Conserved miR-370-3p/BMP-7 axis regulates the phenotypic change of human vascular smooth muscle cells.

Endothelial dysfunction and inflammatory immune response trigger dedifferentiation of vascular smooth muscle cells (SMCs) from contractile to synthetic phenotype and initiate arterial occlusion. However, the complex vascular remodeling process playing roles in arterial occlusion initiation is largely unknown. We performed bulk sequencing of small and messenger RNAs in a rodent arterial injury model. Bioinformatic data analyses reveal that six miRNAs are overexpressed in injured rat carotids as well as synthetic-type human vascular SMCs. In vitro cell-based assays show that four miRNAs (miR-130b-5p, miR-132-3p, miR-370-3p, and miR-410-3p) distinctly regulate the proliferation of and monocyte adhesion to the vascular SMCs. Individual inhibition of the four selected miRNAs strongly prevents the neointimal hyperplasia in the injured rat carotid arteries. Mechanistically, miR-132-3p and miR-370-3p direct the cell cycle progression, triggering SMC proliferation. Gene ontology analysis of mRNA sequencing data consistently reveal that the miRNA targets include gene clusters that direct proliferation, differentiation, and inflammation. Notably, bone morphogenic protein (BMP)-7 is a prominent target gene of miR-370-3p, and it regulates vascular SMC proliferation in cellular and animal models. Overall, this study first reports that the miR-370-3p/BMP-7 axis determines the vascular SMC phenotype in both rodent and human systems.

YH29407 with anti-PD-1 ameliorates anti-tumor effects via increased T cell functionality and antigen presenting machinery in the tumor microenvironment.

Among cancer cells, indoleamine 2, 3-dioxygenase1 (IDO1) activity has been implicated in improving the proliferation and growth of cancer cells and suppressing immune cell activity. IDO1 is also responsible for the catabolism of tryptophan to kynurenine. Depletion of tryptophan and an increase in kynurenine exert important immunosuppressive functions by activating regulatory T cells and suppressing CD8+ T and natural killer (NK) cells. In this study, we compared the anti-tumor effects of YH29407, the best-in-class IDO1 inhibitor with improved pharmacodynamics and pharmacokinetics, with first and second-generation IDO1 inhibitors (epacadostat and BMS-986205, respectively). YH29407 treatment alone and anti-PD-1 (aPD-1) combination treatment induced significant tumor suppression compared with competing drugs. In particular, combination treatment showed the best anti-tumor effects, with most tumors reduced and complete responses. Our observations suggest that improved anti-tumor effects were caused by an increase in T cell infiltration and activity after YH29407 treatment. Notably, an immune depletion assay confirmed that YH29407 is closely related to CD8+ T cells. RNA-seq results showed that treatment with YH29407 increased the expression of genes involved in T cell function and antigen presentation in tumors expressing ZAP70, LCK, NFATC2, B2M, and MYD88 genes. Our results suggest that an IDO1 inhibitor, YH29407, has enhanced PK/PD compared to previous IDO1 inhibitors by causing a change in the population of CD8+ T cells including infiltrating T cells into the tumor. Ultimately, YH29407 overcame the limitations of the competing drugs and displayed potential as an immunotherapy strategy in combination with aPD-1.

Incorporation of SKI-G-801, a Novel AXL Inhibitor, With Anti-PD-1 Plus Chemotherapy Improves Anti-Tumor Activity and Survival by Enhancing T Cell Immunity.

