Bone formation by Irisin-Poly vinyl alchol modified bioglass ceramic beads in the rabbit model.

In the aging society, slow bone regeneration poses a serious hindrance to the quality of life. To deal with this problem, in this study, we have combined irisin with the bioglass regular beads to enhance the bone regeneration process. For this purpose, highly porous bioglass was obtained as spherical beads by using sodium alginate. The bioglass was evaluated by various analytical techniques such as SEM, EDS, XRD, and pore size distribution. The results depicted that porous bioglass was prepared correctly and SEM analysis showed a highly porous bioglass was formulated. On this bioglass, irisin was loaded with the assistance of polyvinyl alcohol (PVA) in three concentrations (50 ng/ml, 100 ng/ml, and 150 ng/ml per 1 g of bioglass). SEM analysis showed that pores are covered with PVA. The irisin release profile showed a sustained release over the time period of 7 days. In vitro, biocompatibility evaluation by the MC3T3E1 cells showed that prepared bioglass and irisin loaded bioglass (BGI50, BGI100, and BG150) are highly biocompatible. Alizarin Red staining analysis showed that after 2 weeks BGI50 samples showed highest calcium nodule formation. In vivo in the rabbit femur model was conducted for 1 and 2 months. BGI150 samples showed highest BV/TV ratio of 37.1 after 2 months. The histological data showed new bone formation surrounding the beads and with beads loaded with irisin. Immunohistochemistry using markers OPN, RUNX, COL, and ALP supported the osteogenic properties of the irisin-loaded bioglass beads. The results indicated that irisin-loaded bioglass displayed remarkable bone regeneration.

Incidence and outcomes of intraoperative periprosthetic acetabular fractures during cementless total hip arthroplasty: a prospective three-dimensional computer tomography-based study.

PURPOSE: Unlike periprosthetic femoral fractures, periprosthetic acetabular fractures during total hip arthroplasty (THA) have not been evaluated in detail. We prospectively evaluated the incidence, patterns, risk factors, and clinical outcomes of intraoperative periprosthetic acetabular fractures using pre- and postoperative computer tomography (CT). METHODS: In this prospective single-centre study, we evaluated 234 consecutive patients (250 hips) who underwent THA and three-dimensional CT before and after the surgery. We assessed the incidence, pattern of fractures, outcomes for each fracture pattern, reoperation and revision rates, Harris hip score, and visual analog scale (VAS) for pain. Multivariate regression models were used to identify risk factors for periprosthetic acetabular fractures. RESULTS: In total, 43 periprosthetic acetabular fractures (17.2%) were identified via CT. Fractures occurred most frequently at the superolateral wall. Early cup migration occurred in three hips. None of the patients underwent revision surgery for acetabular loosening. Regression modeling showed that rheumatoid arthritis was a significant predictor of periprosthetic acetabular fractures. CONCLUSIONS: Periprosthetic acetabular fractures are not infrequent during cementless THA and are more common in patients with rheumatoid arthritis.

Exosomes in ascites from patients with human pancreatic cancer enhance remote metastasis partially through endothelial-mesenchymal transition.

BACKGROUND: Despite advances in multidisciplinary treatment, the prognosis of pancreatic cancer remains poor. Since distant metastasis defines prognosis, elucidation of the mechanism of metastasis is important for improving survival. Exosomes are extracellular secretory vesicles and are responsible for intercellular communication. In this study, we investigated whether exosomes secreted by human pancreatic cancer cells are involved in promoting distant metastasis of cancer and the mechanism that underlies the promotion of metastasis. METHODS: Exosomes were isolated from ascites of a patient with pancreatic cancer and a patient with liver cirrhosis as a control. Three days after the administration of exosomes to nude mice, GFP-labeled human pancreatic cancer cells were injected via the spleen or tail vein, and then the liver and lungs were histologically analyzed. To elucidate the mechanism, vascular permeability was estimated using FITC-dextran in place of pancreatic cancer cells in vivo and human umbilical vascular endothelial cells (HUVECs) were used to analyze vascular permeability and the induction of endothelial-mesenchymal transition (EndMT) in vitro. RESULTS: Distant metastasis and vascular permeability were significantly enhanced in mice treated with exosomes from pancreatic cancer patients in comparison to exosomes from a control patient in vivo. In addition, exosomes from pancreatic cancer patients significantly enhanced vascular permeability and the induction of EndMT in HUVECs in vitro. CONCLUSION: Exosomes derived from pancreatic cancer cells form a pre-metastatic niche and promote the extravasation and colonization of pancreatic cancer cells to remote organs, partially through endothelial-mesenchymal transition.

