Race-specific coregulatory and transcriptomic profiles associated with DNA methylation and androgen receptor in prostate cancer.

BACKGROUND: Prostate cancer is a significant health concern, particularly among African American (AA) men who exhibit higher incidence and mortality compared to European American (EA) men. Understanding the molecular mechanisms underlying these disparities is imperative for enhancing clinical management and achieving better outcomes. METHODS: Employing a multi-omics approach, we analyzed prostate cancer in both AA and EA men. Using Illumina methylation arrays and RNA sequencing, we investigated DNA methylation and gene expression in tumor and non-tumor prostate tissues. Additionally, Boolean analysis was utilized to unravel complex networks contributing to racial disparities in prostate cancer. RESULTS: When comparing tumor and adjacent non-tumor prostate tissues, we found that DNA hypermethylated regions are enriched for PRC2/H3K27me3 pathways and EZH2/SUZ12 cofactors. Olfactory/ribosomal pathways and distinct cofactors, including CTCF and KMT2A, were enriched in DNA hypomethylated regions in prostate tumors from AA men. We identified race-specific inverse associations of DNA methylation with expression of several androgen receptor (AR) associated genes, including the GATA family of transcription factors and TRIM63. This suggests that race-specific dysregulation of the AR signaling pathway exists in prostate cancer. To investigate the effect of AR inhibition on race-specific gene expression changes, we generated in-silico patient-specific prostate cancer Boolean networks. Our simulations revealed prolonged AR inhibition causes significant dysregulation of TGF-ß, IDH1, and cell cycle pathways specifically in AA prostate cancer. We further quantified global gene expression changes, which revealed differential expression of genes related to microtubules, immune function, and TMPRSS2-fusion pathways, specifically in prostate tumors of AA men. Enrichment of these pathways significantly correlated with an altered risk of disease progression in a race-specific manner. CONCLUSIONS: Our study reveals unique signaling networks underlying prostate cancer biology in AA and EA men, offering potential insights for clinical management strategies tailored to specific racial groups. Targeting AR and associated pathways could be particularly beneficial in addressing the disparities observed in prostate cancer outcomes in the context of AA and EA men. Further investigation into these identified pathways may lead to the development of personalized therapeutic approaches to improve outcomes for prostate cancer patients across different racial backgrounds.

CC16 augmentation reduces exaggerated COPD-like disease in Cc16-deficient mice.

Low Club Cell 16 kDa protein (CC16) plasma levels are linked to accelerated lung function decline in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke-exposed (CS-exposed) Cc16-/- mice have exaggerated COPD-like disease associated with increased NF-κB activation in their lungs. It is unclear whether CC16 augmentation can reverse exaggerated COPD in CS-exposed Cc16-/- mice and whether increased NF-κB activation contributes to the exaggerated COPD in CS-exposed Cc16-/- lungs. CS-exposed WT and Cc16-/- mice were treated with recombinant human CC16 (rhCC16) or an NF-κB inhibitor versus vehicle beginning at the midpoint of the exposures. COPD-like disease and NF-κB activation were measured in the lungs. RhCC16 limited the progression of emphysema, small airway fibrosis, and chronic bronchitis-like disease in WT and Cc16-/- mice partly by reducing pulmonary inflammation (reducing myeloid leukocytes and/or increasing regulatory T and/or B cells) and alveolar septal cell apoptosis, reducing NF-κB activation in CS-exposed Cc16-/- lungs, and rescuing the reduced Foxj1 expression in CS-exposed Cc16-/- lungs. IMD0354 treatment reduced exaggerated lung inflammation and rescued the reduced Foxj1 expression in CS-exposed Cc16-/- mice. RhCC16 treatment reduced NF-κB activation in luciferase reporter A549 cells. Thus, rhCC16 treatment limits COPD progression in CS-exposed Cc16-/- mice partly by inhibiting NF-κB activation and represents a potentially novel therapeutic approach for COPD.

[Heterotopic Salivary Gland Tissue at the Hepatic Flexure of the Large Intestine: A Case Report].

