Impaired Reorganization of Centrosome Structure Underlies Human Infantile Dilated Cardiomyopathy.

BACKGROUND: During cardiomyocyte maturation, the centrosome, which functions as a microtubule organizing center in cardiomyocytes, undergoes dramatic structural reorganization where its components reorganize from being localized at the centriole to the nuclear envelope. This developmentally programmed process, referred to as centrosome reduction, has been previously associated with cell cycle exit. However, understanding of how this process influences cardiomyocyte cell biology, and whether its disruption results in human cardiac disease, remains unknown. We studied this phenomenon in an infant with a rare case of infantile dilated cardiomyopathy (iDCM) who presented with left ventricular ejection fraction of 18% and disrupted sarcomere and mitochondria structure. METHODS: We performed an analysis beginning with an infant who presented with a rare case of iDCM. We derived induced pluripotent stem cells from the patient to model iDCM in vitro. We performed whole exome sequencing on the patient and his parents for causal gene analysis. CRISPR/Cas9-mediated gene knockout and correction in vitro were used to confirm whole exome sequencing results. Zebrafish and Drosophila models were used for in vivo validation of the causal gene. Matrigel mattress technology and single-cell RNA sequencing were used to characterize iDCM cardiomyocytes further. RESULTS: Whole exome sequencing and CRISPR/Cas9 gene knockout/correction identified RTTN, the gene encoding the centrosomal protein RTTN (rotatin), as the causal gene underlying the patient's condition, representing the first time a centrosome defect has been implicated in a nonsyndromic dilated cardiomyopathy. Genetic knockdowns in zebrafish and Drosophila confirmed an evolutionarily conserved requirement of RTTN for cardiac structure and function. Single-cell RNA sequencing of iDCM cardiomyocytes showed impaired maturation of iDCM cardiomyocytes, which underlie the observed cardiomyocyte structural and functional deficits. We also observed persistent localization of the centrosome at the centriole, contrasting with expected programmed perinuclear reorganization, which led to subsequent global microtubule network defects. In addition, we identified a small molecule that restored centrosome reorganization and improved the structure and contractility of iDCM cardiomyocytes. CONCLUSIONS: This study is the first to demonstrate a case of human disease caused by a defect in centrosome reduction. We also uncovered a novel role for RTTN in perinatal cardiac development and identified a potential therapeutic strategy for centrosome-related iDCM. Future study aimed at identifying variants in centrosome components may uncover additional contributors to human cardiac disease.

Should the diameter of the proximal femoral nail be large enough to fill the canal in the treatment of intertrochanteric femoral fracture in patients over fifty?

PURPOSE: Many studies have been conducted to evaluate the effects of nail shape, design, or length on the treatment of intertrochanteric fractures. However, the clinical implications of the nail diameter remain unclear. METHODS: This study was conducted with 191 patients aged ≥ 50 years with unilateral intertrochanteric fractures treated with the same type of short cephalomedullary nail and followed for at least one year. We recorded the reduction type, tip-apex distance, cortical contact of the nail, and nail/canal diameter ratio (NCR) just distal to the locking screw. The effects of nail diameter on the clinical results were evaluated. RESULTS: The average NCR was 68.7. The average union time was 4.78 months. Delayed union or nonunion was seen in 17 patients. Eight patients underwent additional surgery. The mean change in the modified Koval activity score was -0.84. The NCR did not significantly affect the clinical results. Comparisons of cases with NCRs above and below the average and the average - 1 standard deviation revealed no significant difference. The clinical outcome was not related to any variable associated with the nail diameter. CONCLUSION: With this specific proximal femoral nail, a small diameter relative to that of the femoral canal had no adverse effect on the union of osteoporotic intertrochanteric fractures, even in patients with unstable fractures and those who had unsatisfactory reductions.

Programmable MZI based on a silicon photonic MEMS-tunable delay line.