Clozapine Blood Concentration Predicts Corrected QT-Interval Prolongation in Patients With Psychoses.

BACKGROUND: Corrected QT-interval (QTc) prolongation (QTP) is a rare but fatal adverse effect of antipsychotics. Clozapine is the only antipsychotic recommended for treatment of resistant schizophrenia; however, clozapine has been reported to cause QTP. We sought factors predictive of QTP in patients who had antipsychotic polypharmacy involving clozapine. We explored whether the clozapine blood concentration might predict QTP. METHODS: We included 133 patients with schizophrenia spectrum disorder who had antipsychotic polypharmacy involving clozapine. We used the χ2 and nonparametric tests to compare clozapine therapeutic drug monitoring (TDM) values and QTc-prolonged person (QTPP) status. Multivariate regression and mediator models were used to identify risk factors for QTPP status and QTP. RESULTS: In total, 111 patients were prescribed clozapine. The QTPP rates were 31.3% (20) for men and 23.2% (16) for women. Compared with the non-QTPP group, the QTPP group exhibited significantly higher daily dose of all antipsychotics including clozapine, a higher clozapine dose, and elevated clozapine and norclozapine TDM values. Furthermore, such patients were prescribed a greater number of antipsychotics. Multivariate logistic regression revealed that only the clozapine TDM value could be predictive factor for QTPP status (P = 0.018). A clozapine TDM value above the therapeutic range (>600 mg/dL) was associated with a high risk of QTPP status (adjusted odds ratio, 6.5; 95% confidence interval, 1.7-25.2; P = 0.006). The mediator model revealed that the clozapine TDM values completely mediated the association between the clozapine dose and the QTc interval. CONCLUSIONS: The clozapine blood concentration reliably predicts QTP in patients with clozapine use.

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Usefulness of intraoperative C-arm image intensifier in reducing errors of acetabular component during primary total hip arthroplasty: an application of Widmer's method.

BACKGROUND: Acetabular prosthesis positioning in total hip arthroplasty (THA) is crucial in reducing the risk of dislocation. There has been minimal research on the proper way to put the acetabular components into the safe zone intraoperatively. Assessment of version by intraoperative imaging intensifier is very valuable. The value of Widmer's method, using the intraoperative C-arm available to determine cup anteversion was assessed. METHODS: One hundred one hips in 91 patients who underwent primary THA were eligible for inclusion. Utilizing intraoperative C-arm images, measurement was performed using the technique described by Widmer. The values obtained using 3D computed tomography postoperatively, which determined the anteversion of the acetabular component, were regarded as the reference standard. RESULTS: The method of Widmer obtained values similar to those obtained using 3D computed tomography and was considered accurate (n.s.). All 101 hips were positioned in the set target zone. Among the 101 hips, the cup position in nine hips (8.9%) was changed. The dislocation rate in our study was 1.0% with all dislocations occurring in hips placed in the target zone. The mean Harris hip score after THA in 1 year was 94.2 (82-98). CONCLUSIONS: The method of Widmer was accurate using intraoperative imaging intensifier for the measurement of the anteversion of the acetabular component during THA, with reference to the anteversion obtained from the 3D computed tomography. Also, utilizing intraoperative C-arm imaging was very useful because it allowed for correction of the position of the acetabular cup.

Biochanin A induces a brown-fat phenotype via improvement of mitochondrial biogenesis and activation of AMPK signaling in murine C3H10T1/2 mesenchymal stem cells.