The occurrence of heterotopic tissue in the large intestine is unusual. The most common heterotopic tissue type described is gastric-type mucosa. On the other hand, heterotopic salivary gland tissue in the large intestine is extremely rare. To the best of the authors' knowledge, only five cases of heterotopic salivary gland in the large intestine have been reported, and all cases arose in the left colon. One out of five cases arose in the sigmoid colon, and the four other cases were found in the rectum-anal canal region. Endoscopically, they usually appeared as a polyp. The presentation of the patients was rectal bleeding or asymptomatic. Heterotopic salivary gland tissue in the colon has not been reported in Korea. This paper reports a case of heterotopic salivary gland tissue at the hepatic flexure of the colon and reviews the literature on similar cases. A 55-year-old male underwent large bowel endoscopy for colorectal carcinoma screening. The colonoscopy revealed five polyps. A sessile polyp at the hepatic flexure, 0.6 cm in size, was resected in a piecemeal manner. The histopathologic findings revealed a salivary gland with mixed mucinous-serous features and ducts. The other four polyps all were diagnosed as tubular adenoma with low-grade dysplasia.

ATF3 Stimulates IL-17A by Regulating Intracellular Ca2+/ROS-Dependent IL-1ß Activation During Streptococcus pneumoniae Infection.

Activating transcription factor-3 (ATF3) in the ER stress pathway induces cytokine production and promotes survival during gram-positive bacterial infection. IL-17A is a critical cytokine that is essential for clearance of Streptococcus pneumoniae. However, the mechanism by which ATF3 induces IL-17A production remains unknown. Here, we show that ATF3 induces IL-17A production via NLRP3 inflammasome-dependent IL-1ß secretion. Survival rates were comparable in IL-17A-depleted and ATF3 KO mice but were lower than in WT mice treated with isotype control, indicating that ATF3 positively regulated IL-17A production. Indeed, ATF3 KO mice showed a marked reduction in IL-17A protein and mRNA expression compared to levels in WT mice. Moreover, mitochondrial IL-1ß production by bone marrow-derived macrophages was significantly reduced in ATF3 KO mice as a result of the disruption of cellular ROS and Ca2+ homeostasis. Accordingly, ATF3 KO mice displayed diminished survival and bacterial clearance following S. pneumoniae infection. Taken together, these data suggest a mechanism in which macrophage ATF3 promotes IL-17A production in γδ T cells to rapidly induce host defenses during early S. pneumoniae infection.

Effect of Korean Red Ginseng extracts on drug-drug interactions.

BACKGROUND: Ginseng has been the subject of many experimental and clinical studies to uncover the diverse biological activities of its constituent compounds. It is a traditional medicine that has been used for its immunostimulatory, antithrombotic, antioxidative, anti-inflammatory, and anticancer effects. Ginseng may interact with concomitant medications and alter metabolism and/or drug transport, which may alter the known efficacy and safety of a drug; thus, the role of ginseng may be controversial when taken with other medications. METHODS: We extensively assessed the effects of Korean Red Ginseng (KRG) in rats on the expression of enzymes responsible for drug metabolism [cytochrome p450 (CYP)] and transporters [multiple drug resistance (MDR) and organic anion transporter (OAT)] in vitro and on the pharmacokinetics of two probe drugs, midazolam and fexofenadine, after a 2-wk repeated administration of KRG at different doses. RESULTS: The results showed that 30 mg/kg KRG significantly increased the expression level of CYP3A11 protein in the liver and 100 mg/kg KRG increased both the mRNA and protein expression of OAT1 in the kidney. Additionally, KRG significantly increased the mRNA and protein expression of OAT1, OAT3, and MDR1 in the liver. Although there were no significant changes in the metabolism of midazolam to its major metabolite, 1'-hydroxymidazolam, KRG significantly decreased the systemic exposure of fexofenadine in a dose-dependent manner. CONCLUSION: Because KRG is used as a health supplement, there is a risk of KRG overdose; thus, a clinical trial of high doses would be useful. The use of KRG in combination with P-glycoprotein substrate drugs should also be carefully monitored.

Protective roles of fenofibrate against cisplatin-induced ototoxicity by the rescue of peroxisomal and mitochondrial dysfunction.