We report on a scalable and programmable integrated Mach-Zehnder interferometer (MZI) with a tunable free spectral range (FSR) and extinction ratio (ER). For the tunable path of the MZI, we designed and utilized a tunable delay line having high flexibility based on silicon photonic microelectromechanical systems (MEMS). By utilizing MEMS, the length of the delay line can be geometrically modified. In this way, there is no optical loss penalty other than the waveguide propagation loss as the number of tunable steps increases. Therefore, our device is more scalable in terms of optical loss than the previous approaches based on cascaded MZIs. In addition, the tuning energy required to reconfigure the length is only 8.46 pJ.

Anticancer activity and metabolic profile alterations by ortho-topolin riboside in in vitro and in vivo models of non-small cell lung cancer.

Lung cancer has the highest incidence and mortality rates among all types of cancer worldwide, and 80%-85% of patients with lung cancer are diagnosed with non-small cell lung cancer (NSCLC), which has 5-year survival rate of only 5% at advanced stages. Development of new therapeutic agents and strategies is required to enhance the treatment efficiency in patients with NSCLC. Metabolic alterations and anticancer effects of plant hormones and their derivatives have not been investigated in NSCLC in vitro and in vivo. The present study investigated the cytotoxic effects of 11 plant hormones and their derivatives against NSCLC cell lines; ortho-topolin riboside (oTR) showed the highest cytotoxicity among all tested compounds against NSCLC cells. Alteration of metabolites and lipids was investigated using gas chromatography-mass spectrometry and nano electrospray ionization-mass spectrometry in oTR-treated NSCLC cells and a xenograft mouse model. oTR reduced amino acid and pyrimidine synthesis in NSCLC cells and xenograft tumors. Moreover, oTR reduced glycolytic function and decreased mitochondrial respiration function by inhibiting glutamine and fatty acid oxidation. Increased levels of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine species suggested that oTR might act as a fatty acid oxidation inhibitor. In addition, the increased level of phosphatidylserine species implied that phosphatidylserine-mediated apoptosis occurred in oTR-treated NSCLC cells and xenograft tumor. The antiproliferative and apoptotic effects of oTR were mediated by the reduced p-ERK and p-AKT levels and increased cleaved Caspase-3 levels, respectively. This is the first study to investigate the metabolic alterations and anticancer activity of oTR in in vitro and in vivo models of NSCLC. Our results provide basis for the development of oTR-based therapeutic agent for patients with NSCLC.

A System to Track Stent Location in the Human Body by Fusing Magnetometer and Accelerometer Measurements.

This paper will introduce a simple locating system to track a stent when it is deployed into a human artery. The stent is proposed to achieve hemostasis for bleeding soldiers on the battlefield, where common surgical imaging equipment such as fluoroscopy systems are not available. In the application of interest, the stent must be guided to the right location to avoid serious complications. The most important features are its relative accuracy and the ease by which it may be quickly set up and used in a trauma situation. The locating approach in this paper utilizes a magnet outside the human body as the reference and a magnetometer that will be deployed inside the artery with the stent. The sensor can detect its location in a coordinate system centered with the reference magnet. In practice, the main challenge is that the locating accuracy will be deteriorated by external magnetic interference, rotation of the sensor, and random noise. These causes of error are addressed in the paper to improve the locating accuracy and repeatability under various conditions. Finally, the system's locating performance will be validated in benchtop experiments, where the effects of the disturbance-eliminating procedures will be addressed.

Weighing the Risk Profile of Cervical Spine MRI in Evaluating Pediatric Cervical Spine Injuries.