In this study, we investigated the effect of Biochanin A (BioA), an O-methylated isoflavone on the brown-fat phenotype formation and on the associated thermogenic program including mitochondrial biogenesis and lipolysis in C3H10T1/2 MSCs. Our data demonstrates that Treatment with BioA in an adipogenic differentiation cocktail induced formation of brown-fat-like adipocytes from C3H10T1/2 MSCs without treatment with a known browning inducer (rosiglitazone or T3) at an early stage of differentiation. The formation of brown-fat-like adipocytes by BioA treatment was evidenced by upregulation of key thermogenic markers: Ucp1, Pgc1α, Prdm16, and Pparγ. BioA also increased the expression of beige (Cd137 and Fgf21) and brown (Elovl3 and Zic1)-specific markers. Additionally, BioA treatment promoted mitochondrial biogenesis, judging by the upregulation of genes; Cox8b, Cidea, Dio2, Sirt1, Opa1, and Fis1. BioA treatment increased the amount of mitochondrial DNA and its encoded proteins: oxidative phosphorylation complexes (I-V); this change was associated with high oxygen consumption by C3H10T1/2 MSCs. A small-interfering-RNA-induced gene knockdown and experiments with dorsomorphin-driven competitive inhibition revealed that BioA exerts the thermogenic action via activation of AMPK signaling. Our study shows the mechanism of BioA-induced promotion of a brown-fat phenotype. Nonetheless, clinical research is necessary to validate BioA as a brown-fat-like signature inducer.

Long-Term Results of Total Hip Arthroplasty in Young Patients With Osteonecrosis After Allogeneic Bone Marrow Transplantation for Hematological Disease: A Multicenter, Propensity-Matched Cohort Study With a Mean 11-Year Follow-Up.

BACKGROUND: The number of young patients with hematological disease requiring total hip arthroplasty (THA) is expected to increase. We aimed to investigate the long-term THA outcomes in patients with osteonecrosis of the femoral head (ONFH) following allogeneic bone marrow transplantation (BMT) for hematological disease. METHODS: All patients who underwent THA for osteonecrosis after BMT from 1997 to 2012 were identified at 2 institutions. Using propensity scores, 75 THAs in 45 patients were matched for age, gender, body mass index, American Society of Anesthesiologists score, and year of surgery with 75 THAs in 58 patients with idiopathic ONFH without a history of hematological disease (1:1 ratio). The mean age at surgery was 36.7 years and 52% were men. Clinical and radiographic evaluations were performed and clinical scores were obtained at last follow-up. Kaplan-Meier analyses were used to compare survivorship. RESULTS: At a mean follow-up of 10.6 ± 3.5 years, clinical, radiographic, and survivorship outcomes, and the Harris hip scores were similar between both groups. The 13-year survivorship for all-cause revision was 93.4% for the BMT group and 95% for the control group (P = .928). No significant differences were observed between groups in the rates of reoperation (4% vs 5.3%, P = 1.000), 90-day readmission (all 5.3%), or overall mortality (4.4% vs 1.7%, P = .681). No hips had periprosthetic joint infection or septic loosening in either group. Osteolysis occurred in none of the BMT patients and in 2 hips (2.7%) of the control patients (P = .497). CONCLUSION: This large cohort multicenter survey at 11-year follow-up shows that contemporary cementless THA in young hematological disease patients after allogeneic BMT is not associated with a higher risk for surgical complications, revision, reoperation, readmission, and mortality compared to a matched cohort of idiopathic ONFH.

Electroconvulsive Seizures Induce Autophagy by Activating the AMPK Signaling Pathway in the Rat Frontal Cortex.

BACKGROUND: It is uncertain how electroconvulsive therapy-induced generalized seizures exert their potent therapeutic effects on various neuropsychiatric disorders. Adenosine monophosphate-activated protein kinase (AMPK) plays a major role in maintaining metabolic homeostasis and activates autophagic processes via unc-51-like kinase (ULK1). Evidence supports the involvement of autophagy system in the action mechanisms of antidepressants and antipsychotics. The effect of electroconvulsive therapy on autophagy-related signaling requires further clarification. METHODS: The effect of electroconvulsive seizure on autophagy and its association with the AMPK signaling pathway were investigated in the rat frontal cortex. Electroconvulsive seizure was provided once per day for 10 days (E10X), and compound C or 3-methyadenine was administered through an intracerebroventricular cannula. Molecular changes were analyzed with immunoblot, immunohistochemistry, and transmission electron microscopy analyses. RESULTS: E10X increased p-Thr172-AMPKα immunoreactivity in rat frontal cortex neurons. E10X increased phosphorylation of upstream effectors of AMPK, such as LKB1, CaMKK, and TAK1, and of its substrates, ACC, HMGR, and GABABR2. E10X also increased p-Ser317-ULK1 immunoreactivity. At the same time, LC3-II and ATG5-ATG12 conjugate immunoreactivity increased, indicating activation of autophagy. An intracerebroventricular injection of the AMPK inhibitor compound C attenuated the electroconvulsive seizure-induced increase in ULK1 phosphorylation as well as the protein levels of LC3-II and Atg5-Atg12 conjugate. Transmission electron microscopy clearly showed an increased number of autophagosomes in the rat frontal cortex after E10X, which was reduced by intracerebroventricular treatment with the autophagy inhibitor 3-methyadenine and compound C. CONCLUSIONS: Repeated electroconvulsive seizure treatments activated in vivo autophagy in the rat frontal cortex through the AMPK signaling pathway.