Cisplatin is an alkylating agent that interferes with DNA replication and kills proliferating carcinogenic cells. Several studies have been conducted to attenuate the side effects of cisplatin; one such side effect in cancer patients undergoing cisplatin chemotherapy is ototoxicity. However, owing to a lack of understanding of the precise mechanism underlying cisplatin-induced side effects, management of cisplatin-induced ototoxicity remains unsolved. We investigated the protective effects of fenofibrate, a PPAR-α activator, on cisplatin-induced ototoxicity. Fenofibrate prevented cisplatin-induced loss of hair cells and improved cell viability; moreover, fenofibrate significantly attenuated the threshold of auditory brainstem responses (ABR) in cisplatin-injected mice. Fenofibrate significantly increased PPAR-α, PPAR-γ, and PGC-1α expression, which consequently resulted in increased number and functional enzyme levels of peroxisomes and mitochondria, and markedly decreased phospho-p53 (S15), activated caspase-3, cleaved-PARP, and NF-κB p65 nuclear translocation, which reduced NADPH oxidase isoform (NOX3 and NOX4) expression, thereby decreasing reactive oxygen species (ROS) production in cisplatin-treated tissues ex vivo. Taken together, these results indicate that fenofibrate rescues cisplatin-induced ototoxicity by maintaining peroxisome and mitochondria number and function, reducing inflammation, and decreasing ROS levels. Our findings suggest that fenofibrate administration might serve as an effective therapeutic agent against cisplatin-induced ototoxicity.

Catalase inhibition induces pexophagy through ROS accumulation.

Peroxisomes are dynamic and multifunctional organelles involved in various cellular metabolic processes, and their numbers are tightly regulated by pexophagy, a selective degradation of peroxisomes through autophagy to maintain peroxisome homeostasis in cells. Catalase, a major peroxisome protein, plays a critical role in removing peroxisome-generated reactive oxygen species (ROS) produced by peroxisome enzymes, but the contribution of catalase to pexophagy has not been reported. Here, we investigated the role of catalase in peroxisome degradation during nutrient deprivation. Both short interfering RNA-mediated silencing of catalase and pharmacological inhibition by 3-aminotriazole (3AT) decreased the number of peroxisomes and resulted in the downregulation of peroxisomal proteins, such as PMP70 and PEX14 under serum starvation. In addition, treatment with 3AT induced NBR1-dependent autophagy and PEX5 ubiquitination in the absence of serum, which was accompanied by accumulation of ROS. Co-treatment with antioxidant agent N-acetyl-l-cysteine (NAC) prevented ROS accumulation and pexophagy by modulating peroxisome protein levels and the association of NBR1, a pexophagy receptor with peroxisomes. Taken together, these findings demonstrate that catalase plays an important role in pexophagy during nutrient deprivation.

Two-stage revision of infected shoulder arthroplasty using prosthesis of antibiotic-loaded acrylic cement: minimum three-year follow-up.

PURPOSE: This study aimed to evaluate the clinical outcomes and persistent infection rate of two-stage revision of infected shoulder arthroplasty. METHODS: We enrolled 12 patients who developed an infection after undergoing shoulder arthroplasty between January 2009 and January 2014. They underwent a two-stage revision with PROSTALAC implantation and shoulder re-implantation in the first- and second-stage surgery, respectively. The mean follow-up period was 40.88 months (range, 36-52 months). After the second-stage re-implantation, clinical scores, erythrocyte sedimentation rate, as well as C-reactive protein level were evaluated, and the presence of re-infection and complications were analyzed. RESULTS: Infection was improved in all the cases after PROSTALAC insertion. The mean range of motion of forward elevation, external rotation, and internal rotation at the final follow-up after the second-stage re-implantation were 81.67°, 40.42°, and 16.67° (vertebral level), respectively. The mean visual analog scale score improved from 7.08 points before surgery to 2.33 points after surgery. The Modified American Shoulder and Elbow Surgeons score improved from 32.25 before surgery to 64.17 after surgery (P < 0.05). The Constant shoulder score also improved from 30.92 before surgery to 66.08 after surgery (P < 0.05). Infection had not recurred until the final follow-up. However, dislocation and separation of components were found in two patients who needed a structural allograft because of segmental bone defects. CONCLUSION: Using PROSTALAC in two-stage revision arthroplasty is effective for infection control and produced good clinical outcomes after second-stage shoulder re-implantation. However, cases involving segmental bone defects require additional precautions in maintaining the appropriate tension and height to prevent complications.

