TNF in Human Tuberculosis: A Double-Edged Sword.

TNF, a pleiotropic proinflammatory cytokine, is important for protective immunity and immunopathology during Mycobacterium tuberculosis (Mtb) infection, which causes tuberculosis (TB) in humans. TNF is produced primarily by phagocytes in the lungs during the early stages of Mtb infection and performs diverse physiological and pathological functions by binding to its receptors in a context-dependent manner. TNF is essential for granuloma formation, chronic infection prevention, and macrophage recruitment to and activation at the site of infection. In animal models, TNF, in cooperation with chemokines, contributes to the initiation, maintenance, and clearance of mycobacteria in granulomas. Although anti-TNF therapy is effective against immune diseases such as rheumatoid arthritis, it carries the risk of reactivating TB. Furthermore, TNF-associated inflammation contributes to cachexia in patients with TB. This review focuses on the multifaceted role of TNF in the pathogenesis and prevention of TB and underscores the importance of investigating the functions of TNF and its receptors in the establishment of protective immunity against and in the pathology of TB. Such investigations will facilitate the development of therapeutic strategies that target TNF signaling, which makes beneficial and detrimental contributions to the pathogenesis of TB.

Rejuvenating aged microglia by p16ink4a-siRNA-loaded nanoparticles increases amyloid-ß clearance in animal models of Alzheimer's disease.

Age-dependent accumulation of amyloid plaques in patients with sporadic Alzheimer's disease (AD) is associated with reduced amyloid clearance. Older microglia have a reduced ability to phagocytose amyloid, so phagocytosis of amyloid plaques by microglia could be regulated to prevent amyloid accumulation. Furthermore, considering the aging-related disruption of cell cycle machinery in old microglia, we hypothesize that regulating their cell cycle could rejuvenate them and enhance their ability to promote more efficient amyloid clearance. First, we used gene ontology analysis of microglia from young and old mice to identify differential expression of cyclin-dependent kinase inhibitor 2A (p16ink4a), a cell cycle factor related to aging. We found that p16ink4a expression was increased in microglia near amyloid plaques in brain tissue from patients with AD and 5XFAD mice, a model of AD. In BV2 microglia, small interfering RNA (siRNA)-mediated p16ink4a downregulation transformed microglia with enhanced amyloid phagocytic capacity through regulated the cell cycle and increased cell proliferation. To regulate microglial phagocytosis by gene transduction, we used poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, which predominantly target microglia, to deliver the siRNA and to control microglial reactivity. Nanoparticle-based delivery of p16ink4a siRNA reduced amyloid plaque formation and the number of aged microglia surrounding the plaque and reversed learning deterioration and spatial memory deficits. We propose that downregulation of p16ink4a in microglia is a promising strategy for the treatment of Alzheimer's disease.

Role of increased neutrophil extracellular trap formation on acute kidney injury in COVID-19 patients.

Background: A strong association between elevated neutrophil extracellular trap (NET) levels and poor clinical outcomes in patients with coronavirus infection 2019 (COVID-19) has been reported. However, while acute kidney injury (AKI) is a common complication of COVID-19, the role of NETs in COVID-19-associated AKI is unclear. We investigated the association between elevated NETs and AKI and the prognostic role of NETs in COVID-19 patients. Methods: Two representative markers of NETs, circulating nucleosomes and myeloperoxidase-DNA, were measured in 115 hospitalized patients. Serum levels of interleukin [IL]-6, monocyte chemotactic protein-1 [MCP-1], plasma von Willebrand factor (vWF) and urinary biomarkers of renal tubular damage (ß2-microglobulin [ß2M] and kidney injury molecule 1 [KIM-1]) were measured. Results: AKI was found in 43 patients (37.4%), and pre-existing chronic kidney disease (CKD) was a strong risk factor for AKI. Higher circulating NET levels were a significant predictor of increased risk of initial ICU admission, in-hospital mortality (adjusted HR 3.21, 95% CI 1.08-9.19) and AKI (OR 3.67, 95% CI 1.30-10.41), independent of age, diabetes, pre-existing CKD and IL-6 levels. There were strong correlations between circulating nucleosome levels and urinary KIM-1/creatinine (r=0.368, p=0.001) and ß2M (r=0.218, p=0.049) levels. NETs were also strongly closely associated with serum vWF (r = 0.356, p<0.001), but not with IL-6 or MCP-1 levels. Conclusions: Elevated NETs were closely associated with AKI, which was a strong predictor of mortality. The close association between NETs and vWF may suggest a role for NETs in COVID-19-associated vasculopathy leading to AKI.