A recently developed treatment strategy for lung cancer that combines immune checkpoint inhibitors with chemotherapy has been applied as a standard treatment for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and it has improved the outcomes of chemotherapy. Maintenance treatment with anti-PD-1 antibody (aPD-1) enhances the effect of immunochemical combination therapy and improves therapeutic efficacy, which contributes toward a significant improvement in patient survival rates. The AXL receptor tyrosine kinase (AXL), which is expressed in tumor cells, plays an essential role in the resistance of cancers to chemotherapy and immunotherapy, and stimulates signaling associated with epithelial-mesenchymal transition (EMT) in metastatic cancer. AXL is thus an attractive target for controlling resistance to anti-tumor therapies. In this study, we examined the effect of AXL inhibitors on immune activation and tumor growth in TC1 and C3PQ mouse tumor models, in the context of clinical immunotherapy/chemotherapy and maintenance treatment, using an aPD-1 with/without pemetrexed. To determine the optimal timing for administration of SKI-G-801, an AXL inhibitor, we investigated its anti-tumor effects based on inclusion at the immunochemotherapy and maintenance therapy stages. We also performed flow cytometry-based immune profiling of myeloid cells and lymphoid cells at different points in the treatment schedule, to investigate the immune activation and anti-tumor effects of the AXL inhibitor. The addition of SKI-G-801 to the immune checkpoint inhibitor and chemotherapy stage, as well as the maintenance therapy stage, produced the best anti-tumor results, and significant tumor growth inhibition was observed in both the TC1 and C3PQ models. Both models also exhibited increased proportion of effector memory helper T cells and increased expression of CD86+ macrophages. Especially, regulatory T cells were significantly reduced in the TC1 tumor model and there was an increase in central memory cytotoxic T cell infiltration and an increased proportion of macrophages with high CD80 expression in the C3PQ tumor model. These results suggest increased infiltration of T cells, consistent with previous studies using AXL inhibitors. It is expected that the results from this study will serve as a stepping stone for clinical research to improve the existing standard of care.

Patterns of femoral neck fracture and its treatment methods in patients with osteogenesis imperfecta.

Femoral neck fracture (FNF) is not common in osteogenesis imperfecta patients but may result in serious complications if not properly treated in due time. We present three types of FNF in osteogenesis imperfecta and their characteristics, treatment methods and outcomes. Cases of FNF followed for more than 2 years were selected from the osteogenesis imperfecta database. Medical records and radiographs were reviewed to obtain demographic information and to determine ambulatory status, mode of injury, location of the fracture line, presence of preexisting implants, treatment methods and complications. Outcomes were evaluated according to the radiographic results and ambulatory function. The study investigated 15 FNFs in 10 patients including 1 Sillence type I, 1 type III and 8 type IV. They were either community or household ambulators. The mean age at fracture was 11.7 years. The fractures were followed for an average of 6.3 years. Six fractures were attributed to accidental injuries and nine without noticeable trauma. The fracture pattern was categorized into undisplaced (n = 3), angulated-stable (n = 7) or displaced-unstable (n = 5) types. Five fractures were fixed in-situ using screws or Kirschner wires. Other five fractures were treated by closed reduction and screw fixation and the remaining five fractures were managed by femoral valgus osteotomy. Bony union was achieved, and prefracture ambulatory status was restored in all cases. A high index of suspicion is required in the diagnosis of undisplaced or angulated-stable fractures. Treatment is usually challenging, but a judicious approach considering the fracture pattern and patient characteristics result in successful outcomes. The angulated-stable pattern of fracture is unique in osteogenesis imperfecta patients and requires special attention.

Primary Tumor Suppression and Systemic Immune Activation of Macrophages through the Sting Pathway in Metastatic Skin Tumor.

PURPOSE: Agonists of the stimulator of interferon genes (STING) play a key role in activating the STING pathway by promoting the production of cytokines. In this study, we investigated the antitumor effects and activation of the systemic immune response of treatment with DMXAA (5,6-dimethylxanthenone-4-acetic acid), a STING agonist, in EML4-ALK lung cancer and CT26 colon cancer. MATERIALS AND METHODS: The abscopal effects of DMXAA in the treatment of metastatic skin nodules were assessed. EML4-ALK lung cancer and CT26 colon cancer models were used to evaluate these effects after DMXAA treatment. To evaluate the expression of macrophages and T cells, we sacrificed the tumor-bearing mice after DMXAA treatment and obtained the formalin-fixed paraffin-embedded (FFPE) tissue and tumor cells. Immunohistochemistry and flow cytometry were performed to analyze the expression of each FFPE and tumor cell. RESULTS: We observed that highly infiltrating immune cells downstream of the STING pathway had increased levels of chemokines after DMXAA treatment. In addition, the levels of CD80 and CD86 in antigen-presenting cells were significantly increased after STING activation. Furthermore, innate immune activation altered the systemic T cell-mediated immune responses, induced proliferation of macrophages, inhibited tumor growth, and increased numbers of cytotoxic memory T cells. Tumor-specific lymphocytes also increased in number after treatment with DMXAA. CONCLUSION: The abscopal effect of DMXAA treatment on the skin strongly reduced the spread of EML4-ALK lung cancer and CT26 colon cancer through the STING pathway and induced the presentation of antigens.