Comparison of Clinical and Structural Outcomes by Subscapularis Tendon Status in Massive Rotator Cuff Tear.

BACKGROUND: The subscapularis tendon is essential in maintaining normal glenohumeral biomechanics. However, few studies have addressed the outcomes of tears extending to the subscapularis tendon in massive rotator cuff tears. PURPOSE: To assess the clinical and structural outcomes of arthroscopic repair of massive rotator cuff tears involving the subscapularis. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Between January 2010 and January 2014, 122 consecutive patients with massive rotator cuff tear underwent arthroscopic rotator cuff repair. Overall, 122 patients were enrolled (mean age, 66 years; mean follow-up period, 39.5 months). Patients were categorized into 3 groups based on subscapularis tendon status: intact subscapularis tendon (I group; n = 45), tear involving less than the superior one-third (P group; n = 35), and tear involving more than one-third of the subscapularis tendon (C group; n = 42). All rotator cuff tears were repaired; however, subscapularis tendon tears involving less than the superior one-third in P group were only debrided. Pain visual analog scale, Constant, and American Shoulder and Elbow Surgeons scores and passive range of motion were measured preoperatively and at the final follow-up. Rotator cuff integrity, global fatty degeneration index, and occupation ratio were determined via magnetic resonance imaging preoperatively and 6 months postoperatively. RESULTS: We identified 37 retears (31.1%) based on postoperative magnetic resonance imaging evaluation. Retear rate in patients in the C group (47.6%) was higher than that in the I group (22.9%) or P group (20.0%) ( P = .011). Retear subclassification based on the involved tendons showed that subsequent subscapularis tendon retears were noted in only the C group. The improvement in clinical scores after repair was statistically significant in all groups but not different among the groups. Between-group comparison showed significant differences in preoperative external rotation ( P = .021). However, no statistically significant difference was found in any shoulder range of motion measurements after surgery. CONCLUSION: Arthroscopic repair of massive tears results in substantial improvements in shoulder function, despite the presence of combined subscapularis tears. However, this study showed a high failure rate of massive posterosuperior rotator cuff tear repair extending more than one-third of the subscapularis tendon. When combined subscapularis tendon tear was less than the superior one-third of the subscapularis tendon, arthroscopic debridement was a reasonable treatment method where comparable clinical and anatomic outcomes could be expected.

Retrospective Comparative Analysis of Elbow Arthroscopy Used to Treat Primary Osteoarthritis With and Without Release of the Posterior Band of the Medial Collateral Ligament.

PURPOSE: To evaluate the clinical and functional outcomes of arthroscopic debridement arthroplasty with the release of the posterior band of the medial collateral ligament in patients with primary osteoarthritis. METHODS: We evaluated 43 patients treated with arthroscopic debridement arthroplasty for elbow osteoarthritis from February 2006 to February 2014. In group A (n = 19), the posterior band of the medial collateral ligament was released, and in group B (n = 24), it was not released. The mean follow-up period in groups A and B was 55.4 months (range, 24-100 months) and 62.2 months (range, 24-103 months), respectively. Clinical results were evaluated by measuring the preoperative and postoperative range of motion (ROM) of the elbow, visual analog scale score, and Mayo Elbow Performance Score. RESULTS: Both groups showed significant improvement in clinical outcome (visual analog scale and Mayo Elbow Performance Score) at the final follow-up compared with preoperative evaluation (group A, P = .009 and .013, respectively; group B, P = .015 and .008, respectively). Group A showed significant improvement in increased flexion at 6 months of follow-up (P = .043). However, there was no statistically significant difference in postoperative ROM and clinical results between the 2 groups at the final follow-up (P = .482). CONCLUSIONS: Arthroscopic debridement arthroplasty with the release of the posterior band of the medial collateral ligament was associated with improved flexion at the 6-month postoperative follow-up, but no significant difference between the groups was observed at the final follow-up. Therefore, the additional release of the posterior band of the medial collateral ligament may be unnecessary for improving postoperative ROM. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Fenofibrate exerts protective effects against gentamicin-induced toxicity in cochlear hair cells by activating antioxidant enzymes.

