Variability between the trial and final implant measurements during the sensor-guided total knee arthroplasty.

PURPOSE: Compartmental load-sensing technology has been used in the attempt to achieve optimal soft tissue balance during total knee arthroplasty (TKA). This study was conducted to investigate the validity of such use of intraoperative sensing technology. METHODS: Ninety-three knees scheduled to undergo total knee arthroplasty for knee osteoarthritis with a tibial sensor were prospectively enrolled. Measurements were divided into three groups according to the three different time points of intraoperative load testing: group Trial (with the trial components), group Final (with the definitive cemented implants and an open joint capsule), and group Closed (with the definitive cemented implants and a closed joint capsule). Load measurements and component rotational alignments were documented at 10°, 30°, 45°, 90°, and 120° of flexion for all three groups, and compared. One year postoperatively, the joint line obliquity angle was obtained radiographically in the valgus and varus stress views at 10° and 30° flexion to evaluate the clinical instability. The Knee Society, Hospital for Special Surgery, and Western Ontario McMaster Universities Osteoarthritis Index scores were used to determine functional outcomes. The correlations of the above outcomes with intraoperative load were evaluated. RESULTS: There were significant differences in medial and lateral loads at all flexion angles (except at a 120° lateral load) between group Trial and group Final (p < 0.05). Tibial trays were internally rotated to a significantly higher degree in group Final than in group Trial (p = 0.010). The lateral compartmental load significantly decreased after patellar inversion (p = 0.037). There were no correlations of intraoperative load with clinical instability and functional outcomes. CONCLUSION: Significant variability was observed between the trial and final implant measurements and intraoperative sensing data were not correlated with instability or functional outcomes over a 1-year period. Therefore, intraoperative sensor technology provides limited feedback and clinical efficacy in the adjustment of the soft tissue balance during TKA. LEVEL OF EVIDENCE: Level II.

Optimal dose of topical tranexamic acid considering efficacy and safety in total knee arthroplasty: a randomized controlled study.

PURPOSE: This study aimed to evaluate the optimal dosage of topical tranexamic acid (TXA) considering the efficacy and safety for controlling bleeding after total knee arthroplasty (TKA). METHODS: This prospective randomized double-blinded placebo-controlled comparative study included 325 patients scheduled to undergo TKA, who were randomly assigned to five groups based on the topical TXA injection (n = 65 per group): control; group 1, 0.5 g TXA; group 2, 1.0 g TXA; group 3, 2.0 g TXA; and group 4, 3.0 g TXA. The primary outcome was decrease in postoperative hemoglobin levels. The secondary outcomes were blood loss calculated using Good's method, drainage volume, frequency of transfusion, and range of motion (ROM). Plasma TXA levels and complications were also evaluated. RESULTS: Significant differences were noted in the decrease in hemoglobin levels between the control group and groups 2 (p = 0.0027), 3 (p = 0.005), and 4 (p = 0.001). No significant differences were shown among the experimental groups. Significant differences in total blood loss and frequency of transfusion were noted between the control group and groups 2 (p = 0.004, 0.002, respectively), 3 (p = 0.007, 0.001, respectively), and 4 (p = 0.001, 0.009, respectively) without showing significant differences among the experimental groups. With respect to drainage volume, no significant differences were observed among the groups. The serum TXA levels increased proportionally with the applied dose of topical TXA immediately and at 3 and 6 h postoperatively. Symptomatic deep vein thrombosis or pulmonary embolism was not observed in any group. Other complications related to TXA administration were not detected. CONCLUSION: Topical application of 1.0 g or more of TXA shows significant bleeding control without a dose-response relationship. Blood TXA levels increase with the TXA dose following topical TXA application. Therefore, to prevent overdosing and reduce potential complications with ensuring the effectiveness, 1.0 g of TXA is recommended as a topical application. LEVEL OF EVIDENCE: I.

Is a Titanium Implant for Total Knee Arthroplasty Better? A Randomized Controlled Study.