OBJECTIVE: Screening for cervical spine injury after blunt trauma is common, but there remains varied practice patterns and clinical uncertainty regarding adequate radiographic evaluation. An oft-cited downside of MRI is the added risk compared to CT in the pediatric population; however, these specific risks have not yet been reported. This study examines the risks of cervical spine MRI in pediatric trauma patients in the context of what value MRI adds. METHODS: This was a retrospective observational study of all pediatric blunt trauma patients who were evaluated with a cervical spine MRI over a 4-year period at a level 1 pediatric trauma center. Clinical and radiographic data were abstracted, as well as anesthesia requirements and MRI-related major adverse events. CT and MRI results were compared for their ability to detect clinically unstable injuries - those requiring halo or surgery. RESULTS: There was one major adverse event related to MRI among the 269 patients who underwent cervical spine MRI - a rate of 0.37%. While 55% of children had an airway and anesthesia for MRI, only 57% of these airways were newly placed for the MRI. None of the 85 patients newly intubated for MRI developed aspiration pneumonitis or ventilator-associated pneumonia, and no patients had a significant neurologic event while at MRI. Another area of the body was imaged concurrently with the cervical spine MRI in 64% of patients and 83% of MRIs were performed within 48 h. CT and MRI were both 100% sensitive for injuries requiring halo or operative intervention. Eighty-three patients had an MRI performed after a negative CT, 11% (9/83) of these patients had a clinically stable injury detected on subsequent MRI, and none of these patients presented for delayed cervical spine complications. CONCLUSIONS: Overall, the safety profile of MRI in this setting is excellent and less than one-third of patients need new airway and anesthesia solely for MRI. In this clinical scenario, MRIs can happen relatively quickly and many patients require another body part to be imaged concurrently anyway. MRI and CT were both 100% sensitive for clinically unstable injuries. In the appropriate patients, MRI remains a safe and radiation-free alternative to CT.

Favorable mid-to-long-term results of impaction bone grafting using a fresh frozen allograft bone with cemented stem for the treatment of Paprosky IV femoral bone defects.

BACKGROUND: Femoral revision surgery in patients with substantial bone loss is challenging. Impaction bone grafting using a cemented stem can be a good solution for reconstruction of the femur with poor bone stock and extensive bone loss. This study aimed to evaluate the mid-to-long-term clinical and radiographic results of impaction bone grafting using a cemented stem for Paprosky IV femoral bone defects. METHODS: Thirteen patients (13 hips) who underwent revision total hip arthroplasty with impaction bone grafting using a cemented stem and were followed up for at least 5 years were enrolled in this study. In all patients, a sufficient amount of fresh frozen bone of good quality was used. When cortical segmental defects were present, peripheral reinforcement with metal mesh and strut allograft was performed. The average follow-up duration was 11.1 (range, 5.3-15.1) years. The clinical and radiographic outcomes were reviewed at the final follow-up. RESULTS: The average Harris hip score was 82.5 (range, 79-94), and the average University of California, Los Angeles activity score was 5.6 (range, 4-8) at the final follow-up. Radiographic assessment revealed an average femoral component subsidence level of 0.67 (range, 0.05-2.81) mm. There were no complications, except one case (7.6%) of periprosthetic fracture. CONCLUSIONS: Impaction bone grafting using a cemented stem yielded excellent mid-to-long-term outcomes. It is a reliable technique for Paprosky IV femoral bone defects, and even when severe femoral cortical bone defects are present, long-term stability can be obtained using a metal mesh and/or strut allograft.

Collateral and permeability imaging derived from dynamic contrast material-enhanced MR angiography in prediction of PH 2 hemorrhagic transformation after acute ischemic stroke: a pilot study.

PURPOSE: To evaluate the role of collateral and permeability imaging derived from dynamic contrast material-enhanced magnetic resonance angiography to predict PH 2 hemorrhagic transformation in acute ischemic stroke. METHODS: The secondary analysis of a published data from participants with acute ischemic stroke. The multiphase collateral map and permeability imaging were generated by using dynamic signals from dynamic contrast material-enhanced magnetic resonance angiography obtained at admission. To identify independent predictors of PH 2 hemorrhagic transformation, age, sex, risk factors, baseline National Institutes of Health Stoke Scale (NIHSS) score, baseline DWI lesion volume, collateral-perfusion status, mode of treatment, and successful early reperfusion were evaluated with multiple logistic regression analyses and the significance of permeability imaging in prediction of PH 2 hemorrhagic transformation was evaluated by subgroup analysis. RESULTS: In 115 participants, including 70 males (mean (SD) age, 69 (12) years), PH 2 hemorrhagic transformation occurred in 6 participants with very poor collateral-perfusion status (MAC 0). MAC 0 (OR, 0.06; 95% CI, 0.01, 0.74; P = .03) was independently associated with PH 2 hemorrhagic transformation. In 22 participants with MAC 0, the permeable signal on Kep permeability imaging was the only significant characteristic associated with PH 2 hemorrhagic transformation (P = .009). The specificity of Kep permeability imaging was 93.8% (95% confidence interval: 69.8, 99.8) in predicting PH 2 hemorrhagic transformation. CONCLUSION: Individual-based prediction of PH 2 hemorrhagic transformation in patients with acute ischemic stroke may be possible with multiphase collateral map and permeability imaging derived from dynamic contrast material-enhanced magnetic resonance angiography.

