[Interictal psychosis of epilepsy]. / Les psychoses épileptiques interictales.

Interictal psychosis (IIP) refers to psychosis that occurs in clear consciousness in persons with epilepsy (PWE) with temporal onset not during or immediately following a seizure. The pooled prevalence estimate of psychosis in PWE is 5.6%. PWE and schizophrenia have very high mortality, and more than one in four persons with both disorders die between the age of 25 and 50years. IIP can manifest in brief or chronic forms. The chronic forms of IIP may closely resemble schizophrenia. However, some authors have described the typical presence of persecutory and religious delusions, sudden mood swings and the preservation of affect, as well as rarity of negative symptoms and catatonic states, but these differences remain controversial. Typically, IIP starts after many years of active temporal lobe epilepsy. Several epilepsy-related variables are considered pathogenically relevant in IIP including epilepsy type and seizure characteristics. Risk factors for developing IIP are family history of psychosis, learning disability, early age of onset of epilepsy, unilateral or bilateral hippocampal sclerosis, history of status epilepticus, history of febrile seizures, and poorly controlled temporal lobe epilepsy. In patients with epilepsy and psychosis, structural imaging studies have shown several relevant changes leading to conflicting findings. Altered neuronal plasticity and excitability have been described in epilepsy and psychotic disorders. Neuropathological data suggest that IIP are not the result of classic epileptic pathology of the temporal lobe. Forced normalization (FN) and alternating psychosis refer to patients with poorly controlled epilepsy (focal or generalized) who have had psychotic episodes associated with remission of their seizures and disappearance of epileptiform activity on their EEGs. FN mainly occurs in temporal lobe epilepsy when patients have frequent seizures that are abruptly terminated triggered by an antiepileptic drug, vagus nerve stimulation or epilepsy surgery. Treatment is based on withdrawal of the responsible drug, and by transient use of antipsychotics for acute symptomatic control on a case-by-case basis. FN is an entity whose pathophysiology remains uncertain. Antiepileptic drugs (AEDs) may sometimes induce psychotic symptoms and psychosis could be a direct effect of the AEDs. IIP has been reported more frequently following the initiation of zonisamide, topiramate, and levetiracetam when compared with other antiepileptic drugs. However, AEDs do not appear to be the only determinant of IIP. The management of IIP requires a multidisciplinary approach with early involvement of a liaison psychiatrist associated with a neurologist. IIP are underdiagnosed and mistreated. Existing recommendations are extrapolated from those established for the treatment of schizophrenia with some additional guidance from expert opinions. A two-step procedure, not necessarily consecutive, is suggested. The first step requires reevaluation of the antiepileptic treatment. The second step requires initiation of atypical neuroleptics. Antipsychotic drugs should be selected with consideration of the balance between pharmacological profiles, efficacy, and adverse effects. Regarding pharmacokinetic interactions, AEDs with inducing properties reduce the blood levels of all antipsychotics. It is important to consider implications of combining neuroleptics and AEDs with a similar spectrum of side effects. Regarding the duration of treatment, IIP episodes are more likely to be recurrent than in primary schizophrenia. In practice, atypical neuroleptics with few motor side effects such as risperidone can be used as first choice, given the low propensity for drug-drug interactions and the low seizure risk, with the added suggestion to start low and go slow. Clozapine could be prescribed in selected cases.

The relationship between central motor conduction time and spinal cord compression in patients with cervical spondylotic myelopathy.

