Search

Introduction Rotator cuff tear (RCT) is a challenging and common musculoskeletal disease. Magnetic resonance imaging (MRI) is a commonly used diagnostic modality for RCT, but the interpretation of the results is tedious and has some reliability issues. In this study, we aimed to evaluate the accuracy and efficacy of the 3-dimensional (3D) MRI segmentation for RCT using a deep learning algorithm. Methods A 3D U-Net convolutional neural network (CNN) was developed to detect, segment, and visualize RCT lesions in 3D, using MRI data from 303 patients with RCTs. The RCT lesions were labeled by two shoulder specialists in the entire MR image using in-house developed software. The MRI-based 3D U-Net CNN was trained after the augmentation of a training dataset and tested using randomly selected test data (training: validation: test data ratio was 6:2:2). The segmented RCT lesion was visualized in a three-dimensional reconstructed image, and the performance of the 3D U-Net CNN was evaluated using the Dice coefficient, sensitivity, specificity, precision, F1-score, and Youden index. Results A deep learning algorithm using a 3D U-Net CNN successfully detected, segmented, and visualized the area of RCT in 3D. The model’s performance reached a 94.3% of Dice coefficient score, 97.1% of sensitivity, 95.0% of specificity, 84.9% of precision, 90.5% of F1-score, and Youden index of 91.8%. Conclusion The proposed model for 3D segmentation of RCT lesions using MRI data showed overall high accuracy and successful 3D visualization. Further studies are necessary to determine the feasibility of its clinical application and whether its use could improve care and outcomes.

Toxoplasma gondii host cellular invasion factors such as the rhoptry proteins, micronemal antigens, or other subcellular compartment proteins have shown limited vaccine efficacies. T. gondii cyst wall protein (CST1) as a cyst persistence factor is critical for cyst wall integrity and bradyzoite persistence. Here, we generated influenza virus-like particles (VLPs) expressing the T. gondii CST1 and evaluated the mucosal as well as systemic immunities induced by VLPs. Intranasal immunization with the VLPs induced parasite-specific IgG and IgA antibody responses in sera and intestines. VLP immunization showed higher levels of germinal center B cell response and antibody-secreting cell (ASC) response upon challenge infection, indicating memory B cell response was induced. VLP-immunized mice showed a significant reduction of cyst counts and lower levels of pro-inflammatory cytokines (IFN-γ, IL-6) production in the brain upon T. gondii ME49 challenge infection compared to unimmunized control. Thus, VLP immunization protected mice from the lethal dose challenge infection with T. gondii ME49 and did not incur bodyweight loss. These results indicated that T. gondii CST1 containing VLPs can induce mucosal and systemic immunity and also suggest its developmental potential as an effective vaccine candidate against T. gondii infection.

CRISPR-Cas9-mediated leptin (Lep) knockout (KO) mice exhibited prominent phenotypes for constipation, even though they were not compared with other model animals. This study compared the stool excretion, gastrointestinal motility, histological structure, mucin secretion, and enteric nerve function in Lep KO and high fat diet (HFD)-treated mice to determine if there were differences in their phenotypes for constipation. Most obesity phenotypes, including fat weight, adipocyte size, expression of lipolytic proteins (HSL, perilipin, and ATGL), and glucose concentrations, were detected similarly in the Lep KO and HFD-treated mice. They showed a similar decrease in the excretion parameters, including the stool number, weight, and water content, while the same pattern was detected in the gastrointestinal motility and intestinal length. A similar decrease in the mucosal layer thickness, muscle thickness, ability for mucin secretion, and expression of water channel (aquaporin 3 and 8) genes was detected in the mid-colon of the Lep KO and HFD-treated mice, but the alteration rate in some levels was greater in the HFD-treated group than the Lep KO mice. On the other hand, the levels of c-kit, nNOS, NSE, and PGP9.5 expression for the enteric neurons and intestitial cells of Cajal (ICC) were remarkably lower in the mid-colon of the HFD-treated mice than in the Lep KO mice, but the level of most proteins in both groups remained lower than those in the control group. A similar alteration pattern in the expression of muscarinic acetylcholine receptors (mAChRs) and serotonin receptors was detected in the Lep KO and HFD-treated mice. These results suggest that most phenotypes for obesity-induced constipation were similarly detected in the Lep KO and HFD-treated mice, but there was a difference in the regulatory function of the enteric nervous system (ENS).