BACKGROUND: Lighter weight and lower modulus are potential advantages of titanium (Ti) implants over cobalt chrome (CoCr) implants in total knee arthroplasty (TKA). This study was conducted to determine whether Ti implants in TKA resulted in better clinical outcomes and radiologic results. METHODS: One hundred and eight patients (216 knees) with knee arthritis warranting bilateral primary TKA were randomly allocated to undergo Ti rotating-platform TKA in one knee and CoCr rotating-platform TKA in the contralateral knee. The mean follow-up period was 5.3 years (range, 1-7 years). The weight of Ti implants was one-third lighter than that of CoCr implants (133.9 g vs 390.1 g, P < .01). Clinical outcomes were evaluated using clinical scores, patient preferences (lightness, comfort, naturalness, and satisfaction), gait analysis (kinetic and kinematic data), range of motion, and degree of pain. Radiologic results were evaluated based on the radiolucent line (RLL), degree of medial tibial bone loss, and loosening as seen on X-ray. RESULTS: No significant differences were observed in clinical scores or patient preference. Regarding implant weight, approximately 70% of patients did not perceive the Ti implant as lighter. No significant differences were observed in gait analysis, range of motion, or degree of pain. The RLL was seen in 9% of the Ti implant group and 19% of the CoCr implant group. CONCLUSION: The lighter Ti implant did not show any clinical benefit over CoCr implants. The lightness of the Ti implant is not sufficient to matter or be noticeable. However, the Ti implant showed lower rate of RLL than the CoCr implant. LEVEL OF EVIDENCE: level I, randomized controlled trial.

Do the increment of femoral condyle curvature and the change of tibia shape improve clinical outcome in total knee arthroplasty? A propensity score matching analysis.

PURPOSE: Recently, the Persona total knee arthroplasty (TKA) system with more anatomical features and a similarly high flexion to the previous version, LPS-Flex, was introduced and is widely used. This study aimed to compare the early outcomes obtained using Persona versus an LPS-Flex fixed PS implant. METHODS: A total of 784 knees that underwent primary TKAs (162: Persona group and 622: LPS-Flex group) were included. After 1:2 propensity score matching, there were 143 and 286 knees in Persona and LPS-Flex groups, respectively. Range of motion at the 2-year follow-up was the primary variable. Secondary variables were functional score, ability to perform activities requiring deep knee flexion, patient satisfaction, and radiographic measurements, including radiolucent line (RLL). RESULTS: The average postoperative maximal flexion measured by goniometer at 2 years after TKA was 126.1° ± 10.8° (range 95°-140°) for the Persona group and 132.7° ± 11.7° (range 103°-145°) for the LPS-Flex group (P < 0.05). This significant difference was observed from 1 year postoperatively (P < 0.05). The two groups did not show a significant difference in functional score, postoperative ability in high flexion activities, and satisfaction at the 2-year follow-up. The rate of RLL was significantly lower in the Persona group (P < 0.05). CONCLUSION: At the 2-year follow-up, the Persona group had less maximal flexion; however, the difference in flexion did not seem to affect clinical outcomes. According to the radiological results, the Persona system shows less RLL than does the LPS-Flex system. LEVEL OF EVIDENCE: III.

Efficacy of Systemic Steroid Use Given One Day After Total Knee Arthroplasty for Pain and Nausea: A Randomized Controlled Study.

BACKGROUND: Systemic steroid has been used to control pain and nausea in total knee arthroplasty (TKA), but most studies recommend a single dose administration prior to, or during, surgery. This study aimed to determine the efficacy of administration on 1 day postoperatively. METHODS: Patients who were scheduled to undergo TKA were randomly assigned to the following groups: control group, receiving normal saline injection; group 1, receiving 10 mg dexamethasone intravenously (IV) 1 hour before surgery; group 2, receiving 0.1 mg/kg dexamethasone (IV) 24 hours after surgery; or group 3, receiving 0.2 mg/kg dexamethasone (IV) 24 hours after surgery (n = 44-46 per group). Primary outcomes were pain and nausea visual analogue scale (VAS). Secondary outcomes were analgesic administration, rescue antiemetic administration, C-reactive protein, range of motion, and complications. RESULTS: Postoperative pain and nausea remained high for 48 hours post-TKA. Group 1 had lower pain and nausea VAS scores than did the control group (P < .01) for only 24 hours post-TKA. Groups 2 and 3 had lower pain and nausea VAS scores than did the control group and group 1 (P < .01) 48 hours post-TKA. Analgesic and antiemetic administration were significantly lower in groups 2 and 3 than in the control group during 48 hours after TKA. There were no differences in C-reactive protein level and range of motion, and complications were not detected. CONCLUSION: The effect of preoperative and postoperative administration of dexamethasone for controlling pain and nausea was observed only for 24 hours. Considering that severe pain and nausea persisted for more than 48 hours after TKA, additional administration of dexamethasone at 1 day postoperatively is suggested. LEVEL OF EVIDENCE: Level I.

JPH203, a selective L-type amino acid transporter 1 inhibitor, induces mitochondria-dependent apoptosis in Saos2 human osteosarcoma cells.