STUDY DESIGN: Retrospective study. OBJECTIVES: Few studies have reported a relationship between central motor conduction time (CMCT), which evaluates corticospinal function, and degree of spinal cord compression in patients with myelopathy. Thus, there is no consensus on predicting the degree of prolonged CMCT on the basis of the degree of spinal cord compression. If a correlation exists between CMCT and spinal cord compression, then spinal cord compression may be a useful noninvasive clinical indicator of corticospinal function. Therefore, this study evaluated the relationship between CMCT and cervical spinal cord compression measured by magnetic resonance imaging (MRI) in patients with cervical spondylotic myelopathy (CSM). SETTING: Hiroshima University Hospital in Japan. METHODS: We studied 33 patients undergoing laminoplasty. Patients exhibited significant cervical spinal cord compression on both MRI and intraoperative electrophysiological examination. We assessed transcranial magnetic stimulation measurement of CMCT; spinal cord compression parameters such as area, lateral diameter, anteroposterior diameter and flattening of the spinal cord at the lesion site and C2/3 levels on MRI; and pre- versus postoperative Japanese Orthopaedic Association (JOA) scores. RESULTS: Correlations between CMCT and flattening as well as anteroposterior diameter of the spinal cord at the lesion level were observed. Strong correlations between CMCT and the ratio of the flattening and anteroposterior diameter parameters at the lesion level to that at the C2/3 level were also observed. CONCLUSIONS: Measurement of spinal cord compression may be useful for the evaluation of corticospinal function as a proxy for CMCT in patients with CSM.

Measurement and comparison of individual external doses of high-school students living in Japan, France, Poland and Belarus-the 'D-shuttle' project.

Twelve high schools in Japan (of which six are in Fukushima Prefecture), four in France, eight in Poland and two in Belarus cooperated in the measurement and comparison of individual external doses in 2014. In total 216 high-school students and teachers participated in the study. Each participant wore an electronic personal dosimeter 'D-shuttle' for two weeks, and kept a journal of his/her whereabouts and activities. The distributions of annual external doses estimated for each region overlap with each other, demonstrating that the personal external individual doses in locations where residence is currently allowed in Fukushima Prefecture and in Belarus are well within the range of estimated annual doses due to the terrestrial background radiation level of other regions/countries.

Metastatic patellar bone tumor due to gastric cancer resembling a primary or secondary aneurysmal bone cyst: A case report.

INTRODUCTION AND IMPORTANCE: Patellar bone tumors are very rare, and most are benign or of intermediate type. In this report, we describe our experience of a metastatic patellar bone tumor caused by gastric cancer, which resembled a very rare primary or secondary aneurysmal bone cyst and review the literature. CASE PRESENTATION: A 65-year-old man presented with severe pain in the patellar region and marked limitation of the knee joint range of motion. He had a history of gastric cancer; however, epidemiological, clinical, and imaging findings led us to strongly suspect an aneurysm-like bone cyst. Thus, we performed bone tumor curettage and autologous artificial bone grafting without biopsy because of the severe pain. Pathology results showed gastric cancer metastasis; hence, patellectomy and patellar tendon augmentation with femoral fascia were performed. The Musculoskeletal Tumor Society (MSTS) score was taken postoperatively to assess pain and function. CLINICAL DISCUSSION: We experienced a very rare gastric cancer-related metastatic patellar bone tumor, which resembled a primary or secondary aneurysmal bone cyst in frequency and imaging findings. Patellectomy was ultimately performed, and the patient's MSTS score improved markedly. CONCLUSION: Despite its very low frequency, patellar metastatic bone tumors must be taken into account without being misled by the frequency or imaging findings and a biopsy should necessarily be performed.

New special approach for shoulder stability after Malawer type IVB shoulder girdle resection: A case report.

INTRODUCTION AND IMPORTANCE: Scapular prostheses are useful in shoulder stability after shoulder girdle resection for malignant bone tumors; however, they are difficult to obtain in Japan. Therefore, other methods must be considered, depending on the extent of resection. We report a case in which a clavicle-locking plate, Nesplon tape, and a proximal humeral prosthesis were used to ensure shoulder stability and preserve stable upper limb function. CASE PRESENTATION: A 56-year-old man presented with a large mass and edema over the entire right scapula, which caused severe pain, limited the shoulder's range of motion, and impaired function of the entire upper extremity. Clinical imaging and pathological findings indicated a diagnosis of conventional chondrosarcoma. Using the Malawer technique type IVB, we resected the shoulder girdle and secured shoulder stability with a clavicle-locking plate, Nesplon tape, and a proximal humeral prosthesis. To evaluate the patient, we obtained his Musculoskeletal Tumor Society (MSTS) and Disabilities of Arm, Shoulder, and Hand (DASH) scores 3 months postoperatively. CLINICAL DISCUSSION: To preserve the function of the patient's elbow and hand, the stability of his shoulder was important. We could achieve this stability by using a prosthesis available in Japan. The patient's MSTT and DASH scores improved remarkably. CONCLUSION: A clavicle-locking plate, Nesplon tape, and a proximal humeral prosthesis can be used to ensure shoulder stability after scapular girdle resection and can preserve or improve upper limb function.

