve gap,and 4-AP exerts diffe rential effects on functional recove ry and muscle atrophy.
文摘BACKGROUND Injuries to multiple fingertips pose a significant treatment dilemma.Numerous reconstructive options exist,all with the ultimate goal of restoring function and sensibility to the injured fingertips.CASE SUMMARY A 24-year-old male suffered injury to multiple fingertips of the right hand,resulting in exposed distal phalanges of the middle,ring,and small fingers.The amputated distal stumps were not possible for replantation.Free flap coverage was selected in order to achieve better functional outcome.The fingertip defects were covered by performing a right second toe split tibial flap using local anesthesia at the harvest site and brachial plexus nerve block for the right upper extremity.At 6-month follow-up,all three of the reconstructed fingertips had some preserved nail growth,Semmes-Weinstein Monofilaments testing was equal to the contralateral side and the Static Two-Point Discrimination were comparable to the contralateral side.CONCLUSION This report provides a novel reconstructive option for the management of multiple fingertip injuries and demonstrates the utility of supermicrosurgery in management of these injuries.
基金supported in part by the following United States National Institute of Health grants: R01 grants (AR057022 and AR063071), R21 grant (AR059733 to MJH), a P30 Core Center grant (AR061307), and a T32 training grant that supported both AK and TPR (AR053459 to Regis J.O’Keefe and Michael J.Zuscik)
文摘RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling can regulate Sox9 transcription, although how this occurs at the molecular level in chondrocytes and whether this transcriptional regulation mediates Notch control of chondrocyte hypertrophy and cartilage development is unknown or controversial. Here we have provided conclusive genetic evidence linking RBPjk-dependent Notch signaling to the regulation of Sox9 expression and chondrocyte hypertrophy by examining tissuespecific Rbpjk mutant（Prx1Cre;Rbpjkf/f）, Rbpjk mutant/Sox9 haploinsufficient（Prx1Cre;Rbpjkf/f;Sox9f/1）,and control embryos for alterations in SOX9 expression and chondrocyte hypertrophy during cartilage development. These studies demonstrate that Notch signaling regulates the onset of chondrocyte maturation in a SOX9-dependent manner, while Notch-mediated regulation of terminal chondrocyte maturation likely functions independently of SOX9. Furthermore, our in vitro molecular analyses of the Sox9 promoter and Notch-mediated regulation of Sox9 gene expression in chondrogenic cells identified the ability of Notch to induce Sox9 expression directly in the acute setting, but suppresses Sox9 transcription with prolonged Notch signaling that requires protein synthesis of secondary effectors.
基金supported by a sponsored research agreement between Quadrant Biosciences and the Penn State College of Medicine to ACLsupported by the National Center for Advancing Translational Sciences(Grant KL2 TR002015,Grant UL1 TR002014)。
文摘Background:Recognizing sport-related concussion(SRC)is challenging and relies heavily on subjective symptom reports.An objective,biological marker could improve recognition and understanding of SRC.There is emerging evidence that salivary micro-ribonucleic acids(miRNAs)may serve as biomarkers of concussion;however,it remains unclear whether concussion-related miRNAs are impacted by exercise.We sought to determine whether40 miRNAs previously implicated in concussion pathophysiology were affected by participation in a variety of contact and non-contact sports.Our goal was to refine a miRNA-based tool capable of identifying athletes with SRC without the confounding effects of exercise.Methods:This case-control study harmonized data from concussed and non-concussed athletes recruited across 10 sites.Levels of salivary miRNAs within 455 samples from 314 individuals were measured with RNA sequencing.Within-subjects testing was used to identify and exclude miRNAs that changed with either(a)a single episode of exercise(166 samples from 83 individuals)or(b)season-long participation in contact sports(212 samples from 106 individuals).The miRNAs that were not impacted by exercise were interrogated for SRC diagnostic utility using logistic regression(172 samples from 75 concussed and 97 non-concussed individuals).Results:Two miRNAs(miR-532-5p and miR-182-5p)decreased(adjusted p<0.05)after a single episode of exercise,and 1 miRNA(miR-4510)increased only after contact sports participation.Twenty-three miRNAs changed at the end of a contact sports season.Two of these miRNAs(miR-26b-3p and miR-29c-3p)were associated(R>0.50;adjusted p<0.05)with the number of head impacts sustained in a single football practice.Among the 15 miRNAs not confounded by exercise or season-long contact sports participation,11 demonstrated a significant difference(adjusted p<0.05)between concussed and non-concussed participants,and 6 displayed moderate ability(area under curve>0.70)to identify concussion.A single ratio(miR-27a-5p/miR-30a-3p)displayed the highest accuracy(AUC=0.810,sensitivity=82.4%,specificity=73.3%)for differentiating concussed and non-concussed participants.Accuracy did not differ between participants with SRC and non-SRC(z=0.5,p=0.60).Conclusion:Salivary miRNA levels may accurately identify SRC when not confounded by exercise.Refinement of this approach in a large cohort of athletes could eventually lead to a non-invasive,sideline adjunct for SRC assessment.