ATG9B Is a Poor Prognostic Marker Associated With Immune Evasion in Colon Adenocarcinoma.

BACKGROUND/AIM: Autophagy-related genes (ATGs) are involved in autophagy activation, which has a pleiotropic role in cancer development. However, the potential value of ATG expression levels in colon adenocarcinoma (COAD) is unclear. This study aimed to examine the modulation of ATG expression levels and their association with clinical and molecular aspects of COAD. MATERIALS AND METHODS: We used the clinical and molecular phenotypes and RNA sequencing datasets of the cancer genome atlas (TCGA)-COAD project using TCGAbiolinks and cBioPortal. Comparisons of ATG expression levels between tumor and normal tissues were performed using DESeq2 within R. Gene expression and immune cell infiltration levels were analyzed by TIMER. RESULTS: ATG9B had the highest expression levels among ATGs in COAD tissues compared to normal tissues and was related to advanced stage and poor prognosis in COAD. In addition, ATG9B expression was positively associated with the consensus molecular subtype 4 and chromosomal instability but negatively correlated with tumor mutation burden. Furthermore, high ATG9B expression levels were associated with low immune cell infiltration and decreased expression of natural killer cell activation genes. CONCLUSION: ATG9B is a poor prognostic biomarker driving immune evasion of COAD through negative correlation with immune cell infiltration.

Peroxisome Proliferator-Activated Receptor-Targeted Therapies: Challenges upon Infectious Diseases.

Peroxisome proliferator-activated receptors (PPARs) α, ß, and γ are nuclear receptors that orchestrate the transcriptional regulation of genes involved in a variety of biological responses, such as energy metabolism and homeostasis, regulation of inflammation, cellular development, and differentiation. The many roles played by the PPAR signaling pathways indicate that PPARs may be useful targets for various human diseases, including metabolic and inflammatory conditions and tumors. Accumulating evidence suggests that each PPAR plays prominent but different roles in viral, bacterial, and parasitic infectious disease development. In this review, we discuss recent PPAR research works that are focused on how PPARs control various infections and immune responses. In addition, we describe the current and potential therapeutic uses of PPAR agonists/antagonists in the context of infectious diseases. A more comprehensive understanding of the roles played by PPARs in terms of host-pathogen interactions will yield potential adjunctive personalized therapies employing PPAR-modulating agents.

Inosine: A bioactive metabolite with multimodal actions in human diseases.

The nucleoside inosine is an essential metabolite for purine biosynthesis and degradation; it also acts as a bioactive molecule that regulates RNA editing, metabolic enzyme activity, and signaling pathways. As a result, inosine is emerging as a highly versatile bioactive compound and second messenger of signal transduction in cells with diverse functional abilities in different pathological states. Gut microbiota remodeling is closely associated with human disease pathogenesis and responses to dietary and medical supplementation. Recent studies have revealed a critical link between inosine and gut microbiota impacting anti-tumor, anti-inflammatory, and antimicrobial responses in a context-dependent manner. In this review, we summarize the latest progress in our understanding of the mechanistic function of inosine, to unravel its immunomodulatory actions in pathological settings such as cancer, infection, inflammation, and cardiovascular and neurological diseases. We also highlight the role of gut microbiota in connection with inosine metabolism in different pathophysiological conditions. A more thorough understanding of the mechanistic roles of inosine and how it regulates disease pathologies will pave the way for future development of therapeutic and preventive modalities for various human diseases.