Most normal cells express L-type amino acid transporter 2 (LAT2). However, L-type amino acid transporter 1 (LAT1) is highly expressed in many tumor cells and presumed to support their increased growth and proliferation. This study examined the effects of JPH203, a selective LAT1 inhibitor, on cell growth and its mechanism for cell death in Saos2 human osteosarcoma cells. FOB human osteoblastic cells and Saos2 cells expressed LAT1 and LAT2 together with their associating protein 4F2 heavy chain, but the expression of LAT2 in the Saos2 cells was especially weak. JPH203 and BCH, a non-selective L-type amino acid transporter inhibitor, potently inhibited L-leucine uptake in Saos2 cells. As expected, the intrinsic ability of JPH203 to inhibit L-leucine uptake was far more efficient than that of BCH in Saos2 cells. Likewise, JPH203 and BCH inhibited Saos2 cell growth with JPH203 being superior to BCH in this regard. Furthermore, JPH203 increased apoptosis rates and formed DNA ladder in Saos2 cells. Moreover, JPH203 activated the mitochondria-dependent apoptotic signaling pathway by upregulating pro-apoptotic factors, such as Bad, Bax, and Bak, and the active form of caspase-9, and downregulating anti-apoptotic factors, such as Bcl-2 and Bcl-xL. These results suggest that the inhibition of LAT1 activity via JPH203, which may act as a potential novel anti-cancer agent, leads to apoptosis mediated by the mitochondria-dependent intrinsic apoptotic signaling pathway by inducing the intracellular depletion of neutral amino acids essential for cell growth in Saos2 human osteosarcoma cells.

Regulation of acetylation of histone deacetylase 2 by p300/CBP-associated factor/histone deacetylase 5 in the development of cardiac hypertrophy.

RATIONALE: Histone deacetylases (HDACs) are closely involved in cardiac reprogramming. Although the functional roles of class I and class IIa HDACs are well established, the significance of interclass crosstalk in the development of cardiac hypertrophy remains unclear. OBJECTIVE: Recently, we suggested that casein kinase 2α1-dependent phosphorylation of HDAC2 leads to enzymatic activation, which in turn induces cardiac hypertrophy. Here we report an alternative post-translational activation mechanism of HDAC2 that involves acetylation of HDAC2 mediated by p300/CBP-associated factor/HDAC5. METHODS AND RESULTS: Hdac2 was acetylated in response to hypertrophic stresses in both cardiomyocytes and a mouse model. Acetylation was reduced by a histone acetyltransferase inhibitor but was increased by a nonspecific HDAC inhibitor. The enzymatic activity of Hdac2 was positively correlated with its acetylation status. p300/CBP-associated factor bound to Hdac2 and induced acetylation. The HDAC2 K75 residue was responsible for hypertrophic stress-induced acetylation. The acetylation-resistant Hdac2 K75R showed a significant decrease in phosphorylation on S394, which led to the loss of intrinsic activity. Hdac5, one of class IIa HDACs, directly deacetylated Hdac2. Acetylation of Hdac2 was increased in Hdac5-null mice. When an acetylation-mimicking mutant of Hdac2 was infected into cardiomyocytes, the antihypertrophic effect of either nuclear tethering of Hdac5 with leptomycin B or Hdac5 overexpression was reduced. CONCLUSIONS: Taken together, our results suggest a novel mechanism by which the balance of HDAC2 acetylation is regulated by p300/CBP-associated factor and HDAC5 in the development of cardiac hypertrophy.

Effect of the allelic variant of alcohol dehydrogenase ADH1B*2 on ethanol metabolism.