文摘BACKGROUND Despite over 150000 amputations of lower limbs annually,there remains a wide variation in tourniquet practice patterns and no consensus on their necessity,especially among orthopedic patient populations.The purpose of this study was to determine whether tourniquet use in orthopedic patients undergoing below knee amputation(BKA) was associated with a difference in calculated blood loss relative to no tourniquet use.AIM To determine if tourniquet use in orthopedic patients undergoing BKA was associated with a difference in calculated blood loss relative to no tourniquet use.METHODS We performed a retrospective review of consecutive patients undergoing BKA by orthopedic surgeons at a tertiary care hospital from 2008 through 2018.Blood loss was calculated using a combination of the Nadler equation for preoperative blood volume and a novel formula utilizing preoperative and postoperative hemoglobin levels and transfusions.Univariate and forwards step-wise multivariate linear regressions were performed to determine the association between tourniquet use and blood loss.A Wilcoxon was used to determine the univariate relationship between tourniquet use and blood loss for in the restricted subgroups of patients who underwent BKA for trauma,tumor,and infection.RESULTS Of 97 eligible patients identified,67 underwent surgery with a tourniquet and 30 did not.In multivariate regression,tourniquet use was associated with a 488 mL decrease in calculated blood loss(CI 119-857,P = 0.01).In subgroup analysis,no individual group showed a statistically significant decrease in blood loss with tourniquet use.There was no significant association between tourniquet use and either postoperative transfusions or reoperation at one year.CONCLUSION We found that tourniquet use during BKA is associated with decreased calculated intraoperative blood loss.We recommend that surgeons performing this procedure use a tourniquet to minimize blood loss.
文摘BACKGROUND Direct anterior approach(DAA)total hip arthroplasty(THA)in a supine position provides a unique opportunity to assess leg length discrepancy(LLD)intraoperatively with fluoroscopy.Reported fluoroscopic techniques are useful but are generally complicated or costly.Despite the use of multiple techniques for leg length assessment,LLD continues to be a major post-operative source of patient dissatisfaction further emphasizing the importance of near-anatomic restoration.The utility of an alternative direct measurement of LLD on an intra-operative fluoroscopic pelvic image during DAA THA has not been reported.AIM To determine the reliability of a novel simple intra-operative measurement of LLD using a parallel line technique on a single fluoroscopic digital image of the pelvis.METHODS One hundred and seventy-one patients who underwent DAA THA were included for analysis.Intra-operative fluoroscopic and post-operative anterior-posterior radiographs were imported to TraumaCad and calibrated for LLD measurement.LLD was measured on each image using the right-left hip differences in lesser trochanter to pelvic reference line distances.Pelvic reference points included the teardrops and ischia.Fluoroscopic LLD was compared to the gold-standard measurement of LLD measured on a post-operative radiograph.RESULTS Mean absolute difference in teardrop referenced LLD between fluoroscopic and post-operative radiographs was 2.17 mm and based on the ischia mean absolute difference was 2.63 mm.Linear regression of fluoroscopic and post-operative radiograph LLD based on teardrop and ischia LLD found r2 values of 0.57 and 0.84,respectively.Mean absolute difference between fluoroscopic and postoperative x-ray LLD was within 5 mm in 95%of cases regardless of pelvic reference.CONCLUSION This study demonstrates that a single fluoroscopic view obtained during DAA THA for leg length assessment is clinically useful.
基金supported by the grants from China Scholarship Council(No.201505320002)the National Institutes of Health(No.R01AR062207,R01AR061484,R01AR076900,R01NS103931)+3 种基金Young Medical Talents Program of Jiangsu Province,China(No.QNRC2016878)National Key R&D Program of China(No.SQ2021YFC2501702)Natural Science Foundation of China(No.82072474)Clinical Medicine Technology Project of Jiangsu Province,China(No.BE2019661).