Mycobacterial acyl carrier protein suppresses TFEB activation and upregulates miR-155 to inhibit host defense.

Mycobacterial acyl carrier protein (AcpM; Rv2244), a key protein involved in Mycobacterium tuberculosis (Mtb) mycolic acid production, has been shown to suppress host cell death during mycobacterial infection. This study reports that mycobacterial AcpM works as an effector to subvert host defense and promote bacterial growth by increasing microRNA (miRNA)-155-5p expression. In murine bone marrow-derived macrophages (BMDMs), AcpM protein prevented transcription factor EB (TFEB) from translocating to the nucleus in BMDMs, which likely inhibited transcriptional activation of several autophagy and lysosomal genes. Although AcpM did not suppress autophagic flux in BMDMs, AcpM reduced Mtb and LAMP1 co-localization indicating that AcpM inhibits phagolysosomal fusion during Mtb infection. Mechanistically, AcpM boosted the Akt-mTOR pathway in BMDMs by upregulating miRNA-155-5p, a SHIP1-targeting miRNA. When miRNA-155-5p expression was inhibited in BMDMs, AcpM-induced increased intracellular survival of Mtb was suppressed. In addition, AcpM overexpression significantly reduced mycobacterial clearance in C3HeB/FeJ mice infected with recombinant M. smegmatis strains. Collectively, our findings point to AcpM as a novel mycobacterial effector to regulate antimicrobial host defense and a potential new therapeutic target for Mtb infection.

Effects of Hydrodilatation With Corticosteroid Injection and Biomechanical Properties in Patients With Adhesive Capsulitis After Breast Cancer Surgery.

OBJECTIVE: To compare the biomechanical properties of the glenohumeral joint capsule between adhesive capsulitis (AC) after breast cancer surgery and idiopathic AC and demonstrate the effects of hydrodilatation (HD) with corticosteroid injection for AC after breast cancer surgery. METHODS: Twenty-three prospective patients with AC after breast cancer surgery (BC group) and 44 retrospective patients with idiopathic AC without breast cancer (CON group) underwent HD with corticosteroid injection and home exercise training. We compared their biomechanical characteristics (capsular capacity, maximal pressure, and capsular stiffness). In the BC group, the passive range of motion (ROM) of the affected shoulder and a questionnaire (Shoulder Pain and Disability Index [SPADI]) were evaluated at baseline and 2 and 4 weeks after treatment. RESULTS: The BC group showed higher biomechanical characteristics (maximal pressure and capsular stiffness) than did the CON group. The mean maximal pressure and capsular stiffness were 519.67±120.90 mmHg and 19.69±10.58 mmHg/mL in the BC group and 424.78±104.42 mmHg and 11.55±7.77 mmHg/mL in the CON group (p=0.002 and p=0.001, respectively). And, the BC group showed significant improvements in all ROMs (abduction, flexion, and external rotation) and the SPADI pain and disability sub-scores following the treatment. CONCLUSION: The glenohumeral joint capsular stiffness was greater in the patients with AC after breast cancer surgery than in those with idiopathic AC. HD with corticosteroid injection was effective in treating AC after breast cancer surgery.

Microfluidic chip for rapid and selective isolation of tumor-derived extracellular vesicles for early diagnosis and metastatic risk evaluation of breast cancer.

