Discovery of N-benzylbenzamide-based allosteric inhibitors of Aurora kinase A.

Aurora kinases (AurkA/B/C) regulate the assembly of bipolar mitotic spindles and the fidelity of chromosome segregation during mitosis, and are attractive therapeutic targets for cancers. Numerous ATP-competitive AurkA inhibitors have been developed as potential anti-cancer agents. Recently, a few allosteric inhibitors have been reported that bind to the allosteric Y-pocket within AurkA kinase domain and disrupt the interaction between AurkA and its activator TPX2. Herein we report a novel allosteric AurkA inhibitor (6h) of N-benzylbenzamide backbone. Compound 6h suppressed the both catalytic activity and non-catalytic functions of AurkA. The inhibitory activity of 6h against AurkA (IC50 = 6.50 µM) was comparable to that of the most potent allosteric AurkA inhibitor AurkinA. Docking analysis against the Y-pocket revealed important pharmacophores and interactions that were coherent with structure-activity relationship. In addition, 6h suppressed DNA replication in G1-S phase, which is a feature of allosteric inhibition of AurA. Our current study may provide a useful insight in designing potent allosteric AurkA inhibitors.

Arthroscopic cuff repair: footprint remnant preserving versus debriding rotator cuff repair of transtendinous rotator cuff tears with remnant cuff.

BACKGROUND: In transtendinous full thickness rotator cuff tears (FTRCT) with remnant cuff, conventionally, cuff remnant of the greater tuberosity (GT) is debrided for better tendon to bone healing. However, larger cuff defect caused overtension on the repaired tendon. The purpose of this study was to compare the clinical outcomes and tendon integrity between remnant preserving and remnant debriding cuff repairs in the transtendinous FTRCT with remnant cuff. METHODS: From March, 2012 to October, 2017, a total of 127 patients who had the transtendinous FTRCT with remnant cuff were enrolled in this study. Rotator cuff tears were repaired arthroscopically, with patients divided into two groups: group I (n = 63), where rotator cuff remnants were preserved during the repair, and group II (n = 64), where the remnants were debrided during the repair. Clinical outcomes were assessed at the last follow-up (minimum 2 years) using the UCLA score, ASES score, SST score, Constant Shoulder score, and range of motion (ROM). The analysis of structural integrity and tendon quality was performed using the Sugaya classification on postoperative MRI scans at 8 months after surgery. RESULTS: At the final follow-up, UCLA, ASES, SST, and CS scores significantly improved from preoperative values to postoperative (all p < 0.05): UCLA (I: 19.6 ± 6.0 to 31.7 ± 3.2, II: 18.0 ± 5.7 to 31.5 ± 3.2), ASES (I: 54.3 ± 10.7 to 86.5 ± 12.5, II: 18.0 ± 5.7 to 85.8 ± 12.4), SST (I: 5.6 ± 2.8 to 10.2 ± 2.0, II: 5.0 ± 2.9 to 10.1 ± 2.5), CS (I: 74.0 ± 17.2 to 87.8 ± 9.7, II: 62.0 ± 19.2 to 88.3 ± 6.2). However, there were no significant differences between the two groups (p > 0.05). Also, remnant preserving cuff repair yielded significantly better tendon quality on postoperative MRI (p < 0.05). The incidence of re-tear (Sugaya's Type IV and V) was not significantly different between the two groups (I:17% vs. II:19%; p = 0.053). CONCLUSIONS: Remnant preserving rotator cuff repairs, which facilitate tendon-to-tendon healing, are superior in terms of tendon quality and are the preferred option for transtendinous FTRCT. TRIAL REGISTRATION: Retrospectively registered.

Bright diffusion sign: A sensitive and specific radiologic biomarker for multinodular and vacuolating neuronal tumor.