Combined treatment with auranofin and trametinib induces synergistic apoptosis in breast cancer cells.

Auranofin is a gold complex used as an anti-rheumatic agent and may act as a potent anticancer drug against breast tumors. Trametinib is a specific mitogen-activated protein kinase inhibitor, approved for the treatment of metastatic melanoma. The aim of this study was to examine the synergistic effects of auranofin and trametinib on apoptosis in MCF-7 human breast cancer cells. The combination treatment inhibited cancer cell proliferation and induced cell cycle arrest at the sub-G1 phase and apoptosis via poly (ADP-ribose) polymerase cleavage and caspase-3/7 activation. It is noteworthy that this treatment significantly increased p38 mitogen-activated protein kinase (MAPK) phosphorylation to induce mitochondrial stress, subsequently promoting cancer cell apoptosis through release of apoptosis-inducing factor. Further data demonstrated that combined treatment significantly induced increase in nuclear translocation of AIF. These results indicated that activation of the p38 MAPK signaling pathway and mitochondrial apoptosis may contribute to the synergistic consequences in MCF-7 cells. Collectively, our data demonstrated that combined treatment with auranofin and trametinib exhibited synergistic breast cancer cell death and this combination might be utilized as a novel therapeutic strategy for breast cancer.

Surgical correction for adult spinal deformity increases acetabular lateral coverage of femoral heads.

BACKGROUND: Studies explaining the relationship between hip and spine reported that spinal corrective surgery affected acetabular orientation and changes in pelvic tilt were capable of influencing radiographic measures of acetabular coverage. This study aimed to assess the change in coronal parameters for acetabular coverage as a result of adult spinal deformity (ASD) correction and to analyze the relationship between the postoperative changes in sagittal spinopelvic parameters and coronal acetabular coverage parameters. METHODS: Fifty-two consecutive patients who had undergone multilevel spinal surgical correction were enrolled and evaluated. Coronal acetabular coverage parameters included Tönnis angle (TA), lateral center edge angle (LCEA), and the angle of Sharp (SA). All radiographic parameters were evaluated at the preoperative and the postoperative 1 year. Paired t test was used to determine whether there were significant changes between the time points. Bivariate correlation and linear regression analysis were used to assess the relationship between the postoperative changes of spinal alignment and acetabular orientation. RESULTS: The surgical correction resulted in significant decrease of TA, increase of LCEA and SA, respectively (p < 0.001). The changes in pelvic tilt (PT) demonstrated weak correlation on TA (ß = 0.117, p < 0.001 for right; ß = 0.111, p < 0.001 for left). CONCLUSIONS: Although the surgical correction of ASD significantly changed PT resulting in increased acetabular lateral coverage parameters, the correlation between the changes of PT following sagittal correction of ASD and acetabular coverage parameters was low. TRIAL REGISTRATION: This study was retrospectively registered with approval by the institutional review board (IRB) of our institution (approval number: KHNMC-2020-10-010).

Real-time visualization of titin dynamics reveals extensive reversible photobleaching in human induced pluripotent stem cell-derived cardiomyocytes.