The epithelial-to-mesenchymal transition (EMT) index in cancer is a complementary approach for estimating metastatic risk. Considering the demand for evaluating metastatic risk based on liquid biopsies, tumor-derived extracellular vesicles (EVs) can be exploited to generate the EMT index. For the generation of EVs-based EMT index, it is essential to selectively isolate each epithelial cell and mesenchymal cell-derived EVs. This study proposes a novel microfluidic chip for selectively separating two types of EVs in an efficient and timely manner. The microfluidic chip is fully integrated with a micromixer for the creation of efficient collision between EVs and specific antibody-coated microbeads (7 and 15 µm in diameter) and a hydrodynamic particle separator for the stratification of EVs bound microbeads according to the sizes of microbeads. Using this chip, over 90% of EVs expressing the epithelial marker (epithelial cell adhesion molecule, EpCAM) and the mesenchymal marker (CD49f) can be selectively isolated within 6.7 min per 100 µL of sample volume. The clinical relevance of EMT is investigated using plasma samples from 20 breast cancer patients and 10 age-matched controls. The EMT index produced from the microfluidic chip is in a good agreement with the conventional tissue-based EMT index and is significantly high in patients with aggressive breast cancer subtypes, compared with healthy controls. In addition, the patients with high scores on the EMT index (≥5) shows recurrence within 5 years after adjuvant treatment. Predicting EMT-index-based metastatic risk using our microfluidic chip can be beneficial for cancer diagnosis and prognosis.

MiR-144-3p is associated with pathological inflammation in patients infected with Mycobacteroides abscessus.

Infection with rapidly growing nontuberculous mycobacteria is emerging as a global health issue; however, key host factors remain elusive. Here, we investigated the characteristic immune profiles of peripheral blood mononuclear cells (PBMCs) from patients infected with Mycobacteroides abscessus subsp. abscessus (Mabc) and M. abscessus subsp. massiliense (Mmass). Using an integrated analysis of global mRNA and microRNA expression profiles, we found that several inflammatory cytokines/chemokines [interleukin (IL)-1ß, IL-6, C-X-C motif chemokine ligand 2, and C-C motif chemokine ligand 2] and miR-144-3p were significantly upregulated in PBMCs from patients compared with those from healthy controls (HCs). Notably, there was a strong correlation between the expression levels of miR-144-3p and proinflammatory cytokines/chemokines. Similarly, upregulated expression of miR-144-3p and proinflammatory cytokines/chemokines was found in macrophages and lungs from mice after infection with Mabc and Mmass. We showed that the expression of negative regulators of inflammation (SARM1 and TNIP3) was significantly downregulated in PBMCs from the patients, although they were not putative targets of miR-144-3p. Furthermore, overexpression of miR-144-3p led to a marked increase in proinflammatory cytokines/chemokines and promoted bacterial growth in macrophages. Together, our results highlight the importance of miR-144-3p linking to pathological inflammation during M. abscessus infection.

Frequent Premature Atrial Contractions as a Poor Prognostic Factor in Cryptogenic Stroke Patients with Concomitant Non-Sustained Atrial Tachycardia.

In cryptogenic stroke patients, early detection of new-onset atrial fibrillation (AF) and recurrent stroke is required to prevent poor clinical outcomes. Therefore, we investigated the predictors of new-onset AF and recurrent stroke in cryptogenic stroke patients without previously diagnosed AF. In total, 390 patients who were diagnosed with stroke and non-sustained atrial tachycardia (NSAT) on 24-hour Holter monitoring were followed up to assess new-onset AF and recurrent stroke. The 5-year event-free survival as well as the predictors of recurrent stroke or new-onset AF were investigated. Based on receiver operating characteristic analysis, frequent premature atrial contractions (PACs) were defined as PACs >44 beats/day. The median follow-up period was 35 months. The composite event rate was 11.5%. In Kaplan-Meier analysis, the 5-year cumulative incidence of composite events was higher in cryptogenic stroke patients with frequent PACs than in those without frequent PACs. Multivariate analysis revealed that current smoking, increased left atrial volume index, and frequent PACs were poor prognostic predictors of composite event, and frequent PACs were an independent poor prognostic factor of new-onset AF in cryptogenic stroke patients. Therefore, frequent PACs might be associated with poor clinical outcomes (new-onset AF and recurrent stroke) in cryptogenic stroke patients with concomitant NSAT.

