Calcitonin Gene-Related Peptide Negatively Regulates Alarmin-Driven Type 2 Innate Lymphoid Cell Responses.

Neuroimmune interactions have emerged as critical modulators of allergic inflammation, and type 2 innate lymphoid cells (ILC2s) are an important cell type for mediating these interactions. Here, we show that ILC2s expressed both the neuropeptide calcitonin gene-related peptide (CGRP) and its receptor. CGRP potently inhibited alarmin-driven type 2 cytokine production and proliferation by lung ILC2s both in vitro and in vivo. CGRP induced marked changes in ILC2 expression programs in vivo and in vitro, attenuating alarmin-driven proliferative and effector responses. A distinct subset of ILCs scored highly for a CGRP-specific gene signature after in vivo alarmin stimulation, suggesting CGRP regulated this response. Finally, we observed increased ILC2 proliferation and type 2 cytokine production as well as exaggerated responses to alarmins in mice lacking the CGRP receptor. Together, these data indicate that endogenous CGRP is a critical negative regulator of ILC2 responses in vivo.

Prevalence and Clinical Characteristics of Mitochondrial DNA Mutations in Korean Patients With Sensorineural Hearing Loss.

BACKGROUND: Mutations in mitochondrial DNA (mtDNA) are associated with several genetic disorders, including sensorineural hearing loss. However, the prevalence of mtDNA mutations in a large cohort of Korean patients with hearing loss has not yet been investigated. Thus, this study aimed to investigate the frequency of mtDNA mutations in a cohort of with pre- or post-lingual hearing loss of varying severity. METHODS: A total of 711 Korean families involving 1,099 individuals were evaluated. Six mitochondrial variants associated with deafness (MTRNR1 m.1555A>G, MTTL1 m.3243A>G, MTCO1 m.7444G>A and m.7445A>G, and MTTS1 m.7471dupC and m.7511T>C) were screened using restriction fragment length polymorphism. The prevalence of the six variants was also analyzed in a large control dataset using whole-genome sequencing data from 4,534 Korean individuals with unknown hearing phenotype. RESULTS: Overall, 12 of the 711 (1.7%) patients with hearing loss had mtDNA variants, with 10 patients from independent families positive for the MTRNR1 m.1555A>G mutation and 2 patients positive for the MTCO1 m.7444G>A mutation. The clinical characteristics of patients with the mtDNA variants were characterized by post-lingual progressive hearing loss due to the m.1555A>G variant (9 of 472; 1.9%). In addition, 18/4,534 (0.4%) of the Korean population have mitochondrial variants associated with hearing loss, predominantly the m.1555A>G variant. CONCLUSION: A significant proportion of Korean patients with hearing loss is affected by the mtDNA variants, with the m.1555A>G variant being the most prevalent. These results clarify the genetic basis of hearing loss in the Korean population and emphasize the need for genetic testing for mtDNA variants.

MR1- and HLA-E-Dependent Antigen Presentation of Mycobacterium tuberculosis.

MR1 and HLA-E are highly conserved nonclassical antigen-presenting molecules. They can present antigens derived from Mycobacterium tuberculosis to a distinct subset of MR1-restricted or HLA-restricted CD8+ T cells. MR1 presents small microbial metabolites, and HLA-E presents peptides and glycopeptides. In this review, we will discuss the current understanding of MR1 and HLA-E antigen presentation in the context of Mycobacterium tuberculosis infection.

Slc25a17 acts as a peroxisomal coenzyme A transporter and regulates multiorgan development in zebrafish.

Slc25a17 is known as a peroxisomal solute carrier, but the in vivo role of the protein has not been demonstrated. We found that the zebrafish genome contains two slc25a17 genes that function redundantly, but additively. Notably, peroxisome function in slc25a17 knockdown embryos is severely compromised, resulting in an altered lipid composition. Along the defects found in peroxisome-associated phenotypic presentations, we highlighted that development of the swim bladder is also highly dependent on Slc25a17 function. As Slc25a17 showed substrate specificity towards coenzyme A (CoA), injecting CoA, but not NAD+ , rescued the defective swim bladder induced by slc25a17 knockdown. These results indicated that Slc25a17 acts as a CoA transporter, involved in the maintenance of functional peroxisomes that are essential for the development of multiple organs during zebrafish embryogenesis. Given high homology in protein sequences, the role of zebrafish Slc25a17 may also be applicable to the mammalian system.

Safety, tolerability and pharmacokinetics and pharmacodynamics of HL2351, a novel hybrid fc-fused interleukin-1 receptor antagonist, in healthy subjects: A first-in-human study.