Clinical decision support algorithm based on machine learning to assess the clinical response to anti-programmed death-1 therapy in patients with non-small-cell lung cancer.

OBJECTIVE: Anti-programmed death (PD)-1 therapy confers sustainable clinical benefits for patients with non-small-cell lung cancer (NSCLC), but only some patients respond to the treatment. Various clinical characteristics, including the PD-ligand 1 (PD-L1) level, are related to the anti-PD-1 response; however, none of these can independently serve as predictive biomarkers. Herein, we established a machine learning (ML)-based clinical decision support algorithm to predict the anti-PD-1 response by comprehensively combining the clinical information. MATERIALS AND METHODS: We collected clinical data, including patient characteristics, mutations and laboratory findings, from the electronic medical records of 142 patients with NSCLC treated with anti-PD-1 therapy; these were analysed for the clinical outcome as the discovery set. Nineteen clinically meaningful features were used in supervised ML algorithms, including LightGBM, XGBoost, multilayer neural network, ridge regression and linear discriminant analysis, to predict anti-PD-1 responses. Based on each ML algorithm's prediction performance, the optimal ML was selected and validated in an independent validation set of PD-1 inhibitor-treated patients. RESULTS: Several factors, including PD-L1 expression, tumour burden and neutrophil-to-lymphocyte ratio, could independently predict the anti-PD-1 response in the discovery set. ML platforms based on the LightGBM algorithm using 19 clinical features showed more significant prediction performance (area under the curve [AUC] 0.788) than on individual clinical features and traditional multivariate logistic regression (AUC 0.759). CONCLUSION: Collectively, our LightGBM algorithm offers a clinical decision support model to predict the anti-PD-1 response in patients with NSCLC.

Morphological Characteristics of Os Subfibulare Related to Failure of Conservative Treatment of Chronic Lateral Ankle Instability.

BACKGROUND: The os subfibulare is usually asymptomatic and found incidentally on radiographs. However, sometimes it may cause subfibular pain and may be associated with chronic lateral ankle instability (CLAI). We hypothesized that os subfibulare could interrupt the talofibular space causing impingement, resulting in chronic pain and functional instability around the lateral malleolus. The purposes of this study were to analyze morphologic characteristics of os subfibulare, and to evaluate the clinical significance of the os subfibulare in patients with CLAI. METHODS: Between November 2011 and April 2015, 70 patients who had both computed tomography (CT) and magnetic resonance imaging (MRI) among 252 patients who visited our hospital with the symptom of lateral ankle instability were included in this study. The location of the ossicle was classified into 3 zones in reference to the attachment site of the lateral ankle ligaments. The impingement was classified into 2 groups according to the presence of talofibular encroachment. Digital radiographs were used to measure the ossicle width and shape determined by the length and width on an magnetic resonance (MR) image. RESULTS: The most common shape of ossicles was oval, and the most common location of ossicles was at the anterior talofibular ligament (ATFL) attachment site. Sixty-one percent of patients showed talofibular impingement on coronal MR images. In 48 cases, the dimension of fibula plus os subfibulare was larger than that of the contralateral normal fibula. The larger size and talofibular impingement of the ossicle were associated with greater need for operative treatment in patients with ankle instability. CONCLUSION: The morphologic analysis of the os subfibulare revealed that there might be impingement of the talofibular space by the ossicle in some patients. We suggest that morphologic characteristics of the os subfibulare should be considered when selecting treatment options in patients with CLAI and os subfibulare. LEVEL OF EVIDENCE: Level III, retrospective comparative series.

Foot and Ankle Radiographic Parameters in Korean Adults Vary by Sex and Age.