Long-term fine particulate matter exposure and cardiovascular mortality in the general population: a nationwide cohort study.

BACKGROUND: Although eastern Asian countries are exposed to high levels of air pollution, the impact of long-term exposures to fine particulate matter (PM2.5) air pollution on all-cause and cardiovascular mortality is not well identified. We assessed the relationship between long-term PM2.5 exposure and all-cause/cardiovascular mortalities. METHODS: We included 436,933 subjects who received national health examinations from the Korean National Health Insurance Service-based National Sample Cohort. We matched subjects' residential-address areas with hourly-measurements of PM2.5 concentration data. We estimated the risk of mortality with average PM2.5 exposure during the study period using a Cox proportional-hazards model. RESULTS: During 1,683,271 person·years, all-cause and cardiovascular mortalities were observed in 6432 and 1603 subjects (382 and 95 per 100,000 person·years, respectively). An increase in 10 µg/m3 in PM2.5 was associated with increases in all-cause and cardiovascular mortalities by 3.4 % [2.7-4.1] and 4.7 % [3.6-5.8], respectively (each p < 0.001). PM2.5 was linearly and significantly correlated with these all-cause and cardiovascular mortalities above 18 µg/m3 of PM2.5 (p < 0.001), but it was not significant below 18 µg/m3 of PM2.5. To investigate the specific PM2.5 concentration for raising cardiovascular mortality more, we analyzed the sensitivities/specificities for different PM2.5 levels, and 18 µg/m3 showed the highest Youden's index (sensitivity + specificity-1) with c-index of 0.85 (0.84-0.86). PM2.5 effect on all-cause mortality was more profound in subjects with previous myocardial infarction compared to the opposite population. CONCLUSIONS: In the Korean general population exposed to high-air pollution, long-term PM2.5 exposure was linearly associated with increased risk for all-cause and cardiovascular mortality, especially above 18 µg/m3 of PM2.5.

Radiofrequency catheter ablation of accessory pathways at the site of prior valve surgery.

BACKGROUND: Radiofrequency catheter ablation (RFCA) for accessory pathways (APs) at the site of prior valve surgery (VS) remains challenging. We aimed to clarify the factors associated with successful RFCA for such APs. METHODS: Upon reviewing a RFCA registry and previous case reports, we included nine patients who underwent RFCA of APs at the site of prior VS (total-VS group; age, 34.0 [24.5-45.0] years; men, 4/9) and 196 patients who underwent RFCA of APs with no history of VS (no-VS group; age, 40.5 [23.0-54.0] years; men, 114/196). Electrophysiological features, procedural details, and outcomes were examined. RESULTS: Accessory pathway exhibited decremental conduction in four of nine patients in the total-VS group. The number of RFCA attempts was significantly higher in the total-VS group than in the no-VS group (10.0 [4.5-14.5] vs 2.0 [1.0-3.0]; P < 0.001). In four patients who underwent mitral VS, successful RFCA was achieved using the transaortic approach, coronary sinus (CS) approach, or bipolar ablation. In three patients who underwent tricuspid VS, successful RFCA was achieved using the above-prosthetics or trans-prosthetics approach. In two patients, RFCA failed. The trans-prosthetics approach and bipolar ablation technique were effective. The transaortic and CS approaches were occasionally effective. The transseptal approach was ineffective. CONCLUSIONS: Successful RFCA of APs at the site of prior VS can be achieved by detailed mapping of the areas both above and below the prosthetic valve, as well as by ensuring effective radiofrequency energy delivery using various catheter approaches and RFCA techniques.

Non-vitamin K antagonist oral anticoagulants with amiodarone, P-glycoprotein inhibitors, or polypharmacy in patients with atrial fibrillation: Systematic review and meta-analysis.