BACKGROUND: It has been known that ADH1B*2 allele has a protective effect against the development of alcohol dependence. However, the protection mechanism is still unknown. We investigated whether ADH1B gene polymorphism affects ethanol (EtOH) metabolism. METHODS: In a parent study, we conducted a randomized crossover trials on 24 healthy male subjects who were selected by genotyping: 12 with ALDH2*1/*1 (active form) and 12 with ALDH2*1/*2 (inactive form). In the present study, the 24 subjects were reclassified into 2 groups of 11 with ADH1B*1/*2 and 13 with ADH1B*2/*2 according to the ADH1B genotypes. Each subject was administered 1 of 3 doses of EtOH (0.25, 0.5, 0.75 g/kg) or a placebo in 4 trials. After the administration of alcohol, blood EtOH and acetaldehyde concentrations were measured 9 times over 4 hours. RESULTS: In the case of EtOH, the area under the concentration-time curve from 0 to 4 hours (AUC0-4 ) and the peak blood concentration of EtOH (Cmax ) in subjects with ADH1B*2/*2 were significantly higher than those in subjects with ADH1B*1/*2 at all 3 dosages before stratifying by ALDH2 genotype. However, after stratifying by ALDH2 genotype, a statistically significant difference between ADH1B*2/*2 and ADH1B*1/*2 was found only at the 0.5 g/kg dosage regardless of ALDH2 genotype. In the case of acetaldehyde, the AUC0-4 and Cmax of acetaldehyde of ADH1B*2/*2 after administration of 0.25 g/kg alcohol and the AUC0-4 of acetaldehyde of ADH1B*2/*2 at 0.5 g/kg were significantly higher than corresponding values of ADH1B*1/*2 only in the group of ALDH2*1/*2. CONCLUSIONS: Our findings indicate that the blood EtOH concentrations of ADH1B*2/*2 group are higher than those of ADH1B*1/*2 group regardless of ALDH2 genotype, and the blood acetaldehyde concentrations of ADH1B*2/*2 are also higher than those of ADH1B*1/*2 only in the ALDH2*1/*2 group. To our knowledge, this is the first report to demonstrate the association of ADH1B*2 allele with blood EtOH and acetaldehyde levels in humans, and these results suggest that higher blood EtOH and acetaldehyde concentrations in ADH1B*2/*2 may constitute the mechanism of protection against alcoholism by ADH1B*2/*2.

Do the Clinical and Radiological Features of Knees with Mucoid Degeneration of the Anterior Cruciate Ligament Differ According to Knee Osteoarthritis Status?

Background: The etiology and pathology of mucoid degeneration of the anterior cruciate ligament (MD-ACL) remain poorly understood. MD-ACL may be associated with knee osteoarthritis (OA) or a mechanism other than OA. This study evaluated the radiological differences between knees with MD-ACL and those with a normal ACL and compared the clinical and radiological features of knees with MD-ACL according to the knee OA status. Methods: This retrospective study compared the radiological features of the intercondylar notch width index (NWI) and posterior tibial slope (PTS) of 67 MD-ACL patients (MD group) and 67 age-, sex-, and OA grade-matched patients with a normal ACL (control group). During the subgroup analysis, MD-ACL patients were divided into the non-OA subgroup (n = 41) and OA subgroup (n = 26). The pain location and characteristics of the knee, PTS, and NWI were compared between these subgroups. Results: Compared to the control group, the MD group had a lower NWI (0.26 ± 0.03 vs. 0.28 ± 0.01, p < 0.001) and a larger PTS (11.3° ± 3.0° vs. 9.2° ± 2.5°, p < 0.001). During the subgroup analysis, the most common pain locations were the posterior and medial aspects of the knee in the non-OA subgroup (43.9%) and OA subgroup (53.8%), respectively. Pain on terminal flexion was the most common pain characteristic in both subgroups (non-OA subgroup, 73.1%; OA subgroup, 53.8%). The PTS was not different between subgroups (11.7° ± 3.2° in the non-OA subgroup vs. 10.6° ± 2.7° in the OA subgroup; p = 0.159). However, the non-OA subgroup had a lower NWI than the OA subgroup (0.25 ± 0.03 vs. 0.28 ± 0.02, p = 0.001). Conclusions: Patients with MD-ACL had a lower NWI and a larger PTS than patients with a normal ACL. Furthermore, the clinical and radiological features of MD-ACL differed according to the knee OA status. A narrow intercondylar notch may be more closely associated with the development of MD-ACL without OA.

Enhanced deep learning model enables accurate alignment measurement across diverse institutional imaging protocols.