Although many radiographic measurements of the foot and ankle have been used, reference values for normal functional groups are rarely reported. These can change according to sex and age; therefore, this study aimed to: (1) determine reference values for radiographic foot and ankle angles in an asymptomatic healthy Korean population, and (2) compare differences in the measurements according to sex and age. A total of 200 healthy volunteers were recruited, including 100 young adults (50 males, 50 females) aged 20 to 35 years, and 100 older adults (50 males, 50 females) aged 60 to 69 years. Weightbearing ankle anteroposterior views, talar tilt, and tibiotalar angles were measured. On the weightbearing foot anteroposterior views, the hallux valgus, hallux interphalangeal, and talo-first metatarsal angles were measured. On the weightbearing lateral foot views, the calcaneal pitch, lateral talo-calcaneal, lateral talo-first metatarsal, and lateral calcaneo-first metatarsal angles were measured. Values were stratified by sex and age, and statistically compared. The hallux valgus, calcaneal pitch, and lateral calcaneo-first metatarsal angles were affected by both sex and age; the hallux interphalangeal angle was affected by age and the lateral talo-first metatarsal angle by sex. We presented reference values for foot and ankle radiographic measurements in a healthy Korean population; several radiographic indices varied significantly by sex or age, which were grossly similar to previous studies based on white race. The study data can serve as a basis for evaluation of foot and ankle disorders.

Knockout rat models mimicking human atherosclerosis created by Cpf1-mediated gene targeting.

The rat is a time-honored traditional experimental model animal, but its use is limited due to the difficulty of genetic modification. Although engineered endonucleases enable us to manipulate the rat genome, it is not known whether the newly identified endonuclease Cpf1 system is applicable to rats. Here we report the first application of CRISPR-Cpf1 in rats and investigate whether Apoe knockout rat can be used as an atherosclerosis model. We generated Apoe- and/or Ldlr-deficient rats via CRISPR-Cpf1 system, characterized by high efficiency, successful germline transmission, multiple gene targeting capacity, and minimal off-target effect. The resulting Apoe knockout rats displayed hyperlipidemia and aortic lesions. In partially ligated carotid arteries of rats and mice fed with high-fat diet, in contrast to Apoe knockout mice showing atherosclerotic lesions, Apoe knockout rats showed only adventitial immune infiltrates comprising T lymphocytes and mainly macrophages with no plaque. In addition, adventitial macrophage progenitor cells (AMPCs) were more abundant in Apoe knockout rats than in mice. Our data suggest that the Cpf1 system can target single or multiple genes efficiently and specifically in rats with genetic heritability and that Apoe knockout rats may help understand initial-stage atherosclerosis.

Absence of Cytosolic 2-Cys Prx Subtypes I and II Exacerbates TNF-α-Induced Apoptosis via Different Routes.

There are abundant peroxiredoxin (Prx) enzymes, but an increase of cellular H2O2 level always happens in apoptotic cells. Here, we show that cellular H2O2 switches different apoptosis pathways depending on which type of Prx enzyme is absent. TNF-α-induced H2O2 burst preferentially activates the DNA damage-dependent apoptosis pathway in the absence of PrxI. By contrast, the same H2O2 burst stimulates the RIPK1-dependent apoptosis pathway in the absence of PrxII by inducing the destruction of cIAP1 in caveolar membrane. Specifically, H2O2 induces the oxidation of Cys308 residue in the cIAP1-BIR3 domain, which induces the dimerization-dependent E3 ligase activation. Thus, the reduction in cIAP level by the absence of PrxII triggers cell-autonomous apoptosis in cancer cells and tumors. Such differential functions of PrxI and PrxII are mediated by interaction with H2AX and cIAP1, respectively. Collectively, this study reveals the distinct switch roles of 2-Cys Prx isoforms in apoptosis signaling.

Dual Interlocking Telescopic Rod Provides Effective Tibial Stabilization in Children With Osteogenesis Imperfecta.