文摘Estrogen deficiency is considered the most important cause of postmenopausal osteoporosis.However,the underlying mechanism is still not completely understood.In this study,progranulin(PGRN)was isolated as a key regulator of bone mineral density in postmenopausal women through high throughput proteomics screening.In addition,PGRN-deficient mice exhibited significantly lower bone mass than their littermates in an ovariectomy-induced osteoporosis model.Furthermore,estrogen-mediated inhibition of osteoclastogenesis and bone resorption as well as its protection against ovariectomy-induced bone loss largely depended on PGRN.Mechanistic studies revealed the existence of a positive feedback regulatory loop between PGRN and estrogen signaling.In addition,loss of PGRN led to the reduction of estrogen receptorα,the important estrogen receptor involved in estrogen regulation of osteoporosis,through enhancing its degradation via K48-linked ubiquitination.These findings not only provide a previously unrecognized interplay between PGRN and estrogen signaling in regulating osteoclastogenesis and osteoporosis but may also present a new therapeutic approach for the prevention and treatment of postmenopausal osteoporosis by targeting PGRN/estrogen receptorα.
基金supported by the National Natural Science Foundation of China(No.81172553 and 81472513 to WB)
文摘Background:Osteosarcoma is the most common bone malignancy in children and adolescents,and 20%-30%of the patients suffer from poor prognosis because of individual chemoresistance.The Hippo/yes-associated protein(YAP) signaling pathway has been shown to play a role in tumor chemoresistance,but no previous report has focused on its involvement in osteosarcoma chemoresistance.This study aimed to investigate the role of the Hippo/YAP signaling pathway in osteosarcoma chemoresistance and to determine potential treatment targets.Methods:Using the Cell Titer-Glo Luminescent cell viability assay and flow cytometry analysis,we determined the proliferation and chemosensitivity of YAP-overexpressing and YAP-knockdown osteosarcoma cells.In addition,using western blotting and the real-time polymerase chain reaction technique,we investigated the alteration of the Hippo/YAP signaling pathway in osteosarcoma cells treated with chemotherapeutic agents.Results:Mammalian sterile 20-like kinase 1(MST1) degradation was increased,and large tumor suppressor kinase1/2(LAT51/2) total protein levels were decreased by methotrexate and doxorubicin,which increased activation and nuclear translocation of YAP.Moreover,YAP increased the proliferation and chemoresistance of MG63 cells.Conclusions:The Hippo/YAP signaling pathway plays a role in osteosarcoma chemoresistance,and YAP is a potential target for reducing chemoresistance.
文摘Purpose: Failure after radial head arthroplasty is uncommon, but clinically significant. Treatment for failure may involve implant removal. We describe fourteen patients who underwent implant removal after failed radial head arthroplasty. Methods: A retrospective review was performed to determine the cause of failure and clinical data were prospectively collected. Results: At mean follow up of 38 months the mean VAS for pain score was 3.0 and the mean DASH score was 40.5. The mean MEPS was 69. All patients demonstrated improved elbow range of motion. Mean elbow flexion at final follow up was 124°to an average extension deficit of 25°. Fifty percent of patients exhibited clinical symptoms of cubital tunnel syndrome. Three patients required additional surgery after implant removal. Conclusions: Implant removal for failed radial head arthroplasty improves range of motion and demonstrates acceptable outcomes at intermediate-term follow up. However, 50% of patients developed cubital tunnel syndrome and 21% required revision surgery.