BACKGROUND AND PURPOSE: Accurate differentiation between multinodular and vacuolating neuronal tumor (MVNT) and dysembryoplastic neuroepithelial tumor (DNET) is important for treatment decision-making. We aimed to develop an accurate radiologic diagnostic model for differentiating MVNT from DNET using T2WI and diffusion-weighted imaging (DWI). MATERIALS AND METHODS: A total of 56 patients (mean age, 47.48±17.78 years; 31 women) diagnosed with MVNT (n = 37) or DNET (n = 19) who underwent brain MRI, including T2WI and DWI, were included. Two board-certified neuroradiologists performed qualitative (bubble appearance, cortical involvement, bright diffusion sign, and bright apparent diffusion coefficient [ADC] sign) and quantitative (nDWI and nADC) assessments. A diagnostic tree model was developed with significant and reliable imaging findings using an exhaustive chi-squared Automatic Interaction Detector (CHAID) algorithm. RESULTS: In visual assessment, the imaging features that showed high diagnostic accuracy and interobserver reliability were the bright diffusion sign and absence of cortical involvement (bright diffusion sign: accuracy, 94.64 %; sensitivity, 91.89 %; specificity, 100.00 %; interobserver agreement, 1.00; absence of cortical involvement: accuracy, 92.86 %; sensitivity, 89.19 %; specificity, 100.00 %; interobserver agreement, 1.00). In quantitative analysis, nDWI was significantly higher in MVNT than in DENT (1.52 ± 0.34 vs. 0.91 ± 0.27, p < 0.001), but the interobserver agreement was fair (intraclass correlation coefficient = 0.321). The overall diagnostic accuracy of the tree model with visual assessment parameters was 98.21 % (55/56). CONCLUSION: The bright diffusion sign and absence of cortical involvement are accurate and reliable imaging findings for differentiating MVNT from DNET. By using simple, intuitive, and reliable imaging findings, such as the bright diffusion sign, MVNT can be accurately differentiated from DNET.

Comparison between arthroscopic suture anchor fixation and open plate fixation in the greater tuberosity fracture of the proximal humerus.

INTRODUCTION: The purpose of this study is to compare the clinical and radiological outcomes of patients undergoing open reduction and internal fixation (OR/IF) using a plate or patients undergoing an arthroscopic suture anchor fixation for the greater tuberosity (GT) fracture of the proximal humerus. The purpose of this study is to compare the clinical and radiological outcomes of patients undergoing OR/IF or an arthroscopic suture anchor fixation for the GT fracture. MATERIALS AND METHODS: Between January, 2010 and December, 2020, 122 patients with GT fracture underwent operative fixation. Either OR/IF using proximal humeral locking plate (50 patients) or arthroscopic suture anchor (72 patients) fixation was performed. Fourteen patients were lost to follow-up and finally, 108 patients were enrolled in this study. We divided these patients into two groups: (1) OR/IF group (Group I: 44 patients) and arthroscopic anchor fixation group (Group II: 64 patients). The primary outcome was subjective shoulder function (shoulder functional scale). Secondary outcomes were range of motion, and complications including GT fixation failure, fracture migration, or neurologic complication. Also, age, sex, BMI, operation time, shoulder dislocation, fracture comminution, AP (anteroposterior), SI (superoinferior) size and displacement were evaluated and compared between two groups. RESULTS: Both groups showed satisfactory clinical and radiological outcomes at mid-term follow-up. Between 2 groups, there were no significant differences in age, sex, BMI, presence of shoulder dislocation or comminution. Group II showed higher clinical scores except VAS score (p < 0.05) and longer surgical times (95.3 vs. 61.5 min). Largest fracture displacement (Group I vs. II: SI displacement: 40 vs. 13 mm, and AP displacement: 49 vs. 11 mm) and higher complication rate (p = 0.049) was found in Group I. CONCLUSIONS: Both arthroscopic anchor fixation and open plate fixation methods showed satisfactory outcomes at mid-term follow-up. Among them, OR/IF is preferred for larger fracture displacement (> 5 mm) and shorter operation time However, arthroscopic anchor fixation group showed better clinical outcomes and less complications than the OR/IF group. LEVEL OF EVIDENCE: Level 4, Case series with subgroup analysis.

Design, synthesis, and study of novel phenethyl-based antitumor phospholipids downregulating p38 mitogen-activated protein kinase.

Phenethyl-based edelfosine-analogs with saturated, monounsaturated, or polyunsaturated alkoxy substituents on phenyl ring were designed as novel antitumor lipids modulating p38 MAPK. Evaluation of the synthesised compounds against nine panels of diverse cancer cells presented saturated and monounsaturated alkoxy-substituted derivatives as the most active than other derivatives. In addition, ortho-substituted compounds were more active than meta- or ortho-substituted compounds. They were potential anticancer agents against blood, lung, colon, CNS, ovary, renal, and prostate cancers but not against skin nor breast cancers. Compounds, 1b and 1a emerged as the most potential anticancer agents. Assessment of compound 1b impact on p38 MAPK and AKT confirmed it as an inhibitor of p38 MAPK but not AKT. In silico study suggested compounds 1b and 1a as possible binders to the lipid binding pocket of p38 MAPK. Overall, compounds 1b and 1a as novel broad spectrum antitumor lipids modulating activity of p38 MAPK for further development.