Nutritional value and in situ degradability of oak wood roughage and its feeding effects on growth performance and behavior of Hanwoo steers during the early fattening period.

OBJECTIVE: This study was conducted to evaluate changes in nutritional value and in situ dry matter (DM) degradability of oak and pine wood before and after steam-digestion process (60 min/160°C/6 atm) and feeding effect of the oak roughage on performance and behavior of Hanwoo steers. METHODS: Chemical composition and tannin concentration were analyzed for oak and pine trees before and after the pretreatment. In situ DM and effective degradability of these samples were assessed using a nylon bag method. In vivo trial was performed to estimate animal performance and behavior, using steers fed total mixed ration (TMR) diets containing 0% (control), 25% (OR-25), and 50% (OR-50) of the oak roughage. Eighteen steers were allocated into nine pens (2 steers/pen, 3 pens/treatment) for 52 days according to body weight (BW) and age. RESULTS: By the steam-digestion treatment, the neutral detergent-insoluble fiber was decreased from 86.5% to 71.5% for oak and from 92.4% to 80.5% for pine, thereby increasing non-fiber carbohydrate. In situ DM degradability of treated oak reached 38% at 72 h, whereas that of untreated oak was only 11.9%. The 0 h degradability of the treated pine increased from 5.9% to 12.1%, but the degradability was unchanged thereafter. Animal performance including BW, average daily gain, DM intake, and feed conversion ratio was not different among control and oak treatments. No differences were detected in animal behavior such as lying, standing, rumination, drinking, and eating, except walking. Walking was higher in control than oak treatments with numerically higher eating and lower lying times, probably due to bulkier characteristics of rice straw in the diet. CONCLUSION: This study demonstrates that the oak roughage can be substituted for 50% of total forage or 100% of rice straw in TMR diets at early fattening stage of Hanwoo steers.

Fourth-generation ceramic-on-ceramic THA results in improvements in midterm outcomes compared to third-generation THA but does not resolve noise problems: a cohort study of a single-hip system.

BACKGROUND: Using data from the Korean Hip Registry, we aimed to investigate mid-term clinical and radiographic outcomes, including the prevalence of periprosthetic joint infection (PJI), osteolysis, and component loosening or dislocation, and to analyze the incidence of bearing-related complications following modern ceramic-on-ceramic (COC) total hip arthroplasty (THA) using a single cementless hip system. METHODS: Four hundred eighty-two patients (602 hips) who underwent Forte or Delta COC THAs with a single hip system and had a minimum 5-year follow-up were identified. The sample included 243 (50.4%) women and 239 (49.6%) men with a mean age of 50.6 years (range: 18-83 years). The Forte group comprised 310 hips, and the Delta group comprised 292 hips. The mean follow-up was 6.1 years (range: 5-10.2 years). RESULTS: Cup orientation did not differ between groups. No hip had a PJI or osteolysis in either group. All acetabular components and all but two femoral components (in the Delta group) were well fixed. Dislocations occurred in six (1.9%) hips in the Forte group and one (0.3%) hip in the Delta group (p = 0.124). A total of nine (1.5%) revisions were performed. The 5-year survival rates for all-cause revisions were 98.4 and 98.6%, respectively. One (0.3%) ceramic head fracture occurred in the Forte group. Sixteen (5%) hips exhibited clicking and 6 (2%) hips had squeaking in the Forte group; 16 (6%) hips exhibited clicking and 5 (2%) hips had squeaking in the Delta group. Multiple regression analysis revealed that noise generation was unassociated with any factor. CONCLUSIONS: From the Korean Hip Registry data, THA with modern ceramic bearings showed encouraging results, with lower risks of PJI, osteolysis, and component loosening. In particular, Delta COC THA resulted in no PJI or ceramic fracture and had a reduced dislocation risk. However, associated noise remains a concern.