Prospective study of kinesthesia after ACL reconstruction.

Previous studies used a variety of methods to assess kinesthesia, thus no consensus exists regarding kinesthetic adaptation after anterior cruciate ligament (ACL) reconstruction. This study prospectively examined whether kinesthesia is adapted after ACL reconstruction, and then discussed the actual angular velocity required to properly assess kinesthesia in ACL-reconstructed patients. 31 patients were evaluated using the threshold to detect passive motion (TTDPM) test, which was applied preoperatively, and at 3, 6, and 12 months following surgery. TTDPMs were measured at 15° or 45° of knee flexion toward both extension and flexion with angular velocities of 0.1°/s or 0.2°/s. ACL-reconstructed knees showed significantly impaired TTDPMs compared to healthy knees before the operation at 15° of knee flexion toward extension and at 45° of knee flexion toward both extension and flexion at 0.2°/s (15° of knee flexion toward extension, P=0.036; 45° of knee flexion toward extension, P=0.015; 45° of knee flexion toward flexion, P=0.030). However, there were no significant differences after 3 months of follow-up. On the basis of these results, applying 0.2°/s seems appropriate to assess TTDPM for patients with an ACL reconstruction, and kinesthesia is adapted within 12 months after the operation. Sensory function and biomechanical stability are also adapted following ACL reconstruction.

Five-year point prevalence survey of healthcare-associated infections and antimicrobial use in a Japanese university hospital.

BACKGROUND: Periodic point prevalence surveys (PPSs) provide a method for assessing changes in healthcare-associated infections (HAIs) and antimicrobial use over time. Following the introduction of an antimicrobial stewardship programme at Nagoya University Hospital (Aichi, Japan) a five-year PPS study was performed to highlight any epidemiological changes. METHODS: One-day PPSs were performed annually in July at Nagoya University Hospital. Data on patient characteristics, medical devices, active HAIs and antimicrobial use were collected using a standard data-collection form. RESULTS: A total of 4339 patients were included. Over the five-year study period the median patient age was 62 years, median duration of hospital admission was nine days, 9% of patients had an HAI and 35.2% received at least one antimicrobial. Overall there were 406 HAIs (95% confidence interval, 369-447) with surgical site infection, pneumonia and febrile neutropenia occurring most frequently. Enterobacterales were the most common pathogens (N = 78, 28.6%) and 32.1% were third-generation cephalosporin-resistant. Meropenem was the most frequently prescribed antimicrobial for HAIs. Surgical antimicrobial prophylaxis changed drastically, with shorter durations and a marked reduction in oral cephalosporin use. However, antimicrobials for medical prophylaxis gradually increased. CONCLUSIONS: This five-year PPS study shows consistent data for patient background, HAIs and causative pathogens and highlights changes in antimicrobial use during the era of the National Action Plan on Antimicrobial Resistance. To describe the epidemiology of Japanese hospitals by PPS, multicentre PPSs including in community hospitals should be performed annually.

Responses of microRNAs 124a and 223 following spinal cord injury in mice.