Mid-term comparative study between the glenoid and humerus lateralization designs for reverse total shoulder arthroplasty: which lateralization design is better?

INTRODUCTION: The complications of the conventional medialized design for reverse total shoulder arthroplasty (RSA) are increased scapular notching, and decreased external rotation and deltoid wrapping. Currently, lateralization design RSA, which avoid scapular notching and improve impingement-free range of motion, is commonly used. Especially, humeral lateralization design was most commonly used and glenoid lateralization design was preferred for glenoid abnormities. We compared mid-term clinical and radiologic outcomes of glenoid and humeral lateralization RSA in an Asian population in this study. MATERIALS AND METHODS: We enrolled 124 shoulders of 122 consecutive patients (mean age 73.8 ± 6.8 years) who received glenoid or humeral lateralization RSA from May, 2012 to March, 2019. We divided these patients into two groups according to RSA using either glenoid or humeral lateralization design. These different designs were introduced consecutively in Korea. The clinical and radiological results of 60 glenoid lateralization RSA (Group I, 60 patients) and 64 humeral lateralization RSA (Group II, 62 patients) were retrospectively evaluated and also were compared between the two groups. All patients were followed for mean 3 years. RESULTS: The clinical and radiologic outcomes of the two groups did not differ significantly, including scapular notching (p = 0.134). However, humeral lateralization RSA showed a larger glenoid-tuberosity (GT) distance (p = 0.000) and less distalization shoulder angle (DSA) (p = 0.035). The complication rate did not differ significantly either. But, revision surgery was performed for 2 humeral loosening in the Group II. CONCLUSION: The clinical and radiologic outcomes of the two groups did not differ significantly, including scapular notching at mid-term follow-up. However, humeral lateralization design showed larger GT distance and less DSA. Humeral lateralization design RSA could preserve the normal shoulder contour due to a larger GT distance (more lateralization) and provide less deltoid tension due to less DSA (less distalization of COR).

Comparisons between treatment of isolated posterosuperior paralabral cysts and simultaneous treatment of cysts combined with associated shoulder pathologies: arthroscopic treatment of posterosuperior paralabral cysts.

INTRODUCTION: The purpose of this study is to report the radiologic and clinical outcomes of arthroscopic intervention for isolated posterosuperior paralabral cysts and simultaneous treatment of cysts combined with associated shoulder pathologies. MATERIALS AND METHODS: From March 2008 through December 2016, 70 cases (48 males and 22 females) operated on for symptomatic posterosuperior paralabral cysts were included. Mean age was 45 (range 18-69). These patients were classified into two groups depending on if they had accompanying lesions: Group I (isolated group, 27 patients) and Group II (concomitant group, 43 patients). Arthroscopic cyst decompression with a labral repair or posterior capsulotomy for patients without labral tear were performed. All concomitant pathologies were also operated simultaneously. Follow-up MRI were performed at postoperative 6 months and clinical outcomes were evaluated during the follow-up. RESULTS: Arthroscopic all intra-articular cyst decompression and labral repair was performed on 67 patients. In three patients, posterior capsulotomy without labral repair was performed for cyst removal. For 43 patients with concomitant lesions, 31 rotator cuff repairs, three SLAP repairs along with biceps tenodesis, two distal clavicle resections due to A-C joint arthritis, one calcific deposit removal, four Bankart repairs, and two acromioplasties were performed. The follow-up MRI showed complete cyst resorption except for two patients. The mean VAS, ASES, UCLA, SST and CS scores significantly improved at the last follow-up. Although both groups showed significantly improved range of motion after the surgery, improvement of ROM in Group II lagged at early periods of the rehabilitation. CONCLUSIONS: Arthroscopic labral repair with all intra-articular cysts decompression or simple posterior capsulotomy were both effective treatment modalities. If paralabral cysts were associated with other shoulder lesions, simultaneous treatment of combined lesions could be performed for the improved clinical outcomes at final follow-up with expected lag in the early rehabilitation period. LEVEL OF EVIDENCE: Level III, Retrospective Comparative Trial, Treatment Study.

Characteristics of plaque lipid-associated macrophages and their possible roles in the pathogenesis of atherosclerosis.