Background According to the rapid response system’s team composition, responding teams were named as rapid response team (RRT), medical emergency team (MET), and critical care outreach. A RRT is often a nurse-led team, whereas a MET is a physician-led team that mainly plays the role of an efferent limb. As few multicenter studies have focused on physician-led METs, we comprehensively analyzed cases for which physician-led METs were activated. Methods We retrospectively analyzed cases for which METs were activated. The study population consisted of subjects over 18 years of age who were admitted in the general ward from January 2016 to December 2017 in 9 tertiary teaching hospitals in Korea. The data on subjects’ characteristics, activation causes, activation methods, performed interventions, in-hospital mortality, and intensive care unit (ICU) transfer after MET activation were collected and analyzed. Results In this study, 12,767 cases were analyzed, excluding those without in-hospital mortality data. The subjects’ median age was 67 years, and 70.4% of them were admitted to the medical department. The most common cause of MET activation was respiratory distress (35.1%), followed by shock (11.8%), and the most common underlying disease was solid cancer (39%). In 7,561 subjects (59.2%), the MET was activated using the screening system. The commonly performed procedures were arterial line insertion (17.9%), intubation (13.3%), and portable ultrasonography (13.0%). Subsequently, 29.4% of the subjects were transferred to the ICU, and 27.2% died during hospitalization. Conclusions This physician-led MET cohort showed relatively high rates of intervention, including arterial line insertion and portable ultrasonography, and low ICU transfer rates. We presume that MET detects deteriorating patients earlier using a screening system and begins ICU-level management at the patient’s bedside without delay, eventually preventing the patient’s condition from worsening and transfer to the ICU.

Airborne transmission of infectious respiratory pathogens is a significant health hazard for the general public as well as healthcare professionals. Face masks have been frequently utilized as safety measures to limit the transmission of these infectious aerosolized particles. However, the efficacy of face masks in reducing respiratory virus infectivity and pathogenicity is unknown. Improving the effectiveness of masks in blocking viruses is urgently needed. In this study, surgical mask filters were modified by coating the filters with 1, 3, or 5 M of sodium dihydrogen phosphate, and subsequently exposed to the aerosolized respiratory influenza viruses (A/H3N2, A/H5N1) generated by a nebulizer set. Mask filter modification significantly reduced the size and counts of filter pores, which enabled entrapment of 40–60% of aerosolized viruses (captured viruses) with more than 90% of the captured viruses losing their infectivity. Upon contact with the coated mask filters, both the captured viruses and the viruses that managed to bypass the filter pore (passed viruses) were found to be inactivated. Passed viruses demonstrated significantly reduced pathogenicity in mice as indicated by significantly reduced lung virus titers, bodyweight loss, and prolonged survival compared to bare control. These findings highlight the potential of modified mask filters for reducing viral activity and pathogenicity, which contributes to improving facial mask efficacy as well as limiting airborne pathogen transmission.