BACKGROUND: Achieving consistent accuracy in radiographic measurements across different equipment and protocols is challenging. This study evaluates an advanced deep learning (DL) model, building upon a precursor, for its proficiency in generating uniform and precise alignment measurements in full-leg radiographs irrespective of institutional imaging differences. METHODS: The enhanced DL model was trained on over 10,000 radiographs. Utilizing a segmented approach, it separately identified and evaluated regions of interest (ROIs) for the hip, knee, and ankle, subsequently integrating these regions. For external validation, 300 datasets from three distinct institutes with varied imaging protocols and equipment were employed. The study measured seven radiologic parameters: hip-knee-ankle angle, lateral distal femoral angle, medial proximal tibial angle, joint line convergence angle, weight-bearing line ratio, joint line obliquity angle, and lateral distal tibial angle. Measurements by the model were compared with an orthopedic specialist's evaluations using inter-observer and intra-observer intraclass correlation coefficients (ICCs). Additionally, the absolute error percentage in alignment measurements was assessed, and the processing duration for radiograph evaluation was recorded. RESULTS: The DL model exhibited excellent performance, achieving an inter-observer ICC between 0.936 and 0.997, on par with an orthopedic specialist, and an intra-observer ICC of 1.000. The model's consistency was robust across different institutional imaging protocols. Its accuracy was particularly notable in measuring the hip-knee-ankle angle, with no instances of absolute error exceeding 1.5 degrees. The enhanced model significantly improved processing speed, reducing the time by 30-fold from an initial 10-11 s to 300 ms. CONCLUSIONS: The enhanced DL model demonstrated its ability for accurate, rapid alignment measurements in full-leg radiographs, regardless of protocol variations, signifying its potential for broad clinical and research applicability.

N-Acetylcysteine Induces Apoptotic, Oxidative and Excitotoxic Neuronal Death in Mouse Cortical Cultures.

N-acetylcysteine (NAC) has been used as an antioxidant to prevent oxidative cell death. However, we found NAC itself to induce neuronal death in mouse cortical cultures. Therefore, the current study was performed to investigate the mechanism of neuronal death caused by NAC. Cell death was assessed by measuring lactate dehydrogenase efflux to bathing media after 24-48 h exposure to NAC. NAC (0.1-10 mM) induced neuronal death in a concentration- and exposure time-dependent manner. However, NAC did not injure astrocytes even at a concentration of 10 mM. Also, 10 mM NAC markedly attenuated oxidative astrocyte death induced by 0.5 mM diethyl maleate or 0.25 mM H2O2. The NMDA receptor antagonist MK-801 (10 µM) markedly attenuated the neuronal death caused by 10 mM NAC, while NBQX did not affect the neuronal death. Cycloheximide (a protein synthesis inhibitor, 0.1 µg/mL) and z-VAD-FMK (a caspase inhibitor, 100 µM) also significantly attenuated neuronal death. Apoptotic features such as chromatin condensation, nuclear fragmentation, and caspase 3 activation were observed 1 h after the NAC treatment. The neuronal death induced by 1 or 10 mM NAC was significantly attenuated by the treatment with 100 µM Trolox or 1 mM ascorbic acid. NAC induced the generation of intracellular reactive oxygen species (ROS), as measured by the fluorescent dye 2',7'-dichlorofluorescein diacetate. The ROS generation was almost completely abolished by treatment with Trolox or ascorbic acid. These findings demonstrate that NAC can cause oxidative, apoptotic, and excitotoxic neuronal death in mouse neuronal cultures.

Increased expression of L-amino acid transporters in balloon cells of tuberous sclerosis.

OBJECTS: Tuberous sclerosis complex (TSC) is a dysgenetic syndrome involved in multiple organs, and the pathognomonic cortical tuber act as an epileptic substrate. The amino acid transport system L (LAT) is a major nutrient transport system, and LAT1 is highly expressed in malignant tumors to support tumor cell growth. To study the life-long epilepsy from the cortical tuber, the expression of LAT1 in balloon cells and dysplastic neurons of the cortical tuber is investigated. MATERIALS AND METHODS: LAT1 expression was investigated by LAT1 mRNA using reverse transcription-polymerase chain reaction and immunohistochemical staining with anti-human LAT1 antibody in nine patients with TSC and three control brains. CONCLUSION: LAT1 mRNA was detectable only in fresh-frozen tissues of TSC, and it was upregulated in the cortical tuber lesion. While the LAT1 immunopositivity of control brains was limited in the capillary endothelial cells in the gray matter, increased LAT1 immunopositivity was noted in balloon cells of the cortical tubers in addition to the capillary endothelial cells as shown in control brains. Linear and strong immunopositivity along the cell membrane and cytoplasm of the balloon cells, and weakly granular immunopositivity in their cytoplasm were noted. Increased expression of LAT1 in the balloon cells is important for the active transport of large neutral amino acids into the balloon cells, and that the biologic process may play an important role in the active protein synthesis with metabolic maintenance of balloon cells in cortical tubers of patients with TSC.

Efficacy and Safety of Bioabsorbable Bone Hemostatic Agent in Total Knee Arthroplasty: A Prospective Randomized Controlled Trial.