BACKGROUND: Interlocking telescopic rods for the management of osteogenesis imperfecta (OI)-related long bone fractures are a modification of the Sheffield rod. An interlocking pin anchors the obturator at the distal epiphysis, which spares the distal joint, while a T-piece anchors the sleeve at the proximal epiphysis. However, these devices are associated with some problems, including failure to elongate and difficulty with removal. A dual interlocking telescopic rod (D-ITR), in which the sleeve and the obturator are anchored with interlocking pins, was developed to address these problems. QUESTIONS/PURPOSES: In this study, we compared the D-ITR with an older version of a single interlocking telescopic rod (S-ITR) based on (1) surgery-free survival and rod survival; (2) cessation of rod elongation and elongated length of the rod; and (3) risk of refracture and complications related to the interlocking telescopic system. METHODS: This article compares the D-ITR with the S-ITR using a historically controlled, single-surgeon, retrospective design comparing two implants for the management of fractures in children with OI. Before August 2007, we exclusively used the S-ITR (n = 17 patients, 29 tibiae); from July 2008 until October 2014, we exclusively used the D-ITR (n = 17 patients, 26 tibiae). During the 1-year transition period, we performed five of these procedures (two S-ITR in two patients and three D-ITR in three patients), and implant use was based on availability with our preference being the D-ITR during that time when it was available. The general indications for use of both devices were the same: patients with OI and a tibial fracture who were older than 3 to 4 years of age and whose tibial canals were wide enough to accept an intramedullary rod. Younger patients were treated other ways (generally without surgery) and those with narrower canals with thinner, nonelongating rods or Kirschner wires, as indicated. All patients in both groups were available for followup at a minimum of 2 years (mean ± SD, 9.6 ± 3.0 years in the S-ITR group and 5.3 ± 2.1 years in the D-ITR group) except for one patient in the D-ITR group who died > 1 year after the procedure resulting from reasons unrelated to it. For the between-group comparison, we used only the followup data collected up to the ninth postoperative year in the S-ITR group. The truncated followup period of the S-ITR group was a mean of 5.0 ± 1.6 years. The mean age in the S-ITR group was 7 years (range, 3-12 years) and it was 8 years (range, 3-14 years) in the D-ITR group. There were nine boys and 10 girls in each group. Two orthopaedic surgeons other than the operating surgeon performed chart review to address our three research purposes. Survival analyses were performed using the Kaplan-Meier method. The overall pooled risk of refracture and major complications potentially associated with the interlocking telescopic rod system was compared between the groups. RESULTS: With the numbers available, there were no differences between the D-ITR and the S-ITR in terms of mean surgery-free survival time (5.7 [95% confidence interval {CI}, 4.5-6.9] versus 5.1 [95% CI, 4.1-6.1]; years; p = 0.653) or mean rod survival time (7.4 [95% CI, 6.4-8.4] versus 6.0 [95% CI, 5.1-6.9] years; p = 0.120). With the numbers available, cessation of elongation (4% in the D-ITR group versus 19% in the S-ITR group; p = 0.112) and elongated length (45.3 ± 24.3 mm in the D-ITR group versus 44.2 ± 22.3 mm in the S-ITR group; p = 0.855) also did not differ between the groups. The pooled proportions of refracture or complications after the index surgery were higher in the S-ITR group (25 tibias [81%]) than in the D-ITR group (15 tibias [54%]; p = 0.049). Eight tibias in the S-ITR group had proximal migration of the sleeve compared with no patients in the D-ITR group (p = 0.005). CONCLUSIONS: In patients with OI, the modified D-ITR provides effective tibial stabilization with similar or better results than the S-ITR design. Anchoring the sleeve at the proximal epiphysis with an interlocking pin provides better anchorage and allows easier removal. LEVEL OF EVIDENCE: Level III, therapeutic study.

Posttraumatic Subfibular Ossicle Formation in Children: Experience in a Single Primary Care Unit.

BACKGROUND: Although subfibular ossicles have been linked to various clinical problems, whether its origin is congenital or traumatic remains unclear. The objectives of this study were to determine the incidence of subfibular ossicle formation after ankle inversion in children. METHODS: Among 896 pediatric patients who visited a single primary care unit after foot and ankle trauma, 593 patients sustaining ankle inversion injury were included in this study. For each pediatric patient, physical examination and radiographic examination were performed. The incidence of subfibular ossicle was evaluated based on initial radiographic examination. To analyze the incidence of unprecedented subfibular ossicle formation after ankle inversion injury, radiographs of 188 patients who were followed up for >6 months were evaluated according to the grade of initial injury. RESULTS: At initial visit, 1.0% of examined ankles (12 from 1186 ankles) showed well-corticated subfibular ossicle not related to initial injuries. Overall incidence of subfibular ossicle at final follow-up after ankle inversion injury was 39.4% (74/188). Incidence of subfibular ossicle at final follow-up was associated with initial injury grade. As for the morphology of ossicle, 93.2% (55/59) of cases with wafer bone fragment at the time of initial injury became oval or round-shaped subfibular ossicle at final radiograph. CONCLUSIONS: The chance of ossicle formation after ankle inversion injury was substantially high in pediatric population. On the basis of the findings of our study, we carefully suggest that majority, if not all, of subfibular ossicles would be posttraumatic in pediatric period. LEVEL OF EVIDENCE: Level IV-case series.