PURPOSE OF REVIEW: Recent findings from single-cell transcriptomic studies prompted us to revisit the role of plaque foamy macrophages in the pathogenesis of atherosclerosis. In this review, we compared the gene expression profile of plaque foamy macrophages with those of other disease-associated macrophages and discussed their functions in the pathogenesis of atherosclerosis. RECENT FINDINGS: To understand the phenotypes of macrophages in atherosclerotic aorta, many research groups performed single-cell RNA sequencing analysis and found that there are distinct phenotypic differences among intimal foamy, nonfoamy and adventitial macrophages. Especially, the plaque foamy macrophages express triggering receptor expressed on myeloid cells 2 (TREM2), a key common feature of disease-associated macrophages in Alzheimer's disease, obesity, cirrhosis and nonalcoholic steatohepatitis. These TREM2 + macrophages seem to be protective against chronic inflammation. SUMMARY: As the gene expression profile of plaque foamy macrophages is highly comparable to that of lipid-associated macrophages from obesity, we named the plaque foamy macrophages as plaque lipid-associated macrophages (PLAMs). PLAMs have a high level of gene expression related to phago/endocytosis, lysosome, lipid metabolism and oxidative phosphorylation. Considering the protective function of lipid-associated macrophages against adipose tissue inflammation, PLAMs may suppress atherosclerotic inflammation by removing modified lipids and cell debris in the plaque.

Synthetic Time of Flight Magnetic Resonance Angiography Generation Model Based on Cycle-Consistent Generative Adversarial Network Using PETRA-MRA in the Patients With Treated Intracranial Aneurysm.

BACKGROUND: Pointwise encoding time reduction with radial acquisition (PETRA) magnetic resonance angiography (MRA) is useful for evaluating intracranial aneurysm recurrence, but the problem of severe background noise and low peripheral signal-to-noise ratio (SNR) remain. Deep learning could reduce noise using high- and low-quality images. PURPOSE: To develop a cycle-consistent generative adversarial network (cycleGAN)-based deep learning model to generate synthetic TOF (synTOF) using PETRA. STUDY TYPE: Retrospective. POPULATION: A total of 377 patients (mean age: 60 ± 11; 293 females) with treated intracranial aneurysms who underwent both PETRA and TOF from October 2017 to January 2021. Data were randomly divided into training (49.9%, 188/377) and validation (50.1%, 189/377) groups. FIELD STRENGTH/SEQUENCE: Ultra-short echo time and TOF-MRA on a 3-T MR system. ASSESSMENT: For the cycleGAN model, the peak SNR (PSNR) and structural similarity (SSIM) were evaluated. Image quality was compared qualitatively (5-point Likert scale) and quantitatively (SNR). A multireader diagnostic optimality evaluation was performed with 17 radiologists (experience of 1-18 years). STATISTICAL TESTS: Generalized estimating equation analysis, Friedman's test, McNemar test, and Spearman's rank correlation. P < 0.05 indicated statistical significance. RESULTS: The PSNR and SSIM between synTOF and TOF were 17.51 [16.76; 18.31] dB and 0.71 ± 0.02. The median values of overall image quality, noise, sharpness, and vascular conspicuity were significantly higher for synTOF than for PETRA (4.00 [4.00; 5.00] vs. 4.00 [3.00; 4.00]; 5.00 [4.00; 5.00] vs. 3.00 [2.00; 4.00]; 4.00 [4.00; 4.00] vs. 4.00 [3.00; 4.00]; 3.00 [3.00; 4.00] vs. 3.00 [2.00; 3.00]). The SNRs of the middle cerebral arteries were the highest for synTOF (synTOF vs. TOF vs. PETRA; 63.67 [43.25; 105.00] vs. 52.42 [32.88; 74.67] vs. 21.05 [12.34; 37.88]). In the multireader evaluation, there was no significant difference in diagnostic optimality or preference between synTOF and TOF (19.00 [18.00; 19.00] vs. 20.00 [18.00; 20.00], P = 0.510; 8.00 [6.00; 11.00] vs. 11.00 [9.00, 14.00], P = 1.000). DATA CONCLUSION: The cycleGAN-based deep learning model provided synTOF free from background artifact. The synTOF could be a versatile alternative to TOF in patients who have undergone PETRA for evaluating treated aneurysms. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 1.

Development and validation of visual grading system for stenosis in intracranial atherosclerotic disease on time-of-flight magnetic resonance angiography.