Although a bioabsorbable bone hemostatic agent (BBHA) was developed approximately 20 years ago to overcome the shortcomings of conventional bone wax, its bleeding control capacity has not yet been studied. This study was aimed at investigating the efficacy and safety of BBHA in total knee arthroplasty (TKA). Sixty-two patients who underwent unilateral primary TKA for knee osteoarthritis were included and randomized to the control or BBHA group. Before releasing the tourniquet, BBHA was applied on the bone-cut surface that was not covered by implants. The primary variable was the drainage volume during the postoperative period. The secondary outcomes were total estimated blood loss (EBL), hemoglobin level, hematocrit level, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, range of motion (ROM), pain visual analog scale (VAS) score, and rate of complications. There were no significant differences in drainage volume or EBL between the 2 groups. Hemoglobin and hematocrit levels were higher in the BBHA group during the 4-week postoperative period; however, the intergroup differences were not significant. The ESR, CRP, ROM, and pain VAS scores in the BBHA group were not significantly different from the corresponding values in the control group. No specific complications were observed. Although BBHA was found to be safe without complications, it did not decrease bleeding after TKA in general cases. Further studies are necessary to evaluate the efficacy of BBHA in patients with coagulation problems.

Enhancement of Cartilage Regeneration of Synovial Stem Cells/Hydrogel by Using Transglutaminase-4.

Although mesenchymal stem cells (MSCs) transplantation is reportedly a promising strategy for repairing damaged articular cartilage, MSCs-based cartilage tissue engineering has numerous limitations, including poor implanted cell adhesion, phenotypic alteration of cells, regulation of mechanical properties, and engraftment rates after implantation. This study aimed to investigate the efficacy of transplantation of synovium-derived mesenchymal stem cells (SDSCs) encapsulated in a hyaluronic acid/collagen/fibrinogen (HA/COL/FG) composite gel by supplementing recombinant human transglutaminase 4 (rhTG-4) in treating osteochondral defects. RhTG-4 treatment induced the expression of integrin ß1 and dynamic actin fiber, enhancing SDSCs adhesion to fibronectin. Supplementation of rhTG-4 significantly induced the proliferation of SDSCs encapsulated in the HA/COL/FG composite gel and increased the hardness of the extracellular matrix. Furthermore, supplementation of rhTG-4 significantly upregulated aggrecan and type II collagen mRNA. Pretreatment with integrin ß1 siRNA markedly suppressed TG4-induced actin remodeling, activation mitogen-activated protein kinase (MAPK), and eventually the chondrogenesis-related genes. Moreover, transplantation of SDSCs encapsulated in HA/COL/FG/rhTG-4 composite gel in vivo yielded reconstructed tissue resembling native hyaline cartilage. These data suggest that rhTG-4 enhances cartilage regeneration of the SDSCs encapsulated in hydrogel in rabbits. Impact statement In this study, we investigated the effects of recombinant human transglutaminase 4 on the ability of synovium-derived mesenchymal stem cells encapsulated in a hyaluronic acid/collagen/fibrinogen composite gel to repair osteochondral defects. We believe that our study makes a significant contribution to the literature because it explores a method of improving an existing modality to mediate tissue repair.

Fluoxetine Induces Apoptotic and Oxidative Neuronal Death Associated with The Influx of Copper Ions in Cultured Neuronal Cells.

We examined the effect of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on neuronal viability in mouse cortical near-pure neuronal cultures. Addition of fluoxetine to the media for 24 hours induced neuronal death in a concentration-dependent manner. To delineate the mechanisms of fluoxetine-induced neuronal death, we investigated the effects of trolox, cycloheximide (CHX), BDNF, z-VAD-FMK, and various metal-chelators on fluoxetine-induced neuronal death. Neuronal death was assessed by MTT assay. The addition of 20 µM fluoxetine to the media for 24 hours induced 60-70% neuronal death, which was associated with the hallmarks of apoptosis, chromatin condensation and DNA laddering. Fluoxetine-induced death was significantly attenuated by CHX, BDNF, or z-VAD-FMK. Treatment with antioxidants, trolox and ascorbate, also markedly attenuated fluoxetine-induced death. Interestingly, some divalent cation chelators (EGTA, Ca-EDTA, and Zn-EDTA) also markedly attenuated the neurotoxicity. Fluoxetine-induced reactive oxygen species (ROS) generation was measured using the fluorescent dye 2',7'-dichlorofluorescin diacetate. Trolox and bathocuproine disulfonic acid (BCPS), a cell membrane impermeable copper ion chelator, markedly attenuated the ROS production and neuronal death. However, deferoxamine, an iron chelator, did not affect ROS generation or neurotoxicity. We examined the changes in intracellular copper concentration using a copper-selective fluorescent dye, Phen Green FL, which is quenched by free copper ions. Fluoxetine quenched the fluorescence in neuronal cells, and the quenching effect of fluoxetine was reversed by co-treatment with BCPS, however, not by deferoxamine. These findings demonstrate that fluoxetine could induce apoptotic and oxidative neuronal death associated with an influx of copper ions.