AIMS: We performed a first-in-human study with HL2351, a novel hybrid Fc-fused interleukin (IL)-1 receptor antagonist, to evaluate its tolerability, pharmacokinetics and pharmacodynamics (PD) after a single subcutaneous (SC) administration in healthy subjects. METHODS: A randomized, double-blind, placebo- and active-controlled, dose-escalation study was conducted. Eligible subjects randomly received a single SC administration of HL2351 (1, 2, 4, 8 and 12 mg/kg) or placebo in a ratio of 8:2. Subjects in the active-controlled group received a single SC administration of anakinra at 100 mg. Serial blood samples were collected for pharmacokinetics and PD analyses. An ex-vivo activation test was performed to evaluate the PD using peripheral blood mononuclear cells treated with IL-1ß. Anti-HL2351 antibodies were determined at baseline and 29 days postdose. Tolerability was assessed throughout the study. RESULTS: HL2351 was eliminated more slowly than anakinra (terminal half-life: 27.21-45.28 vs 3.97 h). Serum concentrations of HL2351 were increased dose-proportionally. The mean apparent clearance of HL2351 were 0.6, 0.66, 0.75, 0.51, 0.65 L/h at 1, 2, 4, 8 and 12 mg/kg, respectively. The percent inhibition of IL-6 expression varied widely (range: 0-92.1%), showing no clear trend or discernible difference between HL2351, anakinra and placebo. HL2351 was well tolerated after a single SC administration. CONCLUSION: HL2351 was well tolerated and showed linear pharmacokinetic characteristics after a single SC administration at doses up to 12 mg/kg in healthy subjects. HL2351 remained in the body 7-11 times longer than anakinra. HL2351 can be developed as a potential therapeutic alternative to anakinra.

Teneligliptin versus sitagliptin in Korean patients with type 2 diabetes inadequately controlled with metformin and glimepiride: A randomized, double-blind, non-inferiority trial.

AIM: To assess the efficacy and safety of add-on therapy with the dipeptidyl peptidase-4 inhibitor teneligliptin compared with sitagliptin in patients with type 2 diabetes (T2DM) inadequately controlled with metformin and glimepiride. MATERIALS AND METHODS: This was a phase 3, randomized, double-blind, non-inferiority study of adult Korean subjects with T2DM (n = 201), with HbA1c ranging from 7.0% to 11.0%, on stable doses of metformin plus glimepiride. Subjects were randomized in a 1:1 fashion to receive either oral teneligliptin 20 mg or sitagliptin 100 mg for 24 weeks. The primary endpoint was change from baseline in HbA1c. RESULTS: At baseline, mean age was 60.56 ± 9.41 years, body mass index was 25.23 ± 2.85 kg/m2 and HbA1c was 8.11% ± 0.79%. At 24 weeks, both groups achieved significant reductions from baseline in HbA1c (teneligliptin, -1.03% ± 0.10% [P < 0.0001]; sitagliptin, -1.02% ± 0.10% [P < 0.0001]). The inter-group difference was -0.01% (95% confidence interval [CI]: -0.28, 0.26; P = 0.9497); the upper limit of the 95% CI was within the preset limit for non-inferiority (0.4%). There were no significant differences between groups in the proportion of patients achieving HbA1c targets, or changes from baseline in fasting plasma glucose, body weight or lipid levels at 24 weeks. Rates of adverse events (teneligliptin, n = 63 [61.76%]; sitagliptin, n = 61 [62.24%]; P = 0.9442) and hypoglycaemia (teneligliptin, n = 32 [31.37%]; sitagliptin, n = 28 [28.57%]; P = 0.6656) were similar. CONCLUSION: Teneligliptin was non-inferior to sitagliptin in the context of triple therapy for T2DM and is an important option in this setting.

Pulmonary Colonization Resistance to Pathogens via Noncanonical Wnt and Interleukin-17A by Intranasal pep27 Mutant Immunization.

Background: Previous studies have focused on colonization resistance of the gut microbiota against antibiotic resistant strains. However, less research has been performed on respiratory colonization resistance. Methods: Because respiratory colonization is the first step of respiratory infections, intervention to prevent colonization would represent a new approach for preventive and therapeutic measures. The Th17 response plays an important role in clearance of respiratory pathogens. Thus, harnessing the Th17 immune response in the mucosal site would be an effective method to design a respiratory mucosal vaccine. Results: In this study, we show that intranasal Δpep27 immunization induces noncanonical Wnt and subsequent interleukin (IL)-17 secretion, and it inhibits Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae colonization. Moreover, IL-17A neutralization or nuclear factor of activated T-cell inhibition augmented bacterial colonization, indicating that noncanonical Wnt signaling is involved in pulmonary colonization resistance. Conclusions: Therefore, Δpep27 immunization can provide nonspecific respiratory colonization resistance via noncanonical Wnt signaling and IL-17A-related pathways.

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.

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.

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.

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.

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.

2,2'-dipyridyl induces pexophagy.