Fluorescence recovery after photobleaching (FRAP) has been useful in delineating cardiac myofilament biology, and innovations in fluorophore chemistry have expanded the array of microscopic assays used. However, one assumption in FRAP is the irreversible photobleaching of fluorescent proteins after laser excitation. Here we demonstrate reversible photobleaching regarding the photoconvertible fluorescent protein mEos3.2. We used CRISPR/Cas9 genome editing in human induced pluripotent stem cells (hiPSCs) to knock-in mEos3.2 into the COOH terminus of titin to visualize sarcomeric titin incorporation and turnover. Upon cardiac induction, the titin-mEos3.2 fusion protein is expressed and integrated in the sarcomeres of hiPSC-derived cardiomyocytes (CMs). STORM imaging shows M-band clustered regions of bound titin-mEos3.2 with few soluble titin-mEos3.2 molecules. FRAP revealed a baseline titin-mEos3.2 fluorescence recovery of 68% and half-life of ~1.2 h, suggesting a rapid exchange of sarcomeric titin with soluble titin. However, paraformaldehyde-fixed and permeabilized titin-mEos3.2 hiPSC-CMs surprisingly revealed a 55% fluorescence recovery. Whole cell FRAP analysis in paraformaldehyde-fixed, cycloheximide-treated, and untreated titin-mEos3.2 hiPSC-CMs displayed no significant differences in fluorescence recovery. FRAP in fixed HEK 293T expressing cytosolic mEos3.2 demonstrates a 58% fluorescence recovery. These data suggest that titin-mEos3.2 is subject to reversible photobleaching following FRAP. Using a mouse titin-eGFP model, we demonstrate that no reversible photobleaching occurs. Our results reveal that reversible photobleaching accounts for the majority of titin recovery in the titin-mEos3.2 hiPSC-CM model and should warrant as a caution in the extrapolation of reliable FRAP data from specific fluorescent proteins in long-term cell imaging.

Multiphase MR Angiography Collateral Map: Functional Outcome after Acute Anterior Circulation Ischemic Stroke.

Background Collateral circulation determines tissue fate and affects treatment result in acute ischemic stroke. A precise method for collateral estimation in an optimal imaging protocol is necessary to make an appropriate treatment decision for acute ischemic stroke. Purpose To verify the value of multiphase collateral imaging data sets (MR angiography collateral map) derived from dynamic contrast material-enhanced MR angiography for predicting functional outcomes after acute ischemic stroke. Materials and Methods This secondary analysis of an ongoing prospective observational study included data from participants with acute ischemic stroke due to occlusion or stenosis of the unilateral internal carotid artery and/or M1 segment of the middle cerebral artery who were evaluated within 8 hours of symptom onset. Data were obtained from March 2016 through August 2018. The collateral grading based on the MR angiography collateral map was estimated by using six-scale MR acute ischemic stroke collateral (MAC) scores. To identify independent predictors of favorable functional outcomes, age, sex, risk factors, baseline National Institutes of Health Stroke Scale (NIHSS) score, baseline diffusion-weighted imaging (DWI) lesion volume, site of steno-occlusion, collateral grade, mode of treatment, and early reperfusion were evaluated with multiple logistic regression analyses. Results One hundred fifty-four participants (mean age ± standard deviation, 69 years ± 13; 99 men) were evaluated. Younger age (odds ratio [OR], 0.45; 95% confidence interval [CI]: 0.29, 0.70; P < .001), lower baseline NIHSS score (OR, 0.85; 95% CI: 0.78, 0.94; P < .001), MAC score of 3 (OR, 27; 95% CI: 4.0, 179; P < .001), MAC score of 4 (OR, 17; 95% CI: 2.1, 134; P = .007), MAC score of 5 (OR, 27; 95% CI: 2.5, 306; P = .007), and successful early reperfusion (OR, 7.5; 95% CI: 2.6, 22; P < .001) were independently associated with favorable functional outcomes in multivariable analysis. There was a linear negative association between collateral perfusion grades and functional outcomes (P < .001). Conclusion An MR angiography collateral map was clinically reliable for collateral estimation in patients with acute ischemic stroke. This map provided patient-specific pacing information for ischemic progression. © RSNA, 2020.