Meniscus Stiffness Measured with Shear Wave Elastography is Correlated with Meniscus Degeneration.

The aim of this study was to evaluate the diagnostic performance of shear wave elastography (SWE) in human meniscus degeneration, with histology serving as the standard of reference. This comparative in vivo and ex vivo study was performed in 15 medial and 15 lateral menisci from 13 patients undergoing total knee arthroplasty (TKA) for primary osteoarthritis with varus deformity. Patients underwent in vivo coronal measurement with SWE for meniscus before surgery. Then, ex vivo assessment of meniscus stiffness with SWE was performed with the tissue obtained after TKA. SWE measurements were made in coronal and sagittal views with respect to the meniscus. Samples were analyzed histologically on a 0-18 scale according to the level of degeneration based on surface integrity, cellularity, fiber organization, collagen alignment and Safranin O staining intensity. The correlation between SWE measurement scale and histology was analyzed using Spearman's correlation. The area under the receiver operating characteristic curve (AUROC) was used to calculate the diagnostic performance of SWE in evaluating meniscus degeneration. Significant increases in stiffness were observed with increasing histologic degeneration in both in vivo and ex vivo coronal SWE. AUROCs were 0.79 (95% confidence interval [CI]: 0.49-1.00) for in vivo coronal SWE, 0.73 (95% CI: 0.53-0.95) for ex vivo coronal SWE and 0.56 (95% CI: 0.27-0.84) for ex vivo sagittal SWE. The medial meniscus, which exhibited more degeneration on histologic analysis, had greater stiffness than the lateral meniscus on ex vivo coronal SWE. The values of meniscus stiffness measured with SWE are correlated with the degree of meniscus degeneration. Further large-scale prospective studies may confirm the diagnostic performance of SWE as a non-invasive tool to assess meniscus degeneration.

Proximal tibiofibular division in lateral closing wedge high tibial osteotomy does not increase varus instability of the knee.

PURPOSE: When performing lateral closing wedge high tibial osteotomy (LCWHTO), fibular untethering can be performed with either fibular shaft osteotomy (FSO) or proximal tibiofibular division (TFD). The aim of this study was to compare the degree of varus instability between the two methods after LCWHTO and to analyze the determinants of varus instability. METHODS: This study retrospectively analyzed 108 consecutive patients with medial compartment osteoarthritis who underwent LCWHTO and had >2 years of follow-up. Patients who underwent unilateral LCWHTO without a previous history of ligament injury were included. Forty-five patients who received LCWHTO with TFD and 51 patients who received LCWHTO with FSO were finally analyzed. The mean follow-up duration was 5.3 years in LCWHTO with TFD and 4.1 years in LCWHTO with FSO. The shortest distance between the lateral tibial plateaus and the corresponding most distal subchondral bone surface of the lateral femoral condyle was measured on varus stress radiographs and compared with that on the unaffected contralateral knee. Multivariable logistic regression analyses were conducted to identify predictors of varus instability. RESULTS: Lateral joint space width showed no significant between-group difference. Multivariable logistic regression analysis revealed that the pre-operative hip-knee-ankle angle was positively correlated with the lateral joint space width. The type of fibular untethering procedure was not associated with postoperative varus instability. CONCLUSION: The degree of pre-operative varus malalignment is associated with postoperative varus instability after LCWHTO. Proximal tibiofibular division is not a variable for postoperative varus instability after LCWHTO. LEVEL OF EVIDENCE: Level III, Retrospective comparative study.

Residual varus alignment after total knee arthroplasty increases knee adduction moment without improving patient function: A propensity score-matched cohort study.