基金National Institutes of Health(NIH)R01 DK121327 to R.A.E。
文摘Maturation of the 3′end of almost all eukaryotic messenger RNAs(m RNAs)requires cleavage and polyadenylation.Most mammalian m RNAs are polyadenylated at different sites within the last exon,generating alternative polyadenylation(APA)isoforms that have the same coding region but distinct 3′untranslated regions(UTRs).The 3′UTR contains motifs that regulate m RNA metabolism;thus,changing the 3′UTR length via APA can significantly affect gene expression.Endochondral ossification is a central process in bone healing,but the impact of APA on gene expression during this process is unknown.Here,we report the widespread occurrence of APA,which impacts multiple pathways that are known to participate in bone healing.Importantly,the progression of endochondral ossification involves global 3′UTR shortening,which is coupled with an increased abundance of shortened transcripts relative to other transcripts;these results highlight the role of APA in promoting gene expression during endochondral bone formation.Our mechanistic studies of transcripts that undergo APA in the fracture callus revealed an intricate regulatory network in which APA enhances the expression of the collagen,type I,alpha 1(Col1a1)and Col1a2 genes,which encode the 2 subunits of the abundantly expressed protein collagen 1.APA exerts this effect by shortening the 3′UTRs of the Col1a1 and Col1a2 m RNAs,thus removing the binding sites of mi R-29a-3p,which would otherwise strongly promote the degradation of both transcripts.Taken together,our study is the first to characterize the crucial roles of APA in regulating the 3′UTR landscape and modulating gene expression during fracture healing.
基金supported in part by the Alex's Lemonade Foundation,and Bankhead-Coley Cancer Research Program,Florida Department of Health(to CL), Public Health Service grants R01 HL-097088 and R21 EB-015684 from the National Institutes of Health,and an institutional grant from the Children's Miracle Network (to AS,CL and GA)supported in part by the state-sponsored program for Graduate Students from China Scholarship Council,Government of China, and the National Natural Science Foundation of China (No.30730114)
文摘OBJECTIVE： In the present study, we systemically evaluated the ability of two bioactive compounds from traditional Chinese medicine, celastrol and pristimerin, to enhance recombinant adeno-associated virus （rAAV） serotype vector-mediated transgene expression both in human cell lines in vitro, and in murine hepatocytes in vivo. METHODS： Human cell lines were infected with rAAV vectors with either mock treatment or treatment with celastrol or pristimerin. The transgene expression, percentage of nuclear translocated viral genomes and the ubiquitination of intracellular proteins were investigated post-treatment. In addition, nonobese diabetic/severe combined immunodeficient gamma （NSG） mice were tail vain-injected with rAAV vectors and co-administered with either dimethyl sulfoxide, celastrol, pristimerin or a positive control, bortezomib. The transgene expression in liver was detected and compared over time. RESULTS： We observed that treatment with pristimerin, at as low as 1 IJmol/L concentration, significantly enhanced rAAV2 vector-mediated transgene expression in vitro, and intraperitoneal co- administration with pristimerin at 4 mg/（kg.d） for 3 d dramatically facilitated viral transduction in murine hepatocytes in vivo. The transduction efficiency of the tyrosine-mutant rAAV2 vectors as well as that of rAAV8 vectors carrying oversized transgene cassette was also augmented significantly by pristimerin. The underlying molecular mechanisms by which pristimerin mediated the observed increase in the transduction efficiency of rAAV vectors include both inhibition of proteasomal degradation of the intracellular proteins and enhanced nuclear translocation of the vector genomes. CONCLUSION： These studies suggest the potential beneficial use of pristimerin and pristimerincontaining herb extract in future liver-targeted gene therapy with rAAV vectors.
文摘Background： Resection of sacral chordomas is challenging. The anatomy is complex, and there are often no bony landmarks to guide the resection. Achieving adequate surgical margins is, therefore, difficult, and the recurrence rate is high. Use of computer navigation may allow optimal preoperative planning and improve precision in tumor resection. The purpose of this study was to evaluate the safety and feasibility of computer navigation-aided resection of sacral chordomas. Methods： Between 2007 and 2013, a total of 26 patients with sacral chordoma underwent computer navigation-aided surgery were included and followed for a minimum of 18 months. There were 21 primary cases and 5 recurrent cases, with a mean age of 55.8 years old （range： 35 84 years old）. Tumors were located above the level of the $3 neural foramen in 23 patients and below the level of the $3 neural foramen in 3 patients. Three-dimensional images were reconstructed with a computed tomography-based navigation system combined with the magnetic resonance images using the navigation software. Tumors were resected via a posterior approach assisted by the computer navigation. Mean follow-up was 38.6 months （range： 18-84 months）. Results： Mean operative time was 307 min. Mean intraoperative blood loss was 3065 ml. For computer navigation, the mean registration deviation during surgery was 1.7 ram. There were 18 wide resections, 4 marginal resections, and 4 intralesional resections. All patients were alive at the final follow-up, with 2 （7.7%） exhibiting tumor recurrence. The other 24 patients were tumor-free. The mean Musculoskeletal Tumor Society Score was 27.3 （range： 19-30）. Conclusions： Computer-assisted navigation can be safely applied to the resection of the sacral chordomas, allowing execution of preoperative plans, and achieving good oncological outcomes. Nevertheless, this needs to be accomplished by surgeons with adequate experience and skill.