OBJECTIVES: Although the overestimation problem of time-of-flight magnetic resonance angiography (TOF-MRA) applying the warfarin-aspirin symptomatic intracranial disease (WASID) method to assess intracranial arterial stenosis has often been suggested, no pertinent grading system for TOF-MRA has been developed. We aimed to develop and evaluate the performance of a visual grading system for intracranial arterial stenosis on TOF-MRA (MRAVICAST). METHODS: This single-center cohort study analyzed prospective observational registry data from a comprehensive stroke center between January 2014 and February 2020. Patients with confirmed stenosis of the intracranial large arteries who underwent confirmative digital subtraction angiography (DSA) were included; a 4-point grading system was developed based on physical characteristics of TOF-MRA. The overall diagnostic accuracies of MRAVICAST for each grade, interobserver reproducibility, and positive predictive values for > 50% and > 70% stenoses were evaluated. RESULTS: We analyzed 132 segments with intracranial atherosclerotic stenosis from 71 patients (34 men and 37 women; mean age, 61.0 ± 15.25 years; range, 21-89 years). The overall diagnostic accuracy of MRAVICAST (93.9%, 124/132) was higher than that of MRAWASID (50.8%, 67/132) for each grade. The degree of stenosis did not differ significantly between MRAVICAST and DSAWASID (p = .849). Regarding reproducibility, MRAVICAST demonstrated excellent interobserver agreement (ICC, 0.989; 95% CI, 0.979-0.999). The positive predictive values of MRAVICAST for the diagnosis of > 50% and > 70% stenoses were 97.3% and 100.0%, respectively. CONCLUSIONS: The new intuitive grading system accurately and reliably determined the degree of stenosis in intracranial arterial atherosclerosis patients. MRAVICAST could be a versatile alternative to MRAWASID for evaluating intracranial arterial stenosis. KEY POINTS: • In this retrospective diagnostic study (sample: 132 stenotic segments), the overall accuracy of the visual grading system (MRAVICAST) was 94%, and positive predictive value for > 50% stenosis was 97%. • In the era of medical treatment for intracranial atherosclerotic stenosis, MRAVICAST could be a versatile alternative method to MRAWASID for evaluating intracranial arterial stenosis.

Diagnostic Criteria and Treatment of Atypical Ulnar Fractures Associated With Prolonged Bisphosphonate Therapy: Multicenter Case Analysis.

PURPOSE: Atypical ulnar fracture (AUF) related to prolonged bisphosphonate therapy is a rare complication. We propose diagnostic criteria of AUFs and present a treatment algorithm. METHODS: Twelve AUFs in 10 patients were studied. The diagnosis of AUF was based on the case definition of atypical femoral fracture (AFF). We investigated clinical and radiographic characteristics of AUFs according to major and minor features of AFFs, and modified the case definition of an AFF to fit the characteristics of AUFs. All AUFs were treated surgically. The radiographic union of fractures was investigated, and delayed fracture healing was defined as a delay of 6 months or more. RESULTS: The average point at which AUFs occurred was at a point 35.1% along the proximal diaphysis of the total ulnar length. All major features of AFFs were identified in the 12 AUFs. Among the minor features, generalized cortical thickening was observed in 6 AUFs, prodromal symptoms in 2 AUFs, bilateral involvement in 2 patients, and delayed fracture healing in 10 AUFs (5 delayed union, 5 nonunion). Initially, 11 of 12 AUFs were treated with plating, and 1 was treated with intramedullary nailing. Two nonunions were revised with sclerotic bone resections, bone grafts, and plate fixation. Finally, union was achieved in 9 AUFs. CONCLUSIONS: The case definition of AFFs can be used for the diagnosis of AUFs, although some modifications must be included in the case definition. Plating is useful in managing AUFs, although sclerotic bone resections and bone grafts may be required. Atypical ulnar fractures occurred in patients who took bisphosphonates longer than AFFs or those whose bisphosphonates were discontinued a few years earlier. Therefore, physicians should be aware of AUFs in those patients and, if necessary, perform a screening test to look for atypical fractures in other bones. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic V.

Evaluation of the Inhibitory Effects of Pyridylpyrazole Derivatives on LPS-Induced PGE2 Productions and Nitric Oxide in Murine RAW 264.7 Macrophages.

A series of thirteen triarylpyrazole analogs were investigated as inhibitors of lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) and nitric oxide (NO) production in RAW 264.7 macrophages. The target compounds 1a-m have first been assessed for cytotoxicity against RAW 264.7 macrophages to determine their non-cytotoxic concentration(s) for anti-inflammatory testing to make sure that the inhibition of PGE2 and NO production would not be caused by cytotoxicity. It was found that compounds 1f and 1m were the most potent PGE2 inhibitors with IC50 values of 7.1 and 1.1 µM, respectively. In addition, these compounds also showed inhibitory effects of 11.6% and 37.19% on LPS-induced NO production, respectively. The western blots analysis of COX-2 and iNOS showed that the PGE2 and NO inhibitory effect of compound 1m are attributed to inhibition of COX-2 and iNOS protein expression through inactivation of p38.

Suture anchor fixation of comminuted inferior pole patella fracture-novel technique: suture bridge anchor fixation technique.