BACKGROUND: Amiodarone, which inhibits CYP2C9 and P-glycoprotein, is commonly prescribed with non-vitamin K antagonist oral anticoagulants (NOACs) and polypharmacy in high-risk atrial fibrillation (AF) patients. We studied efficacy and safety of NOACs in AF patients receiving amiodarone, P-glycoprotein inhibitor, or polypharmacy. METHODS: After a systematic database search (Medline, EMBASE, CENTRAL, SCOPUS, and Web of Science), four phase-III randomized trials comparing NOACs and warfarin in "with/without amiodarone," "with/without P-glycoprotein inhibitors," or "with/without multiple (≥5, polypharmacy) concomitant drugs" subgroups were included. The outcomes were pooled using a random-effects model to determine the relative risks (RRs) for stroke/systemic thromboembolism (SSTE), major bleeding (MB), intracranial hemorrhage (ICH), and all-cause mortality. RESULTS: Among patients taking amiodarone, superiority of NOACs over warfarin in non-amiodarone users disappeared in terms of SSTE (p=0.11), MB (p=0.95), ICH (p=0.26), and mortality (p=0.32). No safety benefit (MB) of NOACs compared to warfarin was shown in patients taking P-glycoprotein inhibitors (p=0.47), but SSTE prevention was still superior with NOACs compared to warfarin in the same patient group [RR=0.78 (0.61-0.99), p=0.04, I2=11%]. In AF patients with polypharmacy, NOACs showed a lower risk of SSTE [RR=0.82 (0.71-0.96), p=0.01, I2=0%] and mortality [RR=0.91 (0.83-0.99), p=0.04, I2=0%], but not MB (p=0.81) compared to warfarin. CONCLUSIONS: NOACs were equivalent to warfarin among AF patients with concomitant amiodarone use in terms of efficacy, safety, and mortality. There was no safety benefit of NOACs over warfarin in patients using polypharmacy or P-glycoprotein inhibitors. SYSTEMATIC REVIEW REGISTRATION: The protocol of this meta-analysis was registered on PROSPERO under CRD42018104808 (https://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42018104808).

Are Seating Systems With a Medial Knee Support Really Helpful for Hip Displacement in Children With Spastic Cerebral Palsy GMFCS IV and V?

OBJECTIVE: To evaluate whether medial knee support (MKS) in seating systems aggravates hip displacement in children with cerebral palsy (CP). DESIGN: Retrospective chart review. SETTING: Rehabilitation department of tertiary university hospital. PARTICIPANTS: Children with CP (N=76) using seating systems (intervention group, n=42; mean age 6.86y) and using regular wheelchairs (control group, n=34; mean age 8.15y). INTERVENTIONS: The intervention group was provided with a seating system with MKS. We enrolled children who did not use a seating system in the control group, retrospectively. MAIN OUTCOME MEASURES: By radiographic images, Reimer's migration index (MI), lateral center edge angle (CEA), and femur neck shaft angle (NSA) were measured. We compared the demographic data, clinical variables, and radiographs between the 2 groups. RESULTS: In the intervention group, there was a significant deterioration in the MI, from 26.89% to 44.18% after using the system (P<.001). The progression of MI was 14.72% and 7.82% per year in the intervention and control groups, respectively (P=.016). CONCLUSION: We should consider the possibility that seating systems with MKS may exacerbate hip displacement in children with CP.

Pulmonary Vein Isolation Alone Versus Additional Linear Ablation in Patients With Persistent Atrial Fibrillation Converted to Paroxysmal Type With Antiarrhythmic Drug Therapy: A Multicenter, Prospective, Randomized Study.