文摘Citrate based polymer poly(octamethylene citrate)(POC)has shown promise when formulated into composite material containing up to 65 wt%hydroxylapatite(HA)for orthopedic applications.Despite significant research into POC,insufficient information about the biocompatibility of the monomers 1,8-Octanediol and Citrate used in its synthesis is available.Herein,we investigated the acute cytotoxicity,immune response,and long-term functionality of both monomers.Our results showed a cell-type dependent cytotoxicity of the two monomers:1,8-Octanediol induced less acute toxicity to 3T3 fibroblasts than Citrate while presenting comparable cytotoxicity to MG63 osteoblast-like cells;however,Citrate demonstrated enhanced compatibility with hMSCs compared to 1,8-Octanediol.The critical cytotoxic concentration values EC30 and EC50,standard for comparing cytotoxicity of chemicals,were also provided.Additionally,Citrate showed slower and less inhibitory effects on long-term hMSC cell proliferation compared with 1,8-Octanediol.Furthermore,osteogenic differentiation of hMSCs exposure to Citrate resulted in less inhibitory effect on alkaline phosphatase(ALP)production.Neither monomer triggered undesired pro-inflammatory responses.In combination with diffusion model analysis of monomer release from cylindrical implants,based on which the maximum concentration of monomers in contact with bone tissue was estimated to be 2.2104 mmol/L,far lower than the critical cytotoxic concentrations as well as the 1,8-Octanediol concentration(0.4 mg/mL or 2.7 mmol/L)affecting hMSCs differentiation,we provide strong evidence for the cytocompatibility of the two monomers degraded from citrate-based composites in the orthopedic setting.
文摘background Although less common in adults,venous thromboembolism(VTE)in children is a highly morbid,preventable adverse event.While VTE has been well studied among pediatric hospitalized and trauma patients,limited work has been done to examine postoperative VTE in children undergoing surgery.Methods Using data from National Surgical Quality Improvement Project Pediatric database(NSQIP-P)from 2012 to 2016,a retrospective cohort analysis was performed to determine the incidence of,and risk factors for,VTE in children undergoing surgery.Additionally,the relationships between VTE and other postoperative adverse outcomes were evaluated.results Of 361384 pediatric surgical patients,378(0.10%)were identified as experiencing postoperative VTE.After controlling for patient and surgical factors,we found that American Society of Anesthesiologists(ASA)class of II or greater,aged 16-18 years,non-elective surgery,general surgery(compared with several other surgical specialties),cardiothoracic surgery(compared with general surgery)and longer operative time were significantly associated with VTE in pediatric patients(p<0.001 for each comparison).Furthermore,a majority of adverse events were found to be associated with increased risk of subsequent VTE(p<0.001).Conclusion In a large pediatric surgical population,an incidence of postoperative VTE of 0.10%was observed.Defined patient and surgical factors,and perioperative adverse events were found to be associated with such VTE events.
基金Project supported by Swebelius Cancer Research Award.
文摘Neurofibroma cell lines derived from mice transgenic for HTLV-I LTR tax express high levels of HTLV-I tax mRNA and protein and exhibit a transformed phenotype. A retrovirus vector carrying HTLV-I tax cDNA in reversed transcriptional orientation was stably transfected into the neurofibroma cells. Antisense RNA inhibited expression of the tax gene with a decrease of more than 40 % in both tax mRNA and protein. Tax antisense RNA reversed the transformed phenotype as exhibited by dramatic changes in cell morphology and growth characteristics. Expression of several cellular genes which are activated by Tax protein including GM-CSF, IL-6, LT/TNF, c-myc and LIF was down-regulated, while M-CSF and c-src proto-oncogene expressions were up-regulated. Accumulation of β-actin mRNA was not affected. The changes that occurred in the tax antisense expressing neurofibroma cells could be the consequence of the decreased concentration of Tax protein. These results also indicate that HTLV-I Tax protein is crucial for maintaining the transformed cell morphology, growth and proliferation of murine neurofibroma cells and suggest that deregulation of endogenous cellular genes by Tax protein is the mechanism through which neurofibromas occur in tax mice.