PURPOSE: Comminuted inferior pole fractures of the patella are notorious fractures where it is difficult to obtain rigid internal fixation by conventional tension band wiring. The purpose of this study is to evaluate the clinical and radiological outcomes of the suture bridge anchor fixation for these comminuted inferior pole fractures of the patella. METHODS: From March 2012 to December 2018, suture bridge anchor fixation for the inferior pole comminuted fracture of the patella was performed in 22 patients. There were 21 patients of inferior pole comminuted fracture and 1 patient of lower periosteal sleeve avulsion fracture. Clinical outcomes including SF-36 score, Knee injury and osteoarthritis outcome score (KOOS) and post-operative range of motion were evaluated. In all patients, suture bridge anchor fixation was performed and, tension band wiring with K wire was added for large fragment fixation in two patients. We evaluated bony union, the patellar height using Insall-Salvati ratio and its complications. RESULTS: Mean age was 46 ± 20 (15-82) years. Mean follow-up period was 25 ± 18 (11-74) months. In all patients, bony union was achieved at postoperative 4 months. At final follow-up, mean SF-36 score was 72 ± 15 (30-91) points and KOOS score was 66.7 ± 16 (43-97). The average range of motion was 134 ± 5 (125-140) degrees. As a complication, one patient developed a wound infection and subsequent osteomyelitis of inferior pole fracture fragment. Compared to the normal knee, the Insall-Salvati ratio of the injured knee averages 0.73 and this smaller ratio less than 0.8 meant patella baja. CONCLUSIONS: In the comminuted inferior pole fractures of the patella, suture bridge anchor fixation showed good bony union and satisfactory clinical outcomes at the short-term follow-up and could be a satisfactory alternative treatment option. Even though suture bridge anchor fixation in these fractures caused decreased Insall-Salvati ratio (patella height), any patellofemoral pain and limited range of motion was not developed. LEVEL OF EVIDENCE: Level IV.

N-terminal methionine excision of proteins creates tertiary destabilizing N-degrons of the Arg/N-end rule pathway.

All organisms begin protein synthesis with methionine (Met). The resulting initiator Met of nascent proteins is irreversibly processed by Met aminopeptidases (MetAPs). N-terminal (Nt) Met excision (NME) is an evolutionarily conserved and essential process operating on up to two-thirds of proteins. However, the universal function of NME remains largely unknown. MetAPs have a well-known processing preference for Nt-Met with Ala, Ser, Gly, Thr, Cys, Pro, or Val at position 2, but using CHX-chase assays to assess protein degradation in yeast cells, as well as protein-binding and RT-qPCR assays, we demonstrate here that NME also occurs on nascent proteins bearing Met-Asn or Met-Gln at their N termini. We found that the NME at these termini exposes the tertiary destabilizing Nt residues (Asn or Gln) of the Arg/N-end rule pathway, which degrades proteins according to the composition of their Nt residues. We also identified a yeast DNA repair protein, MQ-Rad16, bearing a Met-Gln N terminus, as well as a human tropomyosin-receptor kinase-fused gene (TFG) protein, MN-TFG, bearing a Met-Asn N terminus as physiological, MetAP-processed Arg/N-end rule substrates. Furthermore, we show that the loss of the components of the Arg/N-end rule pathway substantially suppresses the growth defects of naa20Δ yeast cells lacking the catalytic subunit of NatB Nt acetylase at 37 °C. Collectively, the results of our study reveal that NME is a key upstream step for the creation of the Arg/N-end rule substrates bearing tertiary destabilizing residues in vivo.

Maintenance and differentiation of human ES cells on polyvinylidene fluoride scaffolds immobilized with a vitronectin-derived peptide.

Polyvinylidene fluoride (PVDF) is biocompatible, easy to fabricate, and has piezoelectric properties; it has been used for many biomedical applications including stem cell engineering. However, long-term cultivation of human embryonic stem cells (hESCs) and their differentiation toward cardiac lineages on PVDF have not been investigated. Herein, PVDF nanoscaled membrane scaffolds were fabricated by electrospinning; a vitronectin-derived peptide-mussel adhesive protein fusion (VNm) was immobilized on the scaffolds. hESCs cultured on the VNm-coated PVDF scaffold (VNm-PVDF scaffold) were stably expanded for more than 10 passages while maintaining the expression of pluripotency markers and genomic integrity. Under cardiac differentiation conditions, hESCs on the VNm-PVDF scaffold generated more spontaneously beating colonies and showed the upregulation of cardiac-related genes, compared with those cultured on Matrigel and VNm alone. Thus, VNm-PVDF scaffolds may be suitable for the long-term culture of hESCs and their differentiation into cardiac cells, thus expanding their application in regenerative medicine.