Fenofibrate, an activator of peroxisome proliferator-activated receptors (PPARs), has been shown to protect the kidneys and brain cells from oxidative stress; however, its role in preventing hearing loss has not been reported to date, at least to the best of our knowledge. In this study, we demonstrated the protective effects of fenofibrate against gentamicin (GM)-induced ototoxicity. We found that the auditory brainstem response threshold which was increased by GM was significantly reduced by pre-treatment with fenofibrate in rats. In cochlear explants, the disruption of hair cell layers by GM was also markedly attenuated by pre-treatment with fenofibrate. In addition, fenofibrate almost completely abolished GM-induced reactive oxygen species generation, which seemed to be mediated at least in part by the restoration of the expression of PPAR­α­dependent antioxidant enzymes, including catalase and superoxide dismutase (SOD)-1. Of note, fenofibrate markedly increased the expression of heme oxygenase-1 (HO-1) which was also induced to a certain degree by GM alone. The induced expression of HO-1 by fenofibrate appeared to be essential for mediating the protective effects of fenofibrate, as the inhibition of HO-1 activity significantly diminished the protective effects of fenofibrate against the GM-mediated death of sensory hair cells in cochlea explant culture, as well as in zebrafish neuromasts. These results suggest that fenofibrate protects sensory hair cells from GM-induced toxicity by upregulating PPAR­α-dependent antioxidant enzymes, including HO-1. Our results provide insight into the preventive therapy for hearing loss caused by aminoglycoside antibiotics.

Is the arthroscopic suture bridge technique suitable for full-thickness rotator cuff tears of any size?

PURPOSE: The purpose of this study was to compare functional outcomes and tendon integrity between the suture bridge and modified tension band techniques for arthroscopic rotator cuff repair. METHODS: A consecutive series of 128 patients who underwent the modified tension band (MTB group; 69 patients) and suture bridge (SB group; 59 patients) techniques were enrolled. The pain visual analogue scale (VAS), Constant, and American Shoulder and Elbow Surgeons (ASES) scores were determined preoperatively and at the final follow-up. Rotator cuff hypotrophy was quantified by calculating the occupation ratio (OR). Rotator cuff integrity and the global fatty degeneration index were determined by using magnetic resonance imaging at 6 months postoperatively. RESULTS: The average VAS, Constant, and ASES scores improved significantly at the final follow-up in both groups (p < 0.05 for all scores). The retear rate of small-to-medium tears was similar in the modified tension band and suture bridge groups (7.0 vs. 6.8%, respectively; p = n.s.). The retear rate of large-to-massive tears was significantly lower in the suture bridge group than in the modified tension band group (33.3 vs. 70%; p = 0.035). Fatty infiltration (postoperative global fatty degeneration index, p = 0.022) and muscle hypotrophy (postoperative OR, p = 0.038) outcomes were significantly better with the suture bridge technique. CONCLUSION: The retear rate was lower with the suture bridge technique in the case of large-to-massive rotator cuff tears. Additionally, significant improvements in hypotrophy and fatty infiltration of the rotator cuff were obtained with the suture bridge technique, possibly resulting in better anatomical outcomes. The suture bridge technique was a more effective method for the repair of rotator cuff tears of all sizes as compared to the modified tension band technique. LEVEL OF EVIDENCE: Retrospective Cohort Design, Treatment Study, level III.

Tetrabromobisphenol-A induces apoptotic death of auditory cells and hearing loss.