Distinctive effects of licarin A on lipolysis mediated by PKA and on formation of brown adipocytes from C3H10T1/2 mesenchymal stem cells.

Obesity increases with the positive energy imbalance and correlates with increased risks for metabolic diseases. Promotion of white adipose tissue beiging has received considerable attention due to possible usefulness for preventing obesity and the comorbidities. Licarin A (LA) is a compound derived from Mexican medicinal plant Aristolochia taliscana. Here, we report that LA stimulates the development of brown-like and beige-like adipocytes from C3H10T1/2 mesenchymal stem cells with phenotypic shifts to formation of smaller lipid droplets. LA also markedly induced the expression of proteins characteristic of brown-like adipocytes in C3H10T1/2 mesenchymal stem cells. LA induced uncoupling protein 1 (Ucp1) and expression of other thermogenic genes in C3H10T1/2 mesenchymal stem cells via a mechanism involving protein kinase A (PKA). LA treatment also inhibited expression of white-adipocyte-specific genes. Moreover, LA treatment promoted lipolysis via PKA mediated pathway. Our findings inaugurate a new role of LA as an inducer of brown-like adipocytes formation with lipolytic properties, which in future might be studied in vivo as a potential anti-obesity agent.

Optical fiber Fabry-Pérot micro-displacement sensor for MEMS in-plane motion stage.

Fabry-Pérot interferometer sensors have been widely used in Micro-Electro-Mechanical-Systems (MEMS) due to high displacement accuracy and immunity to electromagnetic noises, but they are still limited by micro scale measurement range. In this paper, a Fabry-Pérot interferometer in-plane displacement sensor is proposed for measuring the displacement of MEMS devices utilizing a polished optical fiber and a modulated laser source. The polished optical fiber and a sidewall of a MEMS device form an optical cavity for the proposed sensor. The sinusoidal phase modulation with extreme point search algorithm enables the proposed sensor to measure displacements larger than the wavelengths of the laser light in real time. The experimental results show that the proposed displacement sensor has a capability to measure displacements larger than 3 µm and it shows the measurement accuracy less than 35 nm. The proposed displacement sensor is then embedded on a single degree-of-freedom MEMS motion stage and tested to monitor its displacement in real time.

Epithelial Cholesterol Deficiency Attenuates Human Antigen R-linked Pro-inflammatory Stimulation via an SREBP2-linked Circuit.

Patients with chronic intestinal ulcerative diseases, such as inflammatory bowel disease, tend to exhibit abnormal lipid profiles, which may affect the gut epithelial integrity. We hypothesized that epithelial cholesterol depletion may trigger inflammation-checking machinery via cholesterol sentinel signaling molecules whose disruption in patients may aggravate inflammation and disease progression. In the present study, sterol regulatory element-binding protein 2 (SREBP2) as the cholesterol sentinel was assessed for its involvement in the epithelial inflammatory responses in cholesterol-depleted enterocytes. Patients and experimental animals with intestinal ulcerative injuries showed suppression in epithelial SREBP2. Moreover, SREBP2-deficient enterocytes showed enhanced pro-inflammatory signals in response to inflammatory insults, indicating regulatory roles of SREBP2 in gut epithelial inflammation. However, epithelial cholesterol depletion transiently induced pro-inflammatory chemokine expression regardless of the well known pro-inflammatory nuclear factor-κB signals. In contrast, cholesterol depletion also exerts regulatory actions to maintain epithelial homeostasis against excessive inflammation via SREBP2-associated signals in a negative feedback loop. Mechanistically, SREBP2 and its induced target EGR-1 were positively involved in induction of peroxisome proliferator-activated receptor γ (PPARγ), a representative anti-inflammatory transcription factor. As a crucial target of the SREBP2-EGR-1-PPARγ-associated signaling pathways, the mRNA stabilizer, human antigen R (HuR) was retained in nuclei, leading to reduced stability of pro-inflammatory chemokine transcripts. This mechanistic investigation provides clinical insights into protective roles of the epithelial cholesterol deficiency against excessive inflammatory responses via the SREBP2-HuR circuit, although the deficiency triggers transient pro-inflammatory signals.