Trans-tendon suture bridge rotator cuff repair with tenotomized pathologic biceps tendon augmentation in high-grade PASTA lesions.

PURPOSE: The purpose of this study was to evaluate whether trans-tendon suture bridge repair with tenotomized pathologic biceps tendon augmentation improves mid-term clinical outcomes for high-grade partial articular-sided supraspinatus tendon avulsion (PASTA) lesions or not. METHODS: A retrospective review of a consecutive series of arthroscopic trans-tendon suture bridge repair with tenotomized pathologic biceps tendon augmentation was conducted. Total 115 patients (44 men and 71 women) with minimum 2 years follow-up were enrolled in our study. Their mean age was 59.7 ± 7.6 (38-77) years and mean follow-up were 6.9 ± 2.5 (2 ~ 10) years. Clinical assessment and radiological outcomes using post-operative MRI were evaluated at last follow-up. RESULTS: All these tears were high-grade PASTA lesions in which mean cuff tear size (exposed footprint) was anteroposterior length 15.7 ± 6.3 mm (5-25 mm) and mediolateral width 10.1 ± 3.6 mm 6.4 mm (5-16 mm). At last follow-up, mean pain VAS, ASES, UCLA, and SST scores were improved from pre-operative values of 5, 59, 21, and 7 to post-operative values of 1, 84.4, 29.5, and 9.4, respectively (p value < 0.001). ROM such as forward flexion, abduction, and internal rotation to the back were improved from a pre-operative mean of 148° (±24), 144° (±24), L2 (Buttock-T7) to a post-operative mean of 161° (±10), 160.0° (±12), and T12 (L3-T5), respectively (p value < 0.001). Follow-up MRI showed Sugaya classification type I in 24 patients (20.9%), type II in 78 patients (67.8%), type III in 11 patients (9.6%) and type 4 in 2 patients (1.7%) were found. As complications, shoulder stiffness was found in five patients, Popeye deformity in two patients and retear in two patients. Revision surgery of the retear was performed in 2 patients. At the last follow-up, 17% (20/115 patients) reported occasional discomfort at the extremes of range of motion during a heavy work or sports activities. CONCLUSIONS: In high-grade PASTA lesions, arthroscopic trans-tendon suture bridge repair with tenotomized pathologic biceps tendon augmentation could be a useful treatment modality capable of preserving rotator cuff footprint, providing simultaneous biceps tenodesis, inducing better tendon healing and possibly preventing tendon buckling and residual pain of the conventional trans-tendon repair methods. These specific methods showed satisfactory outcomes and decreased residual shoulder discomfort (17%) at mid-term follow-up. LEVEL OF EVIDENCE: Level IV, Retrospective case study.

Narrow locking compression plate vs long philos plate for minimally invasive plate osteosynthesis of spiral humerus shaft fractures.

BACKGROUND: Our hypothesis was that minimally invasive plate osteosynthesis (MIPO) using long philos plate (LPP) would show better clinical and radiological outcomes and less complications than narrow locking compression plate (NLCP) for spiral humerus shaft fractures with or without metaphyseal fracture extension. METHODS: From January 2009 to May 2016, we retrospectively studied 35 patients who underwent MIPO for spiral humerus shaft fractures with or without metaphyseal fracture extension (AO classification 12 A, B, C except A3). Eighteen patients underwent MIPO with a 4.5 mm NLCP (group I) in the early period of this study, while 17 patients underwent MIPO with LPP (group II) in the later period. Range of motion (ROM), pre- and post-operative anteroposterior (AP) and lateral angulation of the fracture, operation time, amount of bleeding, and functional outcomes including American Shoulder and Elbow Surgeons score, University of California at Los Angeles score, and Simple Shoulder Test score were analyzed at the final follow up. RESULTS: All patients had complete bony union and achieved satisfactory functional outcomes except 2 patients. In LPP group, better outcomes in postoperative fracture angulation on X-ray and operation time (p < 0.05) were shown. But, two revision surgery with NLCP and bone graft was performed owing to 2 metal failures. CONCLUSIONS: In spiral humeral shaft fractures, LPP group showed better fracture reduction on X-ray and shorter operation time except metal failure owing to weak fixation. Even though MIPO technique using LPP is easier and more accurate reduction method, rigid fixation should be considered.

Loss of pronation-supination in patients with heterotopic ossification around the elbow.