Phosphorus Regulated Cobalt Oxide@Nitrogen-Doped Carbon Nanowires for Flexible Quasi-Solid-State Supercapacitors.

Battery-type materials are promising candidates for achieving high specific capacity for supercapacitors. However, their slow reaction kinetics hinders the improvement in electrochemical performance. Herein, a hybrid structure of P-doped Co3 O4 (P-Co3 O4 ) ultrafine nanoparticles in situ encapsulated into P, N co-doped carbon (P, N-C) nanowires by a pyrolysis-oxidation-phosphorization of 1D metal-organic frameworks derived from Co-layered double hydroxide as self-template and reactant is reported. This hybrid structure prevents active material agglomeration and maintains a 1D oriented arrangement, which exhibits a large accessible surface area and hierarchically porous feature, enabling sufficient permeation and transfer of electrolyte ions. Theoretical calculations demonstrate that the P dopants in P-Co3 O4 @P, N-C could reduce the adsorption energy of OH- and regulate the electrical properties. Accordingly, the P-Co3 O4 @P, N-C delivers a high specific capacity of 669 mC cm-2 at 1 mA cm-2 and an ultralong cycle life with only 4.8% loss over 5000 cycles at 30 mA cm-2 . During the fabrication of P-Co3 O4 @P, N-C, Co@P, N-C is simultaneously developed, which can be integrated with P-Co3 O4 @P, N-C for the assembly of asymmetric supercapacitors. These devices achieve a high energy density of 47.6 W h kg-1 at 750 W kg-1 and impressive flexibility, exhibiting a great potential in practical applications.

Atroposelective Total Syntheses of Naphthylisoquinoline Alkaloids with (P)-Configuration.

Asymmetric total syntheses of naphthylisoquinoline alkaloids with a (P)-configuration are described. An atroposelective Suzuki-Miyaura reaction between naphthyl pinacol boronate and an aryl iodide bearing an (S)-2-(N-acetylamino)propyl group at the ortho-position using Pd(OAc)2 in the presence of SPhos and Ba(OH)2 provided the (P)-selective biaryl product as the major product without any external chiral sources. This biaryl product was converted into naphthylisoquinoline alkaloids with a (P)-configuration via stereoselective construction of the isoquinoline framework with the appropriate oxidation state and stereochemistry.

Thrombocytopenia during intravenous valproic acid therapy in the neurological intensive care unit.

WHAT IS KNOWN AND OBJECTIVE: Thrombocytopenia is a common laboratory abnormality among critically ill patients under neurological intensive care unit (NCU) care. Valproic acid (VPA), a widely used antiepileptic drug, is one of the common causes of drug-induced thrombocytopenia. The purpose of this study was to estimate the incidence and risk factors of thrombocytopenia after intravenous VPA therapy among the patients admitted to NCU. METHODS: We retrospectively reviewed the medical records of patients who were treated with intravenous VPA during their NCU stay between January 2014 and December 2018. We studied the frequency of thrombocytopenia and further evaluated the risk of thrombocytopenia in these patients. RESULTS: Among the 283 patients (181 male [64.0%], mean age: [61.0 ± 14.9] years) who were treated with intravenous VPA, thrombocytopenia was observed in 104 patients (36.7%). Thrombocytopenia was associated with several risk factors, including lower baseline platelet counts (<200 × 109 /L); aetiologies other than intracranial or subarachnoid haemorrhage; longer use of VPA (more than 3 days); higher daily dose of VPA (more than 1000 mg/d); concurrent use of VPA with other antiepileptic drugs; infection; and the use of mechanical ventilation. Multivariate analysis found several independent risk factors of thrombocytopenia with intravenous VPA therapy, including lower baseline platelet counts, aetiologies other than intracranial or subarachnoid haemorrhage, use of VPA for more than 3 days and infection. WHAT IS NEW AND CONCLUSION: Thrombocytopenia is common in NCU patients. Because several clinical and laboratory factors are associated with thrombocytopenia, careful use of VPA should be considered in patients with these risk factors.