A Report of Two Cases of Adventitial Cystic Disease of the Popliteal Artery.

Two patients were admitted to our department because of recent aggravation of claudication in the leg, which was exacerbated by walking. They were diagnosed as having a Baker cyst or acute thrombosis in the popliteal fossa at another hospital. There was no evidence of ischemia, and the ankle brachial index was normal. Computed tomography and magnetic resonance imaging were performed, revealing a cystic mass of the popliteal artery (PA). Intraoperatively, the cystic lesion was found within the adventitia of the PA; based on the biopsy findings, both patients were diagnosed as having adventitial cystic disease of the PA.

Inter-segment foot motion in girls using a three-dimensional multi-segment foot model.

BACKGROUND: Several multi-segment foot models (MFMs) have been introduced for in vivo analyses of dynamic foot kinematics. However, the normal gait patterns of healthy children and adolescents remain uncharacterized. We sought to determine normal foot kinematics according to age in clinically normal female children and adolescents using a Foot 3D model. METHODS: Fifty-eight girls (age 7-17 years) with normal function and without radiographic abnormalities were tested. Three representative strides from five separate trials were analyzed. Kinematic data of foot segment motion were tracked and evaluated using an MFM with a 15-marker set (Foot 3D model). As controls, 50 symptom-free female adults (20-35 years old) were analyzed. RESULTS: In the hindfoot kinematic analysis, plantar flexion motion in the pre-swing phase was significantly greater in girls aged 11 years or older than in girls aged <11 years, thereby resulting in a larger sagittal range of motion. Coronal plane hindfoot motion exhibited pronation, whereas transverse plane hindfoot motion exhibited increased internal rotation in girls aged <11 years. Hallux valgus angles increased significantly in girls aged 11 years or older. The foot progression angle showed mildly increased internal rotation in the loading response phase and the swing phase in girls aged <11 years old. CONCLUSION: The patterns of inter-segment foot motion in girls aged 11 years or older showed low-arch kinematic characteristics, whereas those in girls aged 11 years or older were more similar to the patterns in young adult women.

Silencing of peroxiredoxin II by promoter methylation is necessary for the survival and migration of gastric cancer cells.

Peroxiredoxin (Prx), a family of ubiquitous thiol peroxidases, functions as a redox signaling regulator that controls cellular H2O2 in mammalian cells and has recently received attention for being overexpressed in various cancer types. In this study, we show that Prx type II (PrxII) is rather silenced in gastric cancer cells. PrxII expression is severely downregulated in 9 out of the 28 gastric cancer cell lines. Strikingly, PrxII expression is completely lost in three cell lines, MKN28, MKN74 and SNU484. Loss of PrxII expression is due to DNA methyltransferase 1-dependent methylation at the promoter region of the PrxII gene. Restoration of PrxII expression using a retroviral system markedly reduces the colony-forming ability and migratory activity of both MKN28 and SNU484 cells by inhibiting Src kinase. Mechanistically, PrxII peroxidase activity is essential for regulating gastric cancer cell migration. Bioinformatics analysis from The Cancer Genome Atlas stomach cancer data (STAD) revealed significantly low PrxII expression in gastric cancer patients and a negative correlation between PrxII expression and methylation levels. More importantly, low PrxII expression also strongly correlates with poor survival in cancer patients. Thus our study suggests that PrxII may be the first thiol peroxidase that simultaneously regulates both survival and metastasis in gastric cancer cells with high clinical relevance.

Clinical and radiological outcomes of arthroscopically assisted cannulated screw fixation for tibial eminence fracture in children and adolescents.