Pexophagy is the selective degradation of peroxisomes for maintaining peroxisome homeostasis within cells. Peroxisome dynamics and pexophagy are important events required to maintain the quality control of peroxisomes, thereby preventing peroxisome-associated diseases. To identify novel pexophagy modulators, we developed a cell-based screening system and selected 2,2'-dipyridyl (2,2-DP) as a candidate molecule. 2,2-DP treatment induced peroxisome degradation as evidenced by an increased number of low-pH autolysosomes originating from peroxisomes and a decrease in the expression of peroxisomal proteins such as catalase, Pex14, and PMP70. The phenotype was defined as pexophagy, because 2,2-DP induced autophagy and inhibition of autophagy significantly reduced the degree of peroxisome degradation. Mechanistically, 2,2-DP-dependent pexophagy seemed to be mediated by iron chelation, since another iron chelator displayed a similar effect on pexophagy, but a copper chelator did not. Notably, iron replenishment prevented 2,2-DP-mediated pexophagy. Taken together, our results suggest that 2,2-DP treatment disrupts peroxisome dynamics and promotes pexophagy through iron depletion.

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.

3-Aminotriazole protects from CoCl2-induced ototoxicity by inhibiting the generation of reactive oxygen species and proinflammatory cytokines in mice.

Cobalt is an essential heavy metal that is necessary for the formation of vitamin B12 (hydroxocobalamin). However, exposure to excess cobalt for a prolonged period can harm the human body, causing pulmonary fibrosis, blindness, deafness, and peripheral neuropathy. 3-Aminotriazole (3-AT) is a catalase inhibitor that is often used to investigate the physiological effects of catalase. The present study found that injection of 3-AT in mice significantly reduced CoCl2-induced hearing impairment. In cultured organ of Corti explants from rats, 3-AT treatment protected hair cells from CoCl2-induced cytotoxicity. To determine the mechanism by which 3-AT protected from CoCl2-induced ototoxicity, we used the HEI-OC1 auditory cell line. Pretreatment with 10 mM 3-AT attenuated CoCl2-induced accumulation of ROS and induction of proinflammatory cytokine expression. Interestingly, these protective effects of 3-AT did not require catalase activity, as demonstrated by a series of experiments using RNA interference-mediated catalase knockdown in HEI-OC1 cells and using catalase-deficient mouse embryonic fibroblasts. Our results demonstrated the mechanisms of CoCl2-induced ototoxicity that may provide better ways to prevent the ototoxic effect of cobalt exposure.

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.

Proteasome inhibitors induce auditory hair cell death through peroxisome dysfunction.

Even though bortezomib, a proteasome inhibitor, is a powerful chemotherapeutic agent used to treat multiple myeloma (MM) and other lymphoma cells, recent clinical reports suggest that the proteasome inhibitor therapy may be associated with severe bilateral hearing loss. We herein investigated the adverse effect of proteasome inhibitor on auditory hair cells. Treatment of a proteasome inhibitor destroys stereocilia bundles of hair cells resulting in the disarray of stereocilia in the organ of Corti explants. Since proteasome activity may be potentially important for biogenesis and function of the peroxisome, we tested whether proteasome activity is necessary for maintaining functional peroxisomes. Our results showed that treatment of a proteasome inhibitor significantly decreases both the number of peroxisomes and expression of peroxisomal proteins such as PMP70 and Catalase. In addition, we also found that proteasome inhibitor impairs the import pathway of PTS1-peroxisome matrix proteins. Taken together, our findings support recent clinical reports of hearing loss associated with proteasome inhibition. Mechanistically, peroxisome dysfunction may contribute to hair cell damage and hearing loss in response to the treatment of a proteasome inhibitor.

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.

Outcomes of rapid corticosteroid tapering in acute eosinophilic pneumonia patients with initial eosinophilia.

BACKGROUND AND OBJECTIVE: Studies have shown that patients with acute eosinophilic pneumonia (AEP) and with initial eosinophilia have a milder disease than those with an initial normal peripheral eosinophil count (PEC). We investigated the effect of a rapid corticosteroid tapering strategy in AEP patients with initial eosinophilia. METHODS: We performed a prospective cohort study in patients with AEP with initial eosinophilia (n = 14) who stopped corticosteroid treatment after achieving clinical stabilization compared with AEP patients with an initial normal PEC (n = 45) who received 2-week treatment with corticosteroid. RESULTS: In total, 59 AEP patients were identified. The median duration of corticosteroid treatment was 4 days (interquartile ranges (IQR), 3-4) in patients with initial eosinophilia and 14 (IQR, 14-14) days in patients with initial normal PEC. No treatment failure occurred in the group with initial eosinophilia; one treatment failure case occurred in the group with an initially normal PEC. The median time to overall clinical stabilization was 3 days, and time to complete resolution of all symptoms and clinical instabilities from diagnosis was 4 days in AEP patients with initial eosinophilia. Both were significantly shorter than those) in the initially normal PEC group, which were 5 and 7 days respectively (both P < 0.001). Adverse effects were lower in AEP patients with initial eosinophilia, and additional medications to relieve adverse effects were only needed in AEP patients with initially normal PEC. CONCLUSIONS: Rapid corticosteroid tapering may be an acceptable treatment strategy for managing AEP patients with initial eosinophilia.