CYP52A23 from Candida albicans and its Substrate Preference for Fatty Acid Hydroxylation.

The pathogenic fungus Candida albicans contains genes encoding five fatty acid hydroxylases belonging to the CYP52 family in its genome. Our previous study reported that CYP52A21 demonstrated typical omega-hydroxylation of lauric acid (Kim D, Cryle MJ, De Voss JJ, Ortiz de Montellano PR (2007) Arch Biochem Biophys 464, 213-220). Functional characterization of CYP52 fatty acid hydroxylases was studied, and their selectivity for hydroxylation was analyzed. Genes for four other CYP52 members (CYP52A22, CYP52A23, CYP52A24, and CYP52C3) from C. albicans were cloned, and their recombinant enzymes were expressed in Escherichia coli. CO-binding spectral analyses showed that the functional P450 holoenzyme was obtained only in CYP52A23, while no holoenzyme peak was observed in the other three CYP52 enzymes. Spectral change of the type II binding was observed in purified CYP52A23 when titrated with fatty acids but none was observed with alkanes. The gas chromatography-mass spectrometry (GC-MS) analysis revealed that CYP52A23 predominantly exhibited omega-hydroxylation activity during the oxidation reaction of fatty acids. Interestingly, it was found that CYP52A23 preferred longer-chain fatty acids (stearic acid and arachidic acid) for its catalytic activities while CYP52A21 preferred mid-chain fatty acids (lauric acid and mystic acid). To analyze the selectivity of fatty acids, hybrid mutagenesis of genes encoding CYP52A21 and CYP52A23 by overlap extension polymerase chain reaction was conducted. Two hybrid mutants containing the N-terminal fragments of CYP52A21 and C-terminal fragments of CYP52A23 displayed higher catalytic activity in palmitic acid and arachidic acid. These results suggested that the C-terminal part of CYP52A23 may be responsible for its preference to longer-chain fatty acids.

Combination treatment with auranofin and nutlin-3a induces synergistic cytotoxicity in breast cancer cells.

Auranofin is a gold complex categorized as an anti-rheumatic agent. Recently, several investigators suggested that auranofin may act as a potent anti-cancer drug for breast tumors. Nutlin-3a is a cis-imidazoline analog which prevents interaction between mouse double minute 2 homolog (MDM2) and the tumor suppressor p53. The aim of this study was to examine cell growth inhibition mediated by auranofin or nutlin-3a individually as well as in combination with MCF-7 and MDA-MB-231 cells. To assess any potential synergistic effects between auranofin and nutlin-3a, low concentrations of auranofin and nutlin-3a were simultaneously incubated with MCF-7 and MDA-MB-231 cells. Cell viability assay, caspase-3/7 assay, and poly (ADP-ribose) polymerase cleavage revealed that auranofin and nutlin-3a exerted a synergistic effect on cancer cell apoptosis. Isobologram analysis of MCF-7 and MDA-MB-231 cells noted evident synergism between auranofin and nutlin-3a. The combined treatment increased the expression of mitochondrial pro-apoptotic factors such as Bcl-2 associated X protein and Bcl-2 homologous antagonist/killer. Further, combination treatment significantly enhanced reactive oxygen species (ROS) generation in MCF-7 and MDA-MB-231 cells. In conclusion, data demonstrated that combined treatment with auranofin and nutlin-3a exhibited a synergistic action on breast cancer cells and this combination may be considered for use as a novel therapeutic strategy for breast cancer.

Arthroscopic Suture Repair With Additional Pronator Quadratus Advancement for the Treatment of Acute Triangular Fibrocartilage Complex Tear With Distal Radioulnar Joint Instability.