Purpose To evaluate the feasibility of using skeletal muscle mass (SMM) at C3 (C3 SMM) as a diagnostic marker for sarcopenia in head and neck cancer (HNC) patients. Methods We evaluated 165 HNC patients and 42 healthy adults who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography scans. The paravertebral muscle area at C3 and skeletal muscle area at L3 were measured by CT. Pearson’s correlation was used to assess the relationship between L3 and C3 SMMs. The prediction model for L3 SMM was developed by multiple linear regression. Then the correlation and the agreement between actual and predicted L3 SMMs were assessed. To evaluate the diagnostic value of C3 SMM for sarcopenia, the receiver operating characteristics (ROC) curves were analyzed. Results Of the 165 HNC patients, 61 (37.0%) were sarcopenic and 104 (63.0%) were non-sarcopenic. A very strong correlation was found between L3 SMM and C3 SMM in both healthy adults (r = 0.864) and non-sarcopenic patients (r = 0.876), while a fair association was found in sarcopenic patients (r = 0.381). Prediction model showed a very strong correlation between actual SMM and predicted L3 SMM in both non-sarcopenic patients and healthy adults (r > 0.9), whereas the relationship was moderate in sarcopenic patients (r = 0.7633). The agreement between two measurements was good for healthy subjects and non-sarcopenic patients, while it was poor for sarcopenic patients. On ROC analysis, predicted L3 SMM showed poor diagnostic accuracy for sarcopenia. Conclusions A correlation between L3 and C3 SMMs was weak in sarcopenic patients. A prediction model also showed a poor diagnostic accuracy. Therefore, C3 SMM may not be a strong predictor for L3 SMM in sarcopenic patients with HNC.

Bone is one of the most common sites of metastasis from advanced solid tumors. Bone metastasis is a leading cause of pain and increases the risk of skeletal-related events (SREs) in cancer patients. In addition to affecting the quality of life, it also increases the medical costs and mortality risk. We aimed to examine the occurrence of bone metastasis and SREs in Korean cancer patients using a nationwide health database. Using claims data from the National Health Insurance Service-National Sample Cohort (2002-2013), we extracted the data of bone metastasis patients diagnosed with any of the seven major cancers in Korea from January 2002 to December 2010. Selected SREs included pathologic fracture, spinal cord compression, radiation therapy, and palliative bone surgery. We used time-to-event analysis to estimate patient survival after bone metastasis. A total of 21,562 newly diagnosed cancer patients were identified; bone metastases developed in 1,849 patients (breast cancer, 18.8%; prostate cancer, 17.5%; lung cancer, 13.7%). The median time from primary cancer diagnosis to bone metastasis was 18.9 months. The cumulative incidence of SREs was 45.1% in all bone metastasis patients. The most common cancer type was lung cancer (53.4%), followed by liver (50.9%), prostate (45.9%), breast (43.6%), and colorectal (40.2%) cancers. Almost all SREs developed 1 month after bone metastasis, except in patients with breast and prostate cancers (median: 5.9 months in breast cancer and 4.7 months in prostate cancer). Survival duration after the development of bone metastasis was < 6 months in stomach, liver, colorectal, and lung cancer patients. Breast and prostate cancer patients survived for > 1 year after the occurrence of SREs. This study reveals the epidemiology of bone metastasis and SREs in Korean cancer patients, and the findings can be used to assess the actual bone health status of cancer patients.

Background A high false-negative rate has been reported for the diagnosis of ossification of the posterior longitudinal ligament (OPLL) using plain radiography. We investigated whether deep learning (DL) can improve the diagnostic performance of radiologists for cervical OPLL using plain radiographs. Materials and methods The training set consisted of 915 radiographs from 207 patients diagnosed with OPLL. For the test set, we used 200 lateral cervical radiographs from 100 patients with cervical OPLL and 100 patients without OPLL. An observer performance study was conducted over two reading sessions. In the first session, we compared the diagnostic performance of the DL-model and the six observers. The diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUC) at the vertebra and patient level. The sensitivity and specificity of the DL model and average observers were calculated in per-patient analysis. Subgroup analysis was performed according to the morphologic classification of OPLL. In the second session, observers evaluated the radiographs by referring to the results of the DL-model. Results In the vertebra-level analysis, the DL-model showed an AUC of 0.854, which was higher than the average AUC of observers (0.826), but the difference was not significant (p = 0.292). In the patient-level analysis, the performance of the DL-model had an AUC of 0.851, and the average AUC of observers was 0.841 (p = 0.739). The patient-level sensitivity and specificity were 91% and 69% in the DL model, and 83% and 68% for the average observers, respectively. Both the DL-model and observers showed decreases in overall performance in the segmental and circumscribed types. With knowledge of the results of the DL-model, the average AUC of observers increased to 0.893 (p = 0.001) at the vertebra level and 0.911 (p < 0.001) at the patient level. In the subgroup analysis, the improvement was largest in segmental-type (AUC difference 0.087; p = 0.002). Conclusions The DL-based OPLL detection model can significantly improve the diagnostic performance of radiologists on cervical radiographs.