BACKGROUND: The purpose of this study was to determine the efficacy and complications of arthroscopically assisted reduction and fixation with cannulated screws for tibial eminence fracture in skeletally immature patients. METHODS: This was a retrospective case series study. Forty-eight patients who were skeletally immature at the time of tibial eminence fracture were treated in a tertiary children's hospital between May 2004 and August 2015. Twenty-one patients were excluded due to non-operative treatment (n = 10), other surgical treatments (n = 9), multiple fracture (n = 1), and follow-up < 1 year (n = 1). Twenty-seven knees of 27 patients were analyzed. Avulsed fragment was reduced arthroscopically. One to three cannulated screws (4.0 mm or 5.0 mm in diameter) were used for fixation. Passive knee motion was started in 3-4 weeks. Clinical outcomes were evaluated by Lysholm score, instability of the knee, and complications. Radiological outcomes including nonunion and malunion of the avulsed fragment and physeal growth disturbance were evaluated. RESULTS: Mean age at the time of surgery was 10.1 years (range, 6.2 to 13.8 years). Patients were followed up for a mean of 3.9 years (range, 1.0 to 7.6 years). Fracture types included type III (n = 13), type II (n = 12), and type IV (n = 2) according to Zaricznyj modification of Meyers and McKeever classification. Meniscus was entrapped in five patients. Six patients showed concomitant meniscal tear. Mean Lysholm score at the latest follow-up was 95 (range, 78 to 100). Joint instability was not observed in any patient except one (instability of 5-10 mm). All patients showed full range of knee motion except one (10 degrees of flexion contracture). Screw head impingement against intercondylar notch of the femur was observed in two patients during screw removal procedure. Five knees showed prominent tibial eminence without symptoms. The injured lower limb was longer than the contralateral normal side by a mean of 6.2 mm (range, - 4 to 18 mm). CONCLUSIONS: Arthroscopically assisted reduction and fixation with cannulated screws is an effective and safe surgical option for treating tibial eminence fracture with few complications.

Percutaneous medial hemi-epiphysiodesis using a transphyseal screw for caput valgum associated with developmental dysplasia of the hip.

BACKGROUND: The purpose of this study was to evaluate the radiologic outcome of percutaneous medial hemi-epiphysiodesis using a transphyseal screw for the management of caput valgum associated with developmental dysplasia of the hip (DDH). METHODS: Eighteen hips (18 patients) having caput valgum treated with screw hemi-epiphysiodesis were followed for more than 2 years, and were included in this study. The mean age at the time of the index operation was 8.3 years (range, 4.3 to 10.7 years) and age at the latest follow-up was 12.2 years (range, 9.4 to 16.4 years). The screw in 5 hips was changed into a longer one at postoperative 21.8 months (range, 14 to 29 months) because the proximal femur outgrew the screw. The screws in 11 hips were removed at the mean age of 10.9 years (range, 8.0 to 14.5 years). We retrospectively analyzed the change in various radiologic parameters over time. RESULTS: The mean Hilgenreiner-epiphyseal angle (HEA) of the operated side was 5.1 ± 11.3° preoperatively, and increased to 20.6 ± 11.3° at the latest follow-up (p = 0.001). The mean difference of the HEA between the operated and contralateral sides was 16.9 ± 15.1° preoperatively, which decreased to 2.4 ± 12.4° at the latest follow-up (p = 0.008). The mean articulo-trochanteric distance of the operated side, which was 3.2 ± 5.5 mm longer than that of the contralateral side preoperatively, became 5.6 ± 9.1 mm shorter at the latest follow-up (p = 0.001). The ratio of femoral neck length of the operated side to that of the contralateral side decreased over the follow-up period. Acetabular shape as measured by the Sharp angle and acetabular roof angle and femoral head coverage as measured by lateral center-edge angle did not change significantly by the index operation. The ratio of medial joint space width of the operated side to that of the contralateral side did not change significantly. CONCLUSIONS: Screw medial hemi-epiphysiodesis can effectively correct caput valgum associated with DDH. However, this technique remains coxa brevis and does not seem to significantly affect acetabular morphology or reduce subluxation.

Inter-segmental motions of the foot: differences between younger and older healthy adult females.

BACKGROUND: Although accumulative evidence exists that support the applicability of multi-segmental foot models (MFMs) in evaluating foot motion in various pathologic conditions, little is known of the effect of aging on inter-segmental foot motion. The objective of this study was to evaluate differences in inter-segmental motion of the foot between older and younger adult healthy females during gait using a MFM with 15-marker set. METHODS: One hundred symptom-free females, who had no radiographic evidence of osteoarthritis, were evaluated using MFM with 15-marker set. They were divided into young (n = 50, 20-35 years old) and old (n = 50, 60-69 years old) groups. Coefficients of multiple correlations were evaluated to assess the similarity of kinematic curve. Inter-segmental angles (hindfoot, forefoot, and hallux) were calculated at each gait phase. To evaluate the effect of gait speed on intersegmental foot motion, subgroup analysis was performed according to the similar speed of walking. RESULTS: Kinematic curves showed good or excellent similarity in most parameters. Range of motion in the sagittal (p < 0.001) and transverse (p = 0.001) plane of the hallux, and sagittal (p = 0.023) plane of the forefoot was lower in older females. The dorsiflexion (p = 0.001) of the hallux at terminal stance and pre-swing phases was significantly lower in older females. When we compared young and older females with similar speed, these differences remained. CONCLUSIONS: Although the overall kinematic pattern was similar between young and older females, reduced range of inter-segmental motion was observed in the older group. Our results suggest that age-related changes need to be considered in studies evaluating inter-segmental motion of the foot.