STUDY DESIGN: We investigated microRNA (miRNA) expression after spinal cord injury (SCI) in mice. OBJECTIVES: The recent discovery of miRNAs suggests a novel regulatory control over gene expression during plant and animal development. MiRNAs are short noncoding RNAs that suppress the translation of target genes by binding to their mRNAs, and play a central role in gene regulation in health and disease. The purpose of this study was to examine miRNA expression after SCI. SETTING: Department of Orthopaedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University. METHODS: We examined the expression of miRNA (miR)-223 and miR-124a in a mouse model at 6 h, 12 h, 1 day, 3 days and 7 days after SCI using quantitative PCR. The miRNA expression was confirmed by in situ hybridization. RESULTS: Quantitative PCR revealed two peaks of miR-223 expression at 6 and 12 h and 3 days after SCI. MiR-124a expression decreased significantly from 1 day to 7 days after SCI. In situ hybridization demonstrated the presence of miR-223 around the injured site. However, miR-124a, which was present in the normal spinal cord, was not observed at the injured site. CONCLUSION: Our results indicate a time-dependent expression pattern of miR-223 and miR-124a in a mouse model of SCI. In this study, the time course of miRNA-223 expression may be related to inflammatory responses after SCI, and the time course of decreased miR-124a expression may reflect cell death.

L-proline is a sedative regulator of acute stress in the brain of neonatal chicks.

The purpose of the present study was to clarify the central nervous system function of amino acids during acute stress. In Experiment 1, changes in free amino acid pattern were investigated in the brain of neonatal chicks exposed to either restraint with isolation-induced or fasting stress. L-proline and L-arginine were decreased in the telencephalon and diencephalon under any stress. Since the central nervous system functions of L-arginine during the stress response has recently been reported, in Experiment 2, the effect of intracerebroventricular injection of L-proline (0.5, 1.0, 2.0 micromol) during isolation-induced stress was investigated. L-proline induced sedative and hypnotic effects in a dose-dependent manner. It is suggested that L: -proline may have an important role to attenuate the stress response in the central nervous system of chicks.

Atelocollagen-associated autologous chondrocyte implantation for the repair of chondral defects of the knee: a prospective multicenter clinical trial in Japan.

BACKGROUND: New tissue-engineering technology was developed to create a cartilage-like tissue in a three-dimensional culture using atelocollagen gel. The minimum 2-year followup outcome of transplanting autologous chondrocytes cultured in atelocollagen gel for the treatment of full-thickness defects of cartilage in knees was reported from the single institution. The present multicenter study was conducted to determine clinical and arthroscopic outcomes in patients who underwent atelocollagen-associated autologous chondrocyte implantation for the repair of chondral defects of the knees. METHODS: At six medical institutes in Japan, we prospectively evaluated the clinical and arthroscopic outcomes of transplanting autologous chondrocytes cultured in atelocollagen gel for the treatment of full-thickness defects of cartilage in 27 patients (27 knees) with cartilage lesions on a femoral condyle or on a patellar facet over 24 months. RESULTS: The Lysholm score significantly increased from 60.0 +/- 13.7 points to 89.8 +/- 9.5 points (P = 0.001). Concerning the ICRS grade for arthroscopic appearance, 6 knees (24%) were assessed as grade I (normal) and 17 knees (68%) as grade II (nearly normal). There were few adverse features, except for detachment of the graft in two cases. CONCLUSIONS: We concluded that transplanting chondrocytes in a newly formed matrix of atelocollagen gel can promote restoration of the articular cartilage of the knee.

Rotational acetabular osteotomy for symptomatic hip dysplasia in patients younger than 21 years of age: seven- to 30-year survival outcomes.