BACKGROUND: Atrial fibrillation (AF) type can vary depending on condition and timing, and some patients who initially present with persistent AF may be changed to paroxysmal AF after antiarrhythmic drug medication and cardioversion. We investigated whether circumferential pulmonary vein isolation (CPVI) alone is an effective rhythm control strategy in patients with persistent AF to paroxysmal AF. METHODS AND RESULTS: We enrolled 113 patients with persistent AF to paroxysmal AF (male 75%, 60.4±10.1 years old) who underwent catheter ablation for nonvalvular AF at 3 tertiary hospitals. The participants were randomly assigned to 2 groups: CPVI alone (n=59) or CPVI plus linear ablation (CPVI+Line; posterior box+anterior line, n=54). Compared with the CPVI+Line, CPVI alone required shorter procedure (187.2±58.0 versus 211.2±63.9 min; P=0.043) and ablation times (4922.1±1110.5 versus 6205.7±1425.2 s; P<0.001) without difference in procedure-related major complication (3% versus 2%; P=0.611). Antiarrhythmic drug utility rates after ablation were not different between the 2 groups (22% versus 30%; P=0.356). Overall, AF-free survival (log-rank; P=0.206) and AF and antiarrhythmic drug-free survival (log-rank; P=0.321) were not different between groups. CONCLUSIONS: CPVI alone is an effective rhythm control strategy with a shorter procedure time in persistent AF patients converted to paroxysmal AF compared with CPVI with linear ablation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02176616.

MIR144* inhibits antimicrobial responses against Mycobacterium tuberculosis in human monocytes and macrophages by targeting the autophagy protein DRAM2.

Autophagy is an important antimicrobial effector process that defends against Mycobacterium tuberculosis (Mtb), the human pathogen causing tuberculosis (TB). MicroRNAs (miRNAs), endogenous noncoding RNAs, are involved in various biological functions and act as post-transcriptional regulators to target mRNAs. The process by which miRNAs affect antibacterial autophagy and host defense mechanisms against Mtb infections in human monocytes and macrophages is largely uncharacterized. In this study, we show that Mtb significantly induces the expression of MIR144*/hsa-miR-144-5p, which targets the 3'-untranslated region of DRAM2 (DNA damage regulated autophagy modulator 2) in human monocytes and macrophages. Mtb infection downregulated, whereas the autophagy activators upregulated, DRAM2 expression in human monocytes and macrophages by activating AMP-activated protein kinase. In addition, overexpression of MIR144* decreased DRAM2 expression and formation of autophagosomes in human monocytes, whereas inhibition of MIR144* had the opposite effect. Moreover, the levels of MIR144* were elevated, whereas DRAM2 levels were reduced, in human peripheral blood cells and tissues in TB patients, indicating the clinical significance of MIR144* and DRAM2 in human TB. Notably, DRAM2 interacted with BECN1 and UVRAG, essential components of the autophagic machinery, leading to displacement of RUBCN from the BECN1 complex and enhancement of Ptdlns3K activity. Furthermore, MIR144* and DRAM2 were critically involved in phagosomal maturation and enhanced antimicrobial effects against Mtb. Our findings identify a previously unrecognized role of human MIR144* in the inhibition of antibacterial autophagy and the innate host immune response to Mtb. Additionally, these data reveal that DRAM2 is a key coordinator of autophagy activation that enhances antimicrobial activity against Mtb.

A Comparison of Implants Used in Double Door Laminoplasty : Allogeneic Bone Spacer versus Hydroxyapatite Spacer.