Cryptotanshinone promotes commitment to the brown adipocyte lineage and mitochondrial biogenesis in C3H10T1/2 mesenchymal stem cells via AMPK and p38-MAPK signaling.

Although white adipose tissue (WAT) stores triglycerides and contributes to obesity, brown adipose tissue (BAT) dissipates energy as heat. Therefore, browning of WAT is regarded as an attractive way to counteract obesity. Our previous studies have revealed that treatment with cryptotanshinone (CT) during adipogenesis of 3T3-L1 cells inhibits their differentiation. Here, we found that pretreatment of C3H10T1/2 mesenchymal stem cells with CT before exposure to adipogenic hormonal stimuli promotes the commitment of these mesenchymal stem cells to the adipocyte lineage as confirmed by increased triglyceride accumulation. Furthermore, CT treatment induced the expression of early B-cell factor 2 (Ebf2) and bone morphogenetic protein 7 (Bmp7), which are known to drive differentiation of C3H10T1/2 mesenchymal stem cells toward preadipocytes and to the commitment to brown adipocytes. Consequently, CT treatment yielded brown-adipocyte-like features as evidenced by elevated expression of brown-fat signature genes including Ucp1, Prdm16, Pgc-1α, Cidea, Zic1, and beige-cell-specific genes such as CD137, Hspb7, Cox2, and Tmem26. Additionally, CT treatment induced mitochondrial biogenesis through upregulation of Sirt1, Tfam, Nrf1, and Cox7a and increased mitochondrial mass and DNA content. Our data also showed that cotreatment with CT and BMP4 was more effective at activating brown-adipocyte-specific genes. Mechanistic experiments revealed that treatment with CT activated AMPKα and p38-MAPK via their phosphorylation: the two major signaling pathways regulating energy metabolism. Thus, these findings suggest that CT is a candidate therapeutic agent against obesity working via activation of browning and mitochondrial biogenesis in C3H10T1/2 mesenchymal stem cells.

Surgical accuracy, function, and quality of life of simultaneous versus staged bilateral Total hip Arthroplasty in patients with Osteonecrosis of the femoral head.

BACKGROUND: The optimal surgical option for patients requiring bilateral hip replacement remains controversial. The purpose of this study was to compare surgical accuracy; functional outcome and health-related quality of life; and prosthetic-related complications and revision surgery of a simultaneous bilateral total hip arthroplasty (THA) with those of a staged bilateral THA with an interval between procedures <12 months. METHODS: A total of 123 unselected consecutive patients (mean age, 43.3 years) who underwent bilateral THAs for osteonecrosis of the femoral head (ONFH) with a minimum follow-up of two years (mean, 60.2 months) were studied retrospectively; 63 simultaneous procedures served as a test group and 60 staged procedures served as a control group. RESULTS: The mean postoperative leg-length discrepancy (LLD) and the percentage of patients who had an LLD >3 mm were significantly lower in the simultaneous group (P < 0.001 and P = 0.001, respectively). A higher number of cups within the safe zones, a higher correction rate, and a lower failure rate for the cup placement in the second-operated hip were also identified in the simultaneous group. The mean Harris hip score, EuroQol-5D index, and EuroQol-visual analogue scale score were all better in the simultaneous group at the latest follow-up (P < 0.001, in all comparisons). We found that the simultaneous procedure was associated with a lower incidence of postoperative prosthetic-related complications and revision surgery. CONCLUSIONS: We suggest that bilateral ONFH could be treated with a simultaneous THA rather than a staged THA to achieve a better surgical outcome.

Wnt/ß-catenin signaling plays a distinct role in methyl gallate-mediated inhibition of adipogenesis.