AIMS: The aim of this study was to report the long-term results of rotational acetabular osteotomy (RAO) for symptomatic hip dysplasia in patients aged younger than 21 years at the time of surgery. PATIENTS AND METHODS: We evaluated 31 patients (37 hips) aged younger than 21 years at the time of surgery retrospectively. There were 29 female and two male patients. Their mean age at the time of surgery was 17.4 years (12 to 21). The mean follow-up was 17.9 years (7 to 30). The RAO was combined with a varus or valgus femoral osteotomy or a greater trochanteric displacement in eight hips, as instability or congruence of the hip could not be corrected adequately using RAO alone. RESULTS: The mean Merle d'Aubigné clinical score improved significantly from 15.4 to 17.2 (p < 0.0001). The mean centre-edge (CE) angle improved from -2.6° to 26°, the mean acetabular roof angle improved from 3.0° to 5.2°, and the mean head lateralization index improved from 0.68 to 0.62. Progression of radiological osteoarthritis (OA) was seen in seven hips, but no patient underwent total hip arthroplasty. CONCLUSION: RAO is an effective form of correction for a severely dysplastic hip in adolescent and young adult patients. Cite this article: Bone Joint J 2019;101-B:390-395.

Multiple intra-articular injections of allogeneic bone marrow-derived stem cells potentially improve knee lesions resulting from surgically induced osteoarthritis: an animal study.

AIM: Mesenchymal stem cells (MSCs) have several properties that may support their use as an early treatment option for osteoarthritis (OA). This study investigated the role of multiple injections of allogeneic bone marrow-derived stem cells (BMSCs) to alleviate the progression of osteoarthritic changes in the various structures of the mature rabbit knee in an anterior cruciate ligament (ACL)-deficient OA model. MATERIALS AND METHODS: Two months after bilateral section of the ACL of Japanese white rabbits aged nine months or more, either phosphate buffered saline (PBS) or 1 x 106 MSCs were injected into the knee joint in single or three consecutive doses. After two months, the articular cartilage and meniscus were assessed macroscopically, histologically, and immunohistochemically using collagen I and II. RESULTS: Within the PBS injection (control group), typical progressive degenerative changes were revealed in the various knee structures. In the single MSC injection (single group), osteoarthritic changes were attenuated, but still appeared, especially in the medial compartments involving fibrillation of the articular cartilage, osteophyte formation in the medial plateau, and longitudinal tear of the meniscus. In the multiple-injections group, the smoothness and texture of the articular cartilage and meniscus were improved. Histologically, absence or reduction in matrix staining and cellularity were noticeable in the control and single-injection groups, respectively, in contrast to the multiple-injections group, which showed good intensity of matrix staining and chondrocyte distribution in the various cartilage zones. Osteoarthritis Research Society International (OARSI) scoring showed significantly better results in the multiple-injections group than in the other groups. Immunohistochemically, collagen I existed superficially in the medial femoral condyle in the single group, while collagen II was more evident in the multiple-injections group than the single-injection group. CONCLUSION: A single injection of MSCs was not enough to restore the condition of osteoarthritic joints. This is in contrast to multiple injections of MSCs, which had the ability to replace lost cells, as well as reducing inflammation. Cite this article: Bone Joint J 2019;101-B:824-831.

Central L-arginine reduced stress responses are mediated by L-ornithine in neonatal chicks.

Recently, we observed that central administration of L-arginine attenuated stress responses in neonatal chicks, but the contribution of nitric oxide (NO) to this response was minimal. The sedative and hypnotic effects of L-arginine may be due to L-arginine itself and/or its metabolites, excluding NO. To clarify the mechanism, the effect of intracerebroventricular (i.c.v.) injection of L-arginine metabolites on behavior under social separation stress was investigated. The i.c.v. injection of agmatine, a guanidino metabolite of L-arginine, had no effect during a 10 min behavioral test. In contrast, the i.c.v. injection of L-ornithine clearly attenuated the stress response in a dose-dependent manner, and induced sleep-like behavior. The L-ornithine concentration in the telencephalon and diencephalon increased following the i.c.v. injection of L-arginine. In addition, several free amino acids including L-alanine, glycine, L-proline and L-glutamic acid concentrations increased in the telencephalon. In conclusion, it appears that L-ornithine, produced by arginase from L-arginine in the brain, plays an important role in the sedative and hypnotic effects of L-arginine observed during a stress response. In addition, several other amino acids having a sedative effect might partly participate in the sedative and hypnotic effects of L-arginine.