Although vaccine delivery through the oral route remains the most convenient and safest way for mass immunization purposes, this method is limited by the requirement for large antigen doses and low vaccine efficacy. In this study, we generated recombinant baculoviruses (rBVs) expressing influenza hemagglutinin (A/PR/8/34) and orally delivered a low dose of rBVs to evaluate its vaccine efficacy in mice. Intranasal rBV vaccination was included in the whole experiment for comparison. We found that oral vaccination elicited high levels of virus-specific IgG and IgA antibody responses in both serum and mucosal samples (lung, tracheal, intestinal, fecal and vaginal). Surprisingly, complete protection from the lethal influenza challenge was observed, as indicated by reductions in the virus titer, inflammatory cytokine production, body weight change, and enhanced survival. These results suggest that oral delivery of the influenza rBV vaccine induces mucosal and systemic immunity, which protect mice from the lethal influenza virus challenge. Oral delivery of baculovirus vaccines can be developed as an effective vaccination route.

Although the efforts to develop vaccine against Toxoplasma gondii infection were made for decades, there is currently no licensed vaccine available for humans. Upon discovering a number of T or B cell epitope regions from T. gondii IMC, ROP18 and MIC8, multi-antigen VLPs or combination VLPs were generated. Mice immunized with multi-antigen VLPs or combination VLPs were challenge infected with T. gondii (ME49). T. gondii-specific IgG, IgG isotypes and IgA antibody responses, memory T and B cell responses and protection were evaluated. All the mice survived upon T. gondii challenge infection by multi-antigen VLPs vaccination. Vaccinated mice elicited higher levels of parasite-specific IgG and IgG2a antibody responses in sera, IgA antibody responses in feces, CD4+ and CD8+ T cell responses, and cytokines (IFN-γ, IL-10) responses compared to combination VLPs. In particular, the multi-antigen VLPs vaccination showed significantly higher levels of antibody secreting cell (ASC) responses, CD4+ and CD8+ effector memory T cells, and memory B cells than combination VLPs. Multi-antigen VLPs vaccination showed significant reduction of brain cyst counts and size, and all mice survived. Prediction and analysis of epitopes have indicated that IMC, ROP18 and MIC8 showed partially overlapping epitopes for T and B cells. Our results indicated that antibody responses, memory T and B cells induced by multi-antigen VLPs vaccination might contribute to the complete protection upon T. gondii (ME49) challenge infection.

Dystrophinopathy is a group of inherited phenotypes arising from pathogenic variants in DMD. We evaluated the clinical and genetic characteristics of Korean patients with genetically confirmed dystrophinopathy. We retrospectively reviewed medical records (January 2004-September 2020) from the myopathy database maintained at the study hospital and found 227 patients from 218 unrelated families with dystrophinopathy. Clinical phenotypes included 120 (53%) Duchenne muscular dystrophy (DMD) cases, 20 (9%) intermediate phenotype muscular dystrophy (IMD) cases, 65 (29%) Becker muscular dystrophy (BMD) cases, 18 (8%) undetermined phenotypes, and 4 (2%) symptomatic carriers. The median ages at symptom onset and diagnosis were 5.0 years (interquartile range [IQR]: 3.8–8.0) and 12.0 years (IQR: 7.0–21.0), respectively. Total manual muscle test (MMT) scores decreased annually in patients with DMD, IMD, and BMD. Overall, when age increased by 1 year, total MMT scores decreased on average by -1.978, -1.681, and -1.303 in patients with DMD (p