Phenolic tetrabromobisphenol-A (TBBPA) and its derivatives are commonly used flame-retardants, in spite of reported toxic effects including neurotoxicity, immunotoxicity, nephrotoxicity, and hepatotoxicity. However, the effects of TBBPA on ototoxicity have not yet been reported. In this study, we investigated the effect of TBBPA on hearing function in vivo and in vitro. Auditory Brainstem Response (ABR) threshold was markedly increased in mice after oral administration of TBBPA, indicating that TBBPA causes hearing loss. In addition, TBBPA induced the loss of both zebrafish neuromasts and hair cells in the rat cochlea in a dose-dependent manner. Mechanistically, hearing loss is largely attributed to apoptotic cell death, as TBBPA increased the expression of pro-apoptotic genes but decreased the expression of anti-apoptotic genes. We also found that TBBPA induced oxidative stress, and importantly, pretreatment with NAC, an anti-oxidant reagent, reduced TBBPA-induced reactive oxygen species (ROS) generation and partially prevented cell death. Our results show that TBBPA-mediated ROS generation induces ototoxicity and hearing loss. These findings implicate TBBPA as a potential environmental ototoxin by exerting its hazardous effects on the auditory system.

Clinical characteristics and factors predicting respiratory failure in adenovirus pneumonia.

BACKGROUND AND OBJECTIVE: Limited data exist regarding factors predicting respiratory failure (RF) in non-immunocompromised patients with adenovirus (AdV) pneumonia. METHODS: We described characteristics of AdV pneumonia (n = 91) versus non-AdV pneumonia (n = 55) and compared clinico-laboratory and radiological characteristics in patient groups categorized by RF. RESULTS: All 91 AdV pneumonia patients presented with acute respiratory symptoms and radiological infiltrations and had significantly lower levels of white blood cell counts and platelet counts compared with non-AdV pneumonia. Of them, 67 patients had mild pneumonia without RF (non-RF), 14 patients had no RF at admission but progressed to RF during hospitalization (progressed to RF) and 10 patients had RF at admission (initial RF). Initial monocyte percentage and absolute monocyte counts in RF patient groups (progressed to RF and initial RF) were significantly lower than those of non-RF patients (both P < 0.001), and the differences among progressed to RF and initial RF patients were not significant. Chest computed tomography findings such as dominant pattern or distribution, clinical symptoms, and bacterial or viral co-infections other than AdV were not discriminable between patients who had RF and those who did not. On univariate analysis, initial monocytopenia, multilobar infiltrations and pleural effusion were associated with RF. However, on multivariable analysis, only initial monocytopenia remained significant (P = 0.004) for predicting RF. CONCLUSION: Our data suggest that initial monocytopenia may help to predict RF during the course of AdV pneumonia in non-immunocompromised patients.

Clinical Characteristics and Factors Influencing the Occurrence of Acute Eosinophilic Pneumonia in Korean Military Personnel.

Acute eosinophilic pneumonia (AEP) is an uncommon inflammatory lung disease, and limited data exist concerning the clinical characteristics and factors that influence its occurrence. We retrospectively reviewed the records of AEP patients treated at Korean military hospitals between January 2007 and December 2013. In total, 333 patients were identified; their median age was 22 years, and all were men. All patients presented with acute respiratory symptoms (cough, sputum, dyspnea, or fever) and had elevated levels of inflammatory markers including median values of 13,185/µL for white blood cell count and 9.51 mg/dL for C-reactive protein. All patients showed diffuse ground glass opacity/consolidation, and most had pleural effusion (n = 265; 80%) or interlobular septal thickening (n = 265; 85%) on chest computed tomography. Most patients had normal body mass index (n = 255; 77%), and only 30 (9%) patients had underlying diseases including rhinitis, asthma, or atopic dermatitis. Most patients had recently changed smoking habits (n = 288; 87%) and were Army personnel (n = 297; 89%).The AEP incidence was higher in the Army group compared to the Navy or Air Force group for every year (P = 0.002). Both the number of patients and patients with high illness severity (oxygen requirement, intensive care unit admission, and pneumonia severity score class ≥ III) tended to increase as seasonal temperatures rose. We describe the clinical characteristics of AEP and demonstrate that AEP patients have recently changed smoking habits and work for the Army. There is an increasing tendency in the numbers of patients and those with higher AEP severity with rising seasonal temperatures.

Surgical Technique for Arthroscopic Lateral Collateral Ligament Repair.