BACKGROUND: Heterotopic ossification (HO) is a well-recognized cause of limited flexion-extension, but it can also limit pronation-supination. There is a paucity of literature concerning restriction of pronation-supination due to HO. METHODS: We conducted a retrospective review of patients who had undergone elbow surgery for HO removal between January 1, 2003, and September 27, 2013. Computed tomography scans were reviewed to determine the presence of HO restricting forearm rotation and were rated independently by 4 observers. Each elbow was given 1 of 4 scores according to the likelihood that HO was restricting forearm rotation. Agreement was achieved when 3 or 4 observers thought that HO definitely or probably caused a loss of pronation-supination. RESULTS: Of 132 post-traumatic patients undergoing HO excision for restricted elbow motion, 61 (46%) also lacked a functional arc of pronation and supination (50° and 50°, respectively). Of these 61 patients, 32 (53%) were considered to have lost forearm rotation because of HO. The remaining 29 patients (47%) were thought to have restricted forearm rotation for reasons unrelated to HO. DISCUSSION: In this study, loss of pronation-supination affected almost half of the patients (61 of 132 [46%]) undergoing HO excision around the elbow. Of these 61 patients, 32 (52%) had HO extending into the proximal forearm and affecting rotation. From our data, one can expect that about one-quarter (24% of patients in this study, or 32 of 132) with post-traumatic HO of the elbow will have a significant functional loss of pronation-supination due to HO extending into the forearm.

Effects of Hat-Shaped Mortised Genioplasty with Genioglossus Muscle Advancement on Retrogenia and Snoring: Assessment of Esthetic, Functional, and Psychosocial Results.

BACKGROUND: An increasing number of patients undergo genioplasty for esthetic purposes to correct micrognathism or retrognathism. However, these conditions are considered an important risk factor for snoring. The purpose of this study was to evaluate both esthetic improvement and functional changes of snoring symptoms in patients who underwent hat-shaped mortised advancing genioplasty with genioglossus muscle advancement. MATERIALS AND METHODS: This retrospective study enrolled 25 patients. We evaluated scores for subjective snoring classification (Stanford scale) and questionnaire findings for esthetic results. RESULTS: Most people (96%) were satisfied with the esthetic improvement after surgery. The grade of subjective snoring classification (Stanford scale) improved from 8.68 (range 0-10) to 4.08 (range 0-10) after surgery. Twenty-four patients had an improved snoring grade. All patients reported a positive impact on their daily activity and self-confidence, and they were willing to recommend the same operation to someone with the same clinical problems. CONCLUSION: We conclude that hat-shaped mortised advancing genioplasty with genioglossus muscle advancement can relieve the symptoms of snoring for patients with hypoplastic chin or retrogenia. Patients were satisfied with the functional and esthetic results. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Non-fracture stem vs fracture stem of reverse total shoulder arthroplasty in complex proximal humeral fracture of asian elderly.

PURPOSE: Fracture stem of the reverse total shoulder arthroplasty (RTSA) was designed for better tuberosity bone healing for the proximal bone defect of complex proximal humeral fractures (PHF). Our purpose was to compare the clinical and radiological outcomes of patients using fracture stem vs non-fracture (conventional) stem of RTSA in complex PHF of elderly patients. METHODS: Between 2008 March and 2017 June, 48 patients who had undergone an RTSA with non-fracture or fracture stem for complex PHF with a minimum 18 months of follow-up were evaluated. Finally, total 45 patients with a mean age of 80 ± 7 years (65-92 years) were enrolled because three patients were excluded due to age related mortality. We divided them into two groups: 25 patients using non-fracture stem (non-fracture stem group) in the early period of this study, and consecutive 20 patients using fracture stem (fracture stem group) in the later period. Between two groups, we compared clinical and radiologic outcomes such as tuberosity failure, heterotopic ossification (HO), dislocation, acromion fracture, notching, loosening and periprosthetic fracture. RESULTS: In all patients, clinical outcomes were improved significantly and tuberosity failure was found in 62% (28/45). Between two groups, there were no statistically significant differences on clinical outcomes and radiologic outcomes except UCLA score. As complications, two humeral stem revision was performed due to tuberosity failure related HO and stem loosening with subsequent periprosthetic fracture in non-fracture stem group. CONCLUSIONS: Compared to non-fracture stem, fracture stem usage of RTSA in complex PHF of elderly patients has no significant different impact on clinical and radiological outcomes. However, tuberosity failure related secondary HO of non-fracture stem might be responsible for stem loosening and periprosthetic fracture in the RTSA for complex PHF of elderly patients. LEVEL OF EVIDENCE: Level IV, case series study.