Histological and biomechanical study of impacted cancellous allografts with cement in the femur: a canine model.

INTRODUCTION: An experimental canine model was used for quantitative histological study using bone morphometry and biomechanical study on impacted cancellous allografting with cement in revision total hip arthroplasty. MATERIALS AND METHODS: The prosthesis had a collarless polished titanium alloy tapered stem with a head diameter of 15 mm. Twelve Beagle dogs were used. Cancellous bone grafts were obtained aseptically from the femoral condyles of other beagles. Histological examinations were performed up to 1 year after surgery. Biomechanical examinations were performed at 8 weeks after surgery. RESULTS: The new bone formation proceeded from the proximal part to the distal site of the femur in the long axis as well as from the host cortical bone to the cement layer. Bone morphometry showed that the mineral apposition rate was higher in the proximal site of the femur than in the distal site at 8 weeks after surgery, but no significant differences were observed at other times. The bone formation rate was higher in the proximal site of the femur at 8 weeks after surgery, while it increased in the distal site at 16 weeks postoperatively but had decreased at 1 year after surgery significantly. The load test at 8 weeks after surgery showed that there was no significant difference at all sites attached strain gauge between impacted cancellous allograft group and control group. CONCLUSION: We concluded that biological replacement of the grafted bone by new bone settled at 1 year after surgery in this experimental model. However, the process was not completed.

Risk factors for progression of articular cartilage damage after anatomical anterior cruciate ligament reconstruction: a second-look arthroscopic evaluation.

Aims: To investigate the risk factors for progression of articular cartilage damage after anatomical anterior cruciate ligament (ACL) reconstruction. Patients and Methods: A total of 174 patients who underwent second-look arthroscopic evaluation after anatomical ACL reconstruction were enrolled in this study. The graded condition of the articular cartilage at the time of ACL reconstruction was compared with that at second-look arthroscopy. Age, gender, body mass index (BMI), ACL reconstruction technique, meniscal conditions, and other variables were assessed by regression analysis as risk factors for progression of damage to the articular cartilage. Results: In the medial compartment, multivariable logistic regression analysis indicated that partial medial meniscectomy (odds ratio (OR) 6.82, 95% confidence interval (CI) 2.11 to 22.04, p = 0.001), pivot-shift test grade at the final follow-up (OR 3.53, CI 1.39 to 8.96, p = 0.008), BMI (OR 1.15, CI 1.03 to 1.28, p = 0.015) and medial meniscal repair (OR 3.19, CI 1.24 to 8.21, p = 0.016) were significant risk factors for progression of cartilage damage. In the lateral compartment, partial lateral meniscectomy (OR 10.94, CI 4.14 to 28.92, p < 0.001) and side-to-side differences in anterior knee laxity at follow-up (OR 0.63, p = 0.001) were significant risk factors. Conclusion: Partial meniscectomy was found to be strongly associated with the progression of articular cartilage damage despite r anatomical ACL reconstruction. Cite this article: Bone Joint J 2018;100-B:285-93.

Outcome of autologous bone grafting with preservation of articular cartilage to treat osteochondral lesions of the talus with large associated subchondral cysts.