Introduction Psychological factors such as anxiety and confidence that students have in the patient care situation are important in that this affects the actual clinical performance. Students who are just starting clinical practice have a lack of clinical knowledge, skill proficiency, and patient communication skills, so they experience anxiety and lack of confidence in clinical setting. Practice in a safe environment, such as simulation education, can help students perform more settled and competently in patient care. The purpose of this study was to analyze the effect of high-fidelity simulation experience on anxiety and confidence in medical students. Materials and methods This study enrolled 37 5th-year students at Ajou University School of Medicine in 2020. Two simulation trainings were implemented, and a survey was conducted to measure students’ level of anxiety and confidence before and after each simulation. Based on the research data, a paired t-test was conducted to compare these variables before and after the simulation, and whether this was their first or second simulation experience. Results Students had a significantly lower level of anxiety and a significantly higher level of confidence after the simulation than before. In addition, after one simulation experience, students had less anxiety and more confidence before the second simulation compared to those without simulation experience. Conclusions We confirmed that medical students need to be repeatedly exposed to simulation education experiences in order to have a sense of psychological stability and to competently deliver medical treatment in a clinical setting. There is a practical limitation in that medical students do not have enough opportunities to meet the patients during clinical practice in hospitals. Therefore, in order to produce excellent doctors, students should have the expanded opportunities to experience simulation education so they can experience real-world medical conditions.

Age assessment has attracted increasing attention in the field of forensics. However, most existing works are laborious and requires domain-specific knowledge. Modern computing power makes it is possible to leverage massive amounts of data to produce more reliable results. Therefore, it is logical to use automated age estimation approaches to handle large datasets. In this study, a fully automated age prediction approach was proposed by assessing 3D mandible and femur scans using deep learning. A total of 814 post-mortem computed tomography scans from 619 men and 195 women, within the age range of 20–70, were collected from the National Forensic Service in South Korea. Multiple preprocessing steps were applied for each scan to normalize the image and perform intensity correction to create 3D voxels that represent these parts accurately. The accuracy of the proposed method was evaluated by 10-fold cross-validation. The initial cross-validation results illustrated the potential of the proposed method as it achieved a mean absolute error of 5.15 years with a concordance correlation coefficient of 0.80. The proposed approach is likely to be faster and potentially more reliable, which could be used for age assessment in the future.

[This corrects the article DOI: 10.1371/journal.pone.0197744.].

Onodera’s prognostic nutritional index (PNI) is useful in predicting prognosis of various diseases. But the usefulness of PNI in non-surgical patients has not been sufficiently proven yet. In patients with mycobacterium avium complex pulmonary disease (MAC-PD), malnutrition is an important factor that affects the quality of life and morbidity. Here, we aimed to evaluate whether PNI is related with clinical outcomes in MAC-PD patients. We examined 663 patients diagnosed with MAC-PD between May 2005 and November 2017. PNI score was calculated at the time of diagnosis and treatment initiation, and patients were divided into malnutrition and non-malnutrition groups according to a cut-off PNI score of 45. As the recommended duration of treatment for MAC-PD is 12 months following sputum conversion, treatment duration less than 12 months was defined as treatment intolerance. Survivals were compared with the log-rank test. Multivariate logistic regression and multivariate Cox proportional hazards models were used to estimate the odds ratio (OR) and hazards ratio (HR) for treatment intolerance and mortality, respectively. Of the 306 patients that received treatment, 193 received treatment longer than 12 months. In the multivariable logistic regression model, malnutrition at the time of treatment initiation was related with treatment intolerance (OR: 2.559, 95% confidence interval [CI]: 1.414–4.634, P = 0.002). Patients in the malnutrition group at the time of diagnosis exhibited lower survival (P