INTRODUCTION: Arthroscopic repair of the lateral collateral ligament (LCL) complex in patients who have posterolateral rotatory instability after an unstable elbow dislocation, with or without an intra-articular fracture, is an alternative treatment for restoring stability of the elbow and obtaining successful clinical and radiographic results. STEP 1 COMPUTED TOMOGRAPHY CT MAGNETIC RESONANCE IMAGING MRI AND PREOPERATIVE PLANNING: Obtain radiographs and CT and MRI scans to make an accurate analysis of the fracture patterns and develop an understanding of soft-tissue comorbidities. STEP 2 POSITION THE PATIENT AND PLACE THE PORTALS: Place the patient in the lateral decubitus position and create proximal anteromedial, proximal anterolateral, anterolateral, and radial head portals as working portals and a posterior soft-spot portal as a viewing portal for the repair of the LCL complex. STEP 3 DIAGNOSTIC ARTHROSCOPY: Identify concomitant radial head and coronoid fractures, and confirm the LCL-complex tear intraoperatively. STEP 4 MANAGEMENT OF CONCOMITANT INJURIES: Treat intra-articular fractures arthroscopically before the LCL-complex repair. STEP 5 ARTHROSCOPIC LCL-COMPLEX REPAIR VIDEO 1: After soft-tissue debridement using the soft-spot portal as a viewing portal and the proximal anterolateral portal as a working portal, decorticate the footprint of the humeral attachment of the LCL complex with use of a shaver or burr and then make a modified Mason-Allen stitch using a needle, fixing the suture with a knotless anchor, to achieve a stable elbow joint. STEP 6 POSTOPERATIVE MANAGEMENT: After postoperative immobilization of the elbow for 2 to 3 days, instruct the patient to perform passive exercises, returning to a full range of motion at 4 to 6 weeks after surgery, and typically returning to full activity at 3 months after the operation. RESULTS: To date, arthroscopic LCL-complex repair has produced excellent results, with all 13 patients in our original study reporting complete resolution of the elbow instability and demonstrating a negative result on the lateral pivot-shift test15.

Cartilage development requires the function of Estrogen-related receptor alpha that directly regulates sox9 expression in zebrafish.

Estrogen-related receptor alpha (ESRRa) regulates a number of cellular processes including development of bone and muscles. However, direct evidence regarding its involvement in cartilage development remains elusive. In this report, we establish an in vivo role of Esrra in cartilage development during embryogenesis in zebrafish. Gene expression analysis indicates that esrra is expressed in developing pharyngeal arches where genes necessary for cartilage development are also expressed. Loss of function analysis shows that knockdown of esrra impairs expression of genes including sox9, col2a1, sox5, sox6, runx2 and col10a1 thus induces abnormally formed cartilage in pharyngeal arches. Importantly, we identify putative ESRRa binding elements in upstream regions of sox9 to which ESRRa can directly bind, indicating that Esrra may directly regulate sox9 expression. Accordingly, ectopic expression of sox9 rescues defective formation of cartilage induced by the knockdown of esrra. Taken together, our results indicate for the first time that ESRRa is essential for cartilage development by regulating sox9 expression during vertebrate development.

Erdosteine protects HEI-OC1 auditory cells from cisplatin toxicity through suppression of inflammatory cytokines and induction of Nrf2 target proteins.