Aims: The aim of this study was to evaluate antegrade autologous bone grafting with the preservation of articular cartilage in the treatment of symptomatic osteochondral lesions of the talus with subchondral cysts. Patients and Methods: The study involved seven men and five women; their mean age was 35.9 years (14 to 70). All lesions included full-thickness articular cartilage extending through subchondral bone and were associated with subchondral cysts. Medial lesions were exposed through an oblique medial malleolar osteotomy, and one lateral lesion was exposed by expanding an anterolateral arthroscopic portal. After refreshing the subchondral cyst, it was grafted with autologous cancellous bone from the distal tibial metaphysis. The fragments of cartilage were fixed with 5-0 nylon sutures to the surrounding cartilage. Function was assessed at a mean follow-up of 25.3 months (15 to 50), using the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot outcome score. The radiological outcome was assessed using MRI and CT scans. Results: The mean AOFAS score improved from 65.7 (47 to 81) preoperatively to 92 (90 to 100) at final follow-up, with 100% patient satisfaction. The radiolucent area of the cysts almost disappeared on plain radiographs in all patients immediately after surgery, and there were no recurrences at the most recent follow-up. The medial malleolar screws were removed in seven patients, although none had symptoms. At this time, further arthroscopy was undertaken, when it was found that the mean International Cartilage Repair Society (ICRS) arthroscopic score represented near-normal cartilage. Conclusion: Autologous bone grafting with fixation of chondral fragments preserves the original cartilage in the short term, and could be considered in the treatment for adult patients with symptomatic osteochondral defect and subchondral cysts. Cite this article: Bone Joint J 2018;100-B:590-5.

Dual inhibition of EZH1/2 breaks the quiescence of leukemia stem cells in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer originating from rare populations of leukemia stem cells (LSCs). AML relapse after conventional chemotherapy is caused by a remaining population of drug-resistant LSCs. Selective targeting of the chemoresistant population is a promising strategy for preventing and treating AML relapse. Polycomb repressive complex 2 (PRC2) trimethylates histone H3 at lysine 27 to maintain the stemness of LSCs. Here, we show that quiescent LSCs expressed the highest levels of enhancer of zeste (EZH) 1 and EZH2, the PRC2 catalytic subunits, in the AML hierarchy, and that dual inactivation of EZH1/2 eradicated quiescent LSCs to cure AML. Genetic deletion of Ezh1/2 in a mouse AML model induced cell cycle progression of quiescent LSCs and differentiation to LSCs, eventually eradicating AML LSCs. Quiescent LSCs showed PRC2-mediated suppression of Cyclin D, and Cyclin D-overexpressing AML was more sensitive to chemotherapy. We have developed a novel EZH1/2 dual inhibitor with potent inhibitory activity against both EZH1/2. In AML mouse models and patient-derived xenograft models, the inhibitor reduced the number of LSCs, impaired leukemia progression, and prolonged survival. Taken together, these results show that dual inhibition of EZH1/2 is an effective strategy for eliminating AML LSCs.

Kudo type-5 total elbow arthroplasty for patients with rheumatoid arthritis: a minimum ten-year follow-up study.

AIMS: We assessed the long-term (more than ten-year) outcomes of the Kudo type-5 elbow prosthesis in patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: We reviewed 41 elbows (Larsen Grade IV, n = 21; Grade V, n = 20) in 31 patients with RA who had undergone a Kudo type-5 total elbow arthroplasty (TEA) between 1994 and 2003, and had been followed up for more than ten years. The humeral component was cementless and the all-polyethylene ulnar component cemented in every patient. Clinical outcome was assessed using the Mayo elbow performance score. We calculated the revision rate and evaluated potential risk factors for revision. The duration of follow-up was a mean 141 months (120 to 203). RESULTS: Aseptic loosening of the ulnar component occurred in 11 elbows. There was no radiolucency around any humeral component. There was one deep infection. The survival rate according to Kaplan-Meier survivorship analysis was 87.8% after five years and 70.7% after ten years. The range of extension/flexion was a mean -38° (-80° to 0°)/105° (30° to 150°) before surgery and -40° (-70° to -20°)/132° (100° to 150°) at the final follow-up, while the mean Mayo elbow performance score was 43 before surgery and 80 at final follow-up. Disease duration of RA up to the TEA of < 15 years and a pre-operative range of movement (ROM) of > 85° were significant risk factors for revision or aseptic loosening. CONCLUSION: Although Kudo type-5 prostheses gave satisfactory results in the short-term, aseptic loosening increased after five years. In most cases, elbow function was maintained in the long-term without loosening of the implant. A short duration from the onset of RA to TEA and a large pre-operative ROM were significant risk factors for revision or aseptic loosening. Cite this article: Bone Joint J 2017;99-B:818-23.