OBJECTIVE: The aim of this study was to compare the clinical and radiological outcomes associated with the use of hydroxyapatite (HA) spacer and allogeneic bone (AB) spacer in laminoplasty. METHODS: From January 2006 to July 2014, 79 patients with cervical spondylotic myelopathy or ossification of the posterior longitudinal ligament underwent cervical laminoplasty. The radiologic parameters were obtained from plain radiography and three-dimensional computed tomography. All images were taken before and after surgery. Cervical lordosis, spinal canal dimension, fusion between lamina and spacer, and resorption of spacer were checked. Clinical outcomes were assessed using visual analog scale and Japanese Orthopedic Association. RESULTS: Double-door laminoplasty was performed on 280 levels : 182 in the HA group and 98 in the AB group. The mean follow-up was 23.1 months (range : 4-69 months). Similar fusion rates were found in these groups (p=0.3). The resorption rate between lamina and spacer was lower in the HA group (p<0.001). During the immediate postoperative period, the canal dimension of both groups increased compared with the results in the preoperative period. However, the canal dimension of the AB group decreased over time compared with that of the HA group (p<0.001). CONCLUSION: Double-door laminoplasty improved the clinical outcomes of both groups. However, the spinal canal dimension in the AB group showed a greater degree of reduction than in the HA group at the final postoperative follow-up. Therefore, we suggest that surgeons consider the use of larger-sized AB spacers in double-door laminoplasties.

Environmental Exposure to Arsenic, Lead, and Cadmium in People Living near Janghang Copper Smelter in Korea.

Concentrations of heavy metals exceed safety thresholds in the soil near Janghang Copper Refinery, a smelter in Korea that operated from 1936 to 1989. This study was conducted to evaluate the level of exposure to toxic metals and the potential effect on health in people living near the smelter. The study included 572 adults living within 4 km of the smelter and compared them with 413 controls group of people living similar lifestyles in a rural area approximately 15 km from the smelter. Urinary arsenic (As) level did not decrease according to the distance from the smelter, regardless of gender and working history in smelters and mines. However, in subjects who had no occupational exposure to toxic metals, blood lead (Pb) and cadmium (Cd) and urinary Cd decreased according to the distance from the smelter, both in men and women. Additionally, the distance from the smelter was a determinant factor for a decrease of As, Pb, and Cd in multiple regression models, respectively. On the other hands, urinary Cd was a risk factor for renal tubular dysfunction in populations living near the smelter. These results suggest that Janghang copper smelter was a main contamination source of As, Pb, and Cd, and populations living near the smelter suffered some adverse health effects as a consequence. The local population should be advised to make efforts to reduce exposure to environmental contaminants, in order to minimize potential health effects, and to pay close attention to any health problems possibly related to toxic metal exposure.

Effects of combination therapy of statin and N-acetylcysteine for the prevention of contrast-induced nephropathy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

BACKGROUND: Acute myocardial infarction (AMI) is a risk factor for contrast-induced nephropathy (CIN). We investigated whether pretreatment with statin, N-acetylcysteine (NAC) and sodium bicarbonate (NaHCO3) reduces the risk of CIN. METHODS: We conducted a prospective trial and enrolled a total of 334 ST-segment elevation myocardial infarction (STEMI) patients. Patients were divided into four groups: Group I (statin 40mg), Group II (statin 80mg), Group III (statin 80mg plus NAC 1200mg) and Group IV (regimen of group III plus NaHCO3 154mEq/L). CIN was defined as ≥25% or ≥0.5mg/dL increase in serum creatinine from the baseline within the 72h after PCI. RESULTS: CIN occurred in 72 (21.6%) patients. The incidence of CIN was the lowest in the group III (14.3%), and multivariate analysis showed the lower incidence of CIN in group III compared to Group I [odds ratio (OR) 0.29, 95% confidence interval (CI) 0.13-0.64, p=0.002]. Admission hyperglycemia [(AHG)>198mg/dL] (OR 2.20, 95% Cl 1.20-3.68, p=0.011) and the use of intra-aortic balloon pump (IABP) (OR 4.20, 95% CI 1.38-12.78, p=0.016) were independent predictors for CIN. The CIN (OR 9.00, 95% CI 1.30-62.06, p=0.026) was an independent predictor for in-hospital mortality. CONCLUSIONS: Combination of high-dose statin plus NAC was associated with lower incidence of CIN in patients with STEMI who underwent primary PCI compared to statin only.