Cisplatin has many adverse effects, which are a major limitation to its use, including ototoxicity, neurotoxicity, and nephrotoxicity. This study aims to elucidate the protective mechanisms of erdosteine against cisplatin in HEI-OC1 cells. Pretreatment with erdosteine protects HEI-OC1 cells from cisplatin-medicated apoptosis, which is characterized by increase in nuclear fragmentation, DNA laddering, sub-G0/G1 phase, H2AX phosphorylation, PARP cleavage, and caspase-3 activity. Erdosteine significantly suppressed the production of reactive nitrogen/oxygen species and pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 in cisplatin-treated cells. Studies using pharmacologic inhibitors demonstrated that phosphatidylinositol-3-kinases (PI3K) and protein kinase B (Akt) have protective roles in the action of erdosteine against cisplatin in HEI-OC1 cells. In addition, pretreatment with erdosteine clearly suppressed the phosphorylation of p53 (Ser15) and expression of p53-upregulated modulator of apoptosis. Erdosteine markedly induces expression of NF-E2-related factor 2 (Nrf2), which may contribute to the increase in expression of glutathione redox genes γ-l-glutamate-l-cysteine-ligase catalytic and γ-l-glutamate-l-cysteine-ligase modifier subunits, as well as in the antioxidant genes HO-1 and SOD2 in cisplatin-treated HEI-OC1 cells. Furthermore, the increase in expression of phosphorylated p53 induced by cisplatin is markedly attenuated by pretreatment with erdosteine in the mitochondrial fraction. This increased expression may inhibit the cytosolic expression of the apoptosis-inducing factor, cytochrome c, and Bax/Bcl-xL ratio. Thus, our results suggest that treatment with erdosteine is significantly attenuated cisplatin-induced damage through the activation of Nrf2-dependent antioxidant genes, inhibition of pro-inflammatory cytokines, activation of the PI3K/Akt signaling, and mitochondrial-related inhibition of pro-apoptotic protein expression in HEI-OC1 auditory cells.

The Clinical Courses of Patients with Congenital Cystic Adenomatoid Malformation Complicated by Pneumonia.

PURPOSE: We evaluated the clinical characteristics and courses of patients with congenital cystic adenomatoid malformation (CCAM) complicated by pneumonia. MATERIALS AND METHODS: We retrospectively reviewed the records of 19 adult patients with surgically confirmed CCAM between March 2005 and July 2013. RESULTS: Eighteen of nineteen patients presented with acute pneumonia symptoms and signs, and inflammatory markers were elevated. On chest computed tomography, all 18 patients had parenchymal infiltration around cystic lesions, 17 (94%) had an air-fluid level, and 2 (11%) had pleural effusion. After antibiotics treatment for a median of 22 days prior to surgery, all acute pneumonia symptoms and signs disappeared in 17 (94%) patients at a median of 10 days. Improvements and normalization of inflammatory marker levels, occurred in 17 (94%) and 9 (50%) patients at medians of 8 and 17 days, respectively. Radiological improvement was evident in 11 (61%) patients, at a median of 18 days, of these patients, partial radiological improvement occurred in 10 (56%) and complete radiological resolution in only 1 (6%). One patient (6%) did not improve in terms of clinical, laboratory, or radiological findings despite antibiotic treatment for 13 days. Consequently, after 17 (94%) elective and 1 (6%) emergency surgeries, all patients improved without development of complications. CONCLUSION: We described the clinical characteristics and courses of patients with CCAM complicated by pneumonia, and showed that surgery may be performed safely after clinicolaboratory improvement is attained upon antibiotic treatment, even in the absence of complete radiological resolution.

The effect of electronic cigarette advertising on intended use among college students.

INTRODUCTION: . Aside from prohibiting health claims, there are presently no restrictions on electronic cigarette advertising in the U.S. Studies have shown college students have a positive view of e-cigarettes and use on campuses is increasing. The purpose of this study was to test if the appeal of e-cigarette advertisements and beliefs about the addictiveness of e-cigarettes may affect their uptake among college students. METHODS: The study was framed within the Theory of Reasoned Action, which posits that behavioral intention can be understood in terms of social norms and attitudes toward a behavior. We also included variables capturing appeal of e-cigarette advertisements, belief that e-cigarettes are not as addictive as cigarettes, and tobacco use. Attitudes toward e-cigarettes, perceived norms concerning their use, beliefs that e-cigarettes are not as addictive as cigarettes, and positive appraisal of e-cigarette advertising videos were all hypothesized to be independently positively associated with intention to use an e-cigarette. Data were collected through a survey of students at a major U.S. university (participation rate 78%, N=296). Participants were exposed to three e-cigarette video advertisements in random order. RESULTS: In a regression analysis we found positive reaction to the ads and holding the belief that e-cigarettes are not as addictive were both independently associated with intention. Attitudes and norms were also associated but were controlled by inclusion of the other variables. CONCLUSIONS: These findings suggest that advertising may promote the uptake of e-cigarettes and may do so in addition to current smoking and alternate tobacco use status.