Background and objectiveEducation of disease plays an important role in management of Parkinson's disease (PD). However, little is known about the link between the understanding of disease and the burden of care. This study was carried out to find the correlation between the burden of care and the understanding of disease in caregivers for PD patients.MethodsNon-demented patients with PD and their caregivers participated in structured interviews. Understanding of patients and caregivers was evaluated through newly-devised questions. The caregiver burden inventory was used to assess the burden of care.ResultsA total of 142 pairs of patients and their caregivers were recruited. A correlation analysis showed that the burden of care was positively associated with low understanding of the disease by the caregiver. Daily care time and female patients were revealed to be independently associated with the burden of care through a multivariate analysis. Further analyses were performed in the caregiver group according to relationship with patients. The spouse group showed an increased burden of care and poor understanding compared to the offspring group. A multivariate analysis revealed that daily care time and understanding were independent predictors for the burden of care in the spouse group. There was no significant association in the offspring group.ConclusionThe burden of care was associated with higher daily caregiving time and female gender of the patient, and was significantly increased in the spouse of the patient. In the spouse group, better understanding of the caregiver correlated with less burden of care.

The current commercial access point (AP) selection schemes are mostly based on received signal strength, but perform poorly in many situations. To address this problem, a number of alternative schemes collect and analyze the actual load of every candidate AP. However, these schemes may incur significant latency and signaling overhead in dense wireless local area networks (WLANs). To mitigate such overhead, we propose a user application-based AP selection scheme that considers historical information about AP performance. Without inducing any signaling activity, our scheme monitors the amount of network traffic used by applications and estimates the achievable throughput of APs. Our scheme employs the characteristics of application traffic with the intent of accurately predicting AP performance. Using a measurement study in dense WLAN environments, we show that our scheme achieves higher throughput and lower association latency than those of existing schemes in places highly accessible to the user.

ObjectiveHealthcare workers (HCWs) are one of the target groups for systematic testing and treatment of latent tuberculosis infection (LTBI) in a setting of low TB incidence. We performed this study to describe the testing of HCWs for LTBI and analyse the acceptance and completion of treatment of LTBI.MethodsThis retrospective cohort study was conducted in four university-affiliated hospitals between January 1 and December 31, 2018. HCWs with positive interferon-gamma release assay (IGRA) during LTBI screening were analysed. We assessed the acceptance and completion of LTBI treatment.ResultsOverall, 893 HCWs were IGRA positive. Among them, 609 HCWs visited the clinic for evaluation of LTBI. Of 609 HCWs who were evaluated, 302 (49.6%) were offered treatment for LTBI. The proportion of acceptance for treatment was 64.5% (195 of 302 HCWs). The treatment course was completed by 143 of 195 HCWs (73.3%). Three months of isoniazid and rifampin (3HR) was used in 137 HCWs (70.3%) and 4 months of rifampin (4R) in 58 (29.7%). 72 HCWs (36.9%) experienced at least one adverse drug events, but there was no different characteristics between completer and non-completer.ConclusionThe acceptance and completion of LTBI treatment were unsatisfactory. Subjective perspective regarding obstacles to treatment of LTBI needs to be explored to increase compliance to LTBI treatment.

BackgroundLow-dose persistent organic pollutants (POPs) have recently been linked to immunosenescence, a key mechanism in carcinogenesis, as well as many aging-related chronic diseases. Since feces are the main excretion route of POPs, the large intestine is a potential target organ for these pollutants. We performed a case-control study to evaluate whether exposure to low-dose POPs is related to the risk of colorectal polyps and cancer.MethodsA total of 277 participants were recruited from one hospital: 99 cancer patients, 102 polyp patients, and 76 control subjects. As typical examples of POPs, we measured the serum concentrations of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs).ResultsAcross the tertiles of the summary measure of POPs, the adjusted odds ratios (ORs) of colorectal polyps and cancer were 2.8 (1.2-6.8) (Ptrend = 0.01) and 3.0 (1.0-8.8) (Ptrend = 0.02), respectively, for subjects in the highest tertile. When OCPs and PCBs were analyzed separately, OCPs were linked to an increased risk of both polyps and cancer; the adjusted ORs were 2.3 (0.9-5.7) (Ptrend = 0.05) for polyps and 3.6 (1.1-11.8) (Ptrend< 0.01) for cancer. However, PCBs were only significantly associated with a high risk of polyps but not cancer; the adjusted OR was 2.8 (1.2-6.6) (Ptrend = 0.01).ConclusionChronic exposure to low-dose POPs may be associated with an increased risk of colorectal polyps and cancer. Our findings suggest the carcinogenic potential of strong lipophilic chemical mixtures such as POPs which are accumulated in adipose tissue, released to circulation, and eliminated through feces.