Treatment of acute triangular fibrocartilage complex (TFCC) tear using arthroscopic suture repair has been used as a general treatment method, but it is difficult to obtain perfect results in all cases. We evaluated clinical and radiologic outcomes of the acute TFCC tear with distal radioulnar joint instability using the arthroscopic suture repair with pronator quadratus (PQ) advancement. Altogether, 80 patients (48 male, 32 female; mean ± SD age, 37.3 ± 11.5 years; mean ± SD follow-up, 23.7 ± 11.4 months) were enrolled in the study. Follow-up was at least 12 months (range, 12-38 months). Patients were divided into group 1 with arthroscopic suture repair alone (34 patients; 17 male, 17 female; mean ± SD age, 35.2 ± 10.8 years; mean ± SD follow-up, 28.1 ± 15.1 months) and group 2 with additional PQ advancement (46 patients; 29 male, 17 female; mean ± SD age, 38.9 ± 11.9 years; mean ± SD follow-up, 18.4 ± 6.2 months), and clinical and radiological assessment was performed. We also compared the ulnar translation of the injured wrist with that of the uninjured wrist using the Push Pull gauge.There was no difference in the range of motion and the grip strength between the 2 groups. However, the disabilities of the arm, shoulder, and hand score (P = 0.042) at 6-month follow-up and disabilities of the arm, shoulder, and hand score (P = 0.015) and patient-rated wrist evaluation score (P = 0.012) at 12-month follow-up were improved in group 2, and patients' satisfaction (P = 0.032) was also higher in group 2. The ulnar translation rate was also improved in group 2 at 6-month follow-up (P = 0.015) and 12-month follow-up (P = 0.045).Arthroscopic suture repair with PQ advancement provided more clinical improvement and proper stability; therefore, it will be an acceptable effective treatment option for acute TFCC tear with distal radioulnar joint instability.

Age and sex-related distribution of alpha angles and the prevalence of the cam morphology of the hip in Asians do not differ from those of other ethnicities.

PURPOSE: This study was performed to evaluate the effects of age on the alpha angle and the incidence of asymptomatic cam morphology. METHODS: The radiographs of asymptomatic individuals between ages 8 and 22 were retrospectively collected. A total of 1417 individuals were included and grouped according to age: 8-12 (Group A), 13-18 (Group B), and 19-22 (Group C) years. Radiographic measurements of the alpha angles of the right hip were obtained from anteroposterior (AP) and frog-leg lateral (FL) radiographs. The correlations among alpha angles, the presence of cam morphology, and age were determined. RESULTS: The mean alpha angles of the three groups were statistically different (p < 0.001, each). The alpha angles on both radiographs were positively correlated with age. Intra-group analysis revealed that this correlation was only evident on the FL images of males in Group B. The presence of a radiographic cam morphology also positively correlated with age (p < 0.001 in both AP and FL images). The cam morphology on AP radiographs was 0 in Group A, 17(3.0%) in Group B, and 21(4.8%) in Group C; that on FL radiographs was 2(0.3%) in Group A, 45(7.9%) in Group B, and 103(23.6%) in Group C. Intra-group analysis revealed that the correlation was only significant in males in Group B. CONCLUSIONS: Higher alpha angles and the presence of cam morphology were positively correlated with age, particularly in males at or before the time of skeletal maturation. The prevalence of cam morphology did not differ from those in other ethnicities. LEVEL OF EVIDENCE: IV.

Headless compression screw fixation for type 2 and 3 articular surface fractures of the distal humerus using transolecranon approach.

The objectives of this study were to determine the clinical and radiologic outcome after headless compression screw fixation through the transolecranon approach in patients who had sustained Dubberley type 2 and 3 articular surface fractures of the distal humerus. Twenty-seven patients were included in the study. There were 23 Dubberley type 2 and 4 type 3 fractures. All patients were available for a minimum of 24 months of follow-up. The evaluation was performed using the VAS, the DASH score, and the MEPS. The outcome was excellent in 18 patients, and 9 patients had a good result by the MEPS. The average range of flexion was 132° (range 110°-140°). The mean extensor lag was 7.9° (range 0°-30°). The main advantages of the transolecranon approach are direct fracture visualization, ease of joint inspection, help in reduction, and ease of correct perpendicular fracture fixation.