BACKGROUND: Targeting residual varus alignment in total knee arthroplasty may be functionally beneficial to preoperative varus patients. METHODS: Bilateral TKA patients were enrolled. According to the postoperative hip-knee-ankle axis, patients were allocated into residual varus (3°â€¯±â€¯1°) alignment group or neutral (0°â€¯±â€¯1°) alignment group. Then, 1:2 propensity score matching was used to match preoperative variables. Finally, matched neutral (n = 45) and varus groups (n = 32) were followed-up for two years and compared. The primary outcome was the Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcomes were range of motion (ROM), Knee Society knee score and function score, spatiotemporal gait parameters, dynamic alignment, knee flexion angle, knee adduction moment (KAM) and internal knee extension moment. RESULTS: At two years after surgery, the mean difference of WOMAC score was 0.3 (95% CI, [-3.1, 3.7]) between the two groups. All secondary outcomes, except KAM and dynamic alignment, showed no significant difference between the two groups. Residual varus alignment group showed increased KAM and maximum KAM was 19% higher (P = 0.006). CONCLUSIONS: Residual varus alignment showed no clinical benefits, and both groups of patients had a functionally identical knee gait biomechanics, except for increased KAM and varus alignment. The authors consider that even in patients with varus alignment, the first principle is still achieving neutral alignment, which is helpful for reducing the KAM. LEVEL OF EVIDENCE: III, retrospective cohort study.

Clinical and Radiological Changes after Microfracture of Knee Chondral Lesions in Middle-Aged Asian Patients.

BACKGROUND: Although microfracture is widely accepted as an effective treatment option for knee chondral lesions, little is known about the deterioration of clinical outcomes and radiological progression in middle-aged patients. Therefore, this study was conducted to evaluate the clinical and radiological changes after microfracture of knee chondral lesions in middle-aged Asian patients. METHODS: A total of 71 patients were included in the study. They were between the ages of 40 and 60 years and underwent arthroscopic microfracture for localized full-thickness cartilage defects of the knee from January 2000 to September 2015. The recovery status of chondral lesions was assessed by using the magnetic resonance observation of cartilage repair tissue (MOCART) score in postoperative magnetic resonance imaging (MRI). Clinical and radiological results were reviewed, and survival rate with conversion to arthroplasty or osteotomy as an end point was evaluated. RESULTS: The mean age of the patients at surgery was 51.3 ± 4.7 years (range, 40 to 60 years), and the mean follow-up period was 7.2 ± 2.6 years (range, 1.0 to 17.4 years). The MOCART scores of 32 patients at mean postoperative 2.1 years showed three cases (9%) of full recovery, two cases (7%) of hyperplastic recovery, 23 cases (70%) with more than 50% filling, and four cases (14%) with less than 50% filling. Clinical scores improved significantly at 1 year after surgery (p < 0.05); however, the scores deteriorated over time after postoperative 1 year, and the mean values reached preoperative levels at postoperative 10 years. Significant radiological progression of arthritis (Kellgren-Lawrence grade) was observed at 5 years after surgery. Four patients underwent total knee arthroplasty during follow-up. CONCLUSIONS: Most patients showed more than 50% of defect filling at 2 years after surgery on MRI. Clinical results of microfracture of knee chondral lesion showed the best improvement at postoperative 1 year but gradually worsened thereafter until postoperative 10 years. Radiological progression of arthritis was observed from 5 years after surgery.

Inhibition of matrix metalloproteinase-9 attenuated neural progenitor cell migration after photothrombotic ischemia.

Recent studies have shown that neuroblasts migrate from the subventricular zone (SVZ) into the injured area after ischemic brain insults. However, it is not well understood which mechanism mediates this ectopic migration and which types of cells migrate into the damaged region from the SVZ. The present study was designed to investigate the characteristics of the migration of nestin-positive neural stem cells toward the region of ischemic injury after focal cortical ischemia. Nestin-eGFP transgenic mice were used to effectively model the migration of SVZ cells. Photothrombotic ischemia was induced by injection of rose bengal (30 mg/kg) and exposure to cold light. Migration of nestin-positive cells was examined using 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) and bromodeoxyuridine (BrdU) labeling. The number of nestin-positive cells was increased significantly in the peri-infarct area at 5 and 7 days after photothrombosis. A subset of nestin-positive cells was co-labeled with DiI or BrdU. Some of the nestin-positive cells co-expressed doublecortin (DCX) and only a few nestin-positive cells co-labeled with anti-epidermal growth factor receptor (EGFr) antibody. However, no nestin-positive cells were immunoreactive for glial fibrillary acidic protein (GFAP). The inhibition of matrix metalloproteinases (MMPs) using the MMP inhibitor, FN-439, decreased nestin-positive cells in the peri-infarct region at 7 days after photothrombosis. Although MMP-9 was not co-expressed in the nestin-positive cells in the peri-infarct cortex, MMP-9 did co-localize with GFAP-positive astrocytes. These results suggest that nestin-positive neural progenitor cells migrate into the peri-infarct cortex after photothrombotic ischemia and that MMP-9 is involved in the migration.