Platelet-Derived Growth Factor Receptor-Positive Pericytic Cells of White Adipose Tissue from Critical Limb Ischemia Patients Display Mesenchymal Stem Cell-Like Properties.

BACKGROUND: The pericytes in the blood vessel wall have recently been identified to be important in regulating vascular formation, stabilization, remodeling, and function. We isolated and identified pericyte-like platelet-derived growth factor receptor beta-positive (PDGFRß+) cells from the stromal vascular fraction (SVF) of adipose tissue from critical limb ischemia (CLI) patients and investigated their potential as a reliable source of stem cells for cell-based therapy. METHODS: De-identified subcutaneous fat tissues were harvested after amputation in CLI patients. Freshly isolated SVF cells and culture-expanded adipose-derived stem cells (ADSCs) were quantified using flow cytometry. A matrigel tube formation assay and multi-lineage differentiation were performed to assess pericytic and mesenchymal stem cell (MSC)-like characteristics of PDGFRß+ ADSCs. RESULTS: PDGFRß+ cells were located in the pericytic area of various sizes of blood vessels and coexpressed mesenchymal stem cell markers. PDGFRß+ cells in freshly isolated SVF cells expressed a higher level of stem cell markers (CD34 and CXCR4) and mesenchymal markers (CD13, CD44, CD54, and CD90) than PDGFRß- cells. In vitro expansion of PDGFRß+ cells resulted in enrichment of the perivascular mesenchymal stem-like (PDGFRß+/CD90+/CD45-/CD31-) cell fractions. The Matrigel tube formation assay revealed that PDGFRß+ cells were located in the peritubular area. CONCLUSIONS: PDGFRß+ ADSCs cells demonstrated a good multilineage differentiation potential. Pericyte-like PDGFRß+ cells from the SVF of adipose tissue from CLI patients had MSC-like characteristics and could be amplified by in vitro culture with preservation of their cell characteristics. We believe PDGFRß+ cells in the SVF of adipose tissue can be used as a reliable source of stem cells even in CLI patients.

Comparison of Multisegmental Foot and Ankle Motion Between Total Ankle Replacement and Ankle Arthrodesis in Adults.

BACKGROUND: Total ankle replacement (TAR) and ankle arthrodesis (AA) are usually performed for severe ankle arthritis. We compared postoperative foot segmental motion during gait in patients treated with TAR and AA. METHODS: Gait analysis was performed in 17 and 7 patients undergoing TAR and AA, respectively. Subjects were evaluated using a 3-dimensional multisegmental foot model with 15 markers. Temporal gait parameters were calculated. The maximum and minimum values and the differences in hallux, forefoot, hindfoot, and arch in 3 planes (sagittal, coronal, transverse) were compared between the 2 groups. One hundred healthy adults were evaluated as a control. RESULTS: Gait speed was faster in the TAR ( P = .028). On analysis of foot and ankle segmental motion, the range of hindfoot sagittal motion was significantly greater in the TAR (15.1 vs 10.2 degrees in AA; P = .004). The main component of motion increase was hindfoot dorsiflexion (12.3 and 8.6 degrees). The range of forefoot sagittal motion was greater in the TAR (9.3 vs 5.8 degrees in AA; P = .004). Maximum ankle power in the TAR (1.16) was significantly higher than 0.32 in AA; P = .008). However, the range of hindfoot and forefoot sagittal motion was decreased in both TAR and AA compared with the control group ( P = .000). CONCLUSION: Although biomechanical results of TAR and AA were not similar to those in the normal controls, joint motions in the TAR more closely matched normal values. Treatment decision making should involve considerations of the effect of surgery on the adjacent joints. LEVEL OF EVIDENCE: Level III, case-control study.