Evaluation of autologous skeletal muscle-derived factors for regenerative medicine applications.

OBJECTIVES: Regenerative medicine is an emerging field aimed at the repair and regeneration of various tissues. To this end, cytokines (CKs), growth factors (GFs), and stem/progenitor cells have been applied in this field. However, obtaining and preparing these candidates requires invasive, costly, and time-consuming procedures. We hypothesised that skeletal muscle could be a favorable candidate tissue for the concept of a point-of-care approach. The purpose of this study was to characterize and confirm the biological potential of skeletal muscle supernatant for use in regenerative medicine. METHODS: Semitendinosus muscle was used after harvesting tendon from patients who underwent anterior cruciate ligament reconstructions. A total of 500 milligrams of stripped muscle was minced and mixed with 1 mL of saline. The collected supernatant was analysed by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. The biological effects of the supernatant on cell proliferation, osteogenesis, and angiogenesis in vitro were evaluated using human mesenchymal stem cells (hMSCs) and human umbilical cord vein endothelial cells (HUVECs). RESULTS: The supernatant contained several GFs/CKs, with especially high levels of basic fibroblast growth factor, and CD34+ cells as the stem/progenitor cell fraction. With regard to biological potential, we confirmed that cell proliferation, osteoinduction, and angiogenesis in hMSCs and HUVECs were enhanced by the supernatant. CONCLUSIONS: The current study demonstrates the potential of a new point-of-care strategy for regenerative medicine using skeletal muscle supernatant. This attractive approach and readily-available material could be a promising option for tissue repair/regeneration in the clinical setting.Cite this article: M. Yoshikawa, T. Nakasa, M. Ishikawa, N. Adachi, M. Ochi. Evaluation of autologous skeletal muscle-derived factors for regenerative medicine applications. Bone Joint Res 2017;6:277-283. DOI: 10.1302/2046-3758.65.BJR-2016-0187.R1.

Angiogenic conditioning of peripheral blood mononuclear cells promotes fracture healing.

OBJECTIVES: The objective of this study was to investigate the therapeutic effect of peripheral blood mononuclear cells (PBMNCs) treated with quality and quantity control culture (QQ-culture) to expand and fortify angiogenic cells on the acceleration of fracture healing. METHODS: Human PBMNCs were cultured for seven days with the QQ-culture method using a serum-free medium containing five specific cytokines and growth factors. The QQ-cultured PBMNCs (QQMNCs) obtained were counted and characterised by flow cytometry and real-time polymerase chain reaction (RT-PCR). Angiogenic and osteo-inductive potentials were evaluated using tube formation assays and co-culture with mesenchymal stem cells with osteo-inductive medium in vitro. In order to evaluate the therapeutic potential of QQMNCs, cells were transplanted into an immunodeficient rat femur nonunion model. The rats were randomised into three groups: control; PBMNCs; and QQMNCs. The fracture healing was evaluated radiographically and histologically. RESULTS: The total number of PBMNCs was decreased after QQ-culture, however, the number of CD34+ and CD206+ cells were found to have increased as assessed by flow cytometry analysis. In addition, gene expression of angiogenic factors was upregulated in QQMNCs. In the animal model, the rate of bone union was higher in the QQMNC group than in the other groups. Radiographic scores and bone volume were significantly associated with the enhancement of angiogenesis in the QQMNC group. CONCLUSION: We have demonstrated that QQMNCs have superior potential to accelerate fracture healing compared with PBMNCs. The QQMNCs could be a promising option for fracture nonunion.Cite this article: K. Mifuji, M. Ishikawa, N. Kamei, R. Tanaka, K. Arita, H. Mizuno, T. Asahara, N. Adachi, M. Ochi. Angiogenic conditioning of peripheral blood mononuclear cells promotes fracture healing. Bone Joint Res 2017;6: 489-498. DOI: 10.1302/2046-3758.68.BJR-2016-0338.R1.