The canonical Wnt/ß-catenin signaling not only features in many developmental processes but also recently emerged as an attractive negative regulator of differentiation of preadipocytes into adipocytes. Here, we show that ß-catenin signaling plays a distinct role in methyl gallate (MG)-mediated inhibition of 3T3-L1 adipocytes differentiation. We found that the expression of ß-catenin decreased after adipogenic hormonal induction, whereas incubation of the differentiating cells with a physiological concentration of MG during adipogenic hormonal induction significantly prevented ß-catenin degradation by activating Wnt signaling components such as Wnt1, Wnt10b, Fzd1, Fzd2, Lrp5, Lrp6, Dvl1, and Dvl2. Mechanistic experiments revealed that MG treatment during early adipocytic differentiation specifically inhibited degradation of ß-catenin caused by phosphorylation at serine-33. In addition, MG treatment led to phosphorylation of GSK3ß, which is one of ß-catenin-degrading enzymes. Consequently, MG treatment facilitated translocation of the stabilized ß-catenin from the cytoplasm to nucleus, and activates its target genes cyclin D1 and c-Myc. Furthermore, MG-induced stabilization of ß-catenin suppresses PPARγ expression. Moreover, pharmacological activation or inhibition of ß-catenin signaling during adipocytes differentiation decreased and increased, respectively, the level of the key adipogenic marker, PPARγ, and of its downstream targets, aP2 and adiponectin while MG treatment effectively reversed their expression level. Collectively, our data suggest that MG is a novel pharmacological stimulator of canonical Wnt/ß-catenin signaling, and therefore represents a promising therapeutic agent in obesity.

Comparative Analysis of Radiographic Hip Joint Geometry Using Measurement Tools on Picture Archiving and Communication System: A Prospective Study of 100 Pelvic Radiographs of Koreans.

BACKGROUND: A contralateral normal hip joint has been often used as a reference standard in preoperative planning and intraoperative assessment of hip arthroplasty, with the assumption that bilateral hip joint geometries have no significant differences. However, one previous study using analog measurements on hardcopy films reported significant bilateral variation in hip joint geometry. We therefore investigated the level of agreement between the right and left hips for each measurement and determined index values and the range of normal bilateral variations. METHODS: We assessed 100 standard anteroposterior radiographs of the pelvis in this study. Two independent observers measured the actual value of femoral head diameter, location of the femoral head center, acetabular offset, femoral offset, hip offset, greater trochanteric height, neck-shaft angle, medullary canal diameter, and proximal femoral diameter. Intraclass correlation coefficients (ICCs) and values of mean difference were calculated for each measurement. RESULTS: The results demonstrated perfect agreement (ICC >0.8) between the right and left hips for most parameters and substantial agreement for greater trochanteric height (ICC = 0.735) and femoral offset (ICC = 0.773). The mean difference and standard deviation in the measurement between the right and left hips for the location of the femoral head center and the acetabular offset were 0.60 ± 0.48 mm and 0.42 ± 0.30 mm, respectively. CONCLUSION: Hip joint geometry is not influenced by side. In hip arthroplasty, a contralateral normal hip can be reliably used as a guide for preoperative planning using measurement tools on a picture archiving and communication system.

Activating transcription factor 3-mediated chemo-intervention with cancer chemokines in a noncanonical pathway under endoplasmic reticulum stress.

The cell-protective features of the endoplasmic reticulum (ER) stress response are chronically activated in vigorously growing malignant tumor cells, which provide cellular growth advantages over the adverse microenvironment including chemotherapy. As an intervention with ER stress responses in the intestinal cancer cells, preventive exposure to flavone apigenin potentiated superinduction of a regulatory transcription factor, activating transcription factor 3 (ATF3), which is also known to be an integral player coordinating ER stress response-related gene expression. ATF3 superinduction was due to increased turnover of ATF3 transcript via stabilization with HuR protein in the cancer cells under ER stress. Moreover, enhanced ATF3 caused inhibitory action against ER stress-induced cancer chemokines that are potent mediators determining the survival and metastatic potential of epithelial cancer cells. Although enhanced ATF3 was a negative regulator of the well known proinflammatory transcription factor NF-κB, blocking of NF-κB signaling did not affect ER stress-induced chemokine expression. Instead, immediately expressed transcription factor early growth response protein 1 (EGR-1) was positively involved in cancer chemokine induction by ER stressors. ER stress-induced EGR-1 and subsequent chemokine production were repressed by ATF3. Mechanistically, ATF3 directly interacted with and recruited HDAC1 protein, which led to epigenetic suppression of EGR-1 expression and subsequent chemokine production. Conclusively, superinduced ATF3 attenuated ER stress-induced cancer chemokine expression by epigenetically interfering with induction of EGR-1, a transcriptional modulator crucial to cancer chemokine production. Thus, these results suggest a potent therapeutic intervention of ER stress response-related cancer-favoring events by ATF3.