Adipose-derived stem cells (ADSCs) transplant has been reported to be a potential treatment for burn wounds. However, the effects of autogenicity and allogenicity of ADSCs on burn wound healing have not been investigated and the method for using ADSCs still needs to be established. This study compared the healing effects of autologous and allogenic ADSCs and determined an optimal method of using ADSCs to treat acute burn wounds. Experiments were performed in 20 male Wistar rats (weight, 176-250 g; age, 6-7 weeks). Two identical full-thickness burn wounds (radius, 4 mm) were created in each rat. ADSCs harvested from inguinal area and characterized by their high multipotency were injected into burn wounds in the original donor rats (autologous ADSCs group) or in other rats (allogenic ADSCs group). The injection site was either the wound center or the four corners 0.5 cm from the wound edge. The reduction of burn surface areas in the two experimental groups and in control group were evaluated with Image J software for 15 days post-wounding to determine the wound healing rates. Wound healing was significantly faster in the autologous ADSCs group compared to both the allogenic ADSCs group (p

Background Advances in bronchoscopy and CT-guided lung biopsy have improved the evaluation of small pulmonary lesions (PLs), leading to an increase in preoperative histological diagnosis. We aimed to evaluate the efficacy and safety of transbronchial lung biopsy using radial endobronchial ultrasound and virtual bronchoscopic navigation (TBLB-rEBUS&VBN) and CT-guided transthoracic needle biopsy (CT-TNB) for tissue diagnosis of small PLs. Methods A systematic search was performed in five electronic databases, including MEDLINE, EMBASE, Cochrane Library Central Register of Controlled Trials, Web of Science, and Scopus, for relevant studies in May 2016; the selected articles were assessed using meta-analysis. The articles were limited to those published after 2000 that studied small PLs ≤ 3 cm in diameter. Results From 7345 records, 9 articles on the bronchoscopic (BR) approach and 15 articles on the percutaneous (PC) approach were selected. The pooled diagnostic yield was 75% (95% confidence interval [CI], 69–80) using the BR approach and 93% (95% CI, 90–96) using the PC approach. For PLs ≤ 2 cm, the PC approach (pooled diagnostic yield: 92%, 95% CI: 88–95) was superior to the BR approach (66%, 95% CI: 55–76). However, for PLs > 2 cm but ≤ 3 cm, the diagnostic yield using the BR approach was improved to 81% (95% CI, 75–85). Complications of pneumothorax and hemorrhage were rare with the BR approach but common with the PC approach. Conclusions CT-TNB was superior to TBLB-rEBUS&VBN for the evaluation of small PLs. However, for lesions greater than 2 cm, the BR approach may be considered considering its diagnostic yield of over 80% and the low risk of procedure-related complications.

Burn-induced neuromuscular dysfunction may contribute to long-term morbidity; therefore, it is imperative to develop novel treatments. The present study investigated whether erythropoietin (EPO) administration attenuates burn-induced motor neuron apoptosis and neuroinflammatory response. To validate our hypothesis, a third-degree hind paw burn rat model was developed by bringing the paw into contact with a metal surface at 75°C for 10 s. A total of 24 male Sprague-Dawley rats were randomly assigned to four groups: Group A, sham-control; Group B, burn-induced; Group C, burn + single EPO dose (5000 IU/kg i.p. at D0); and Group D, burn + daily EPO dosage (3000 IU/kg/day i.p. at D0-D6). Two treatment regimens were used to evaluate single versus multiple doses treatment effects. Before sacrifice, blood samples were collected for hematological parameter examination. The histological analyses of microglia activation, iNOS, and COX-2 in the spinal cord ventral horn were performed at week 1 post-burn. In addition, we examined autophagy changes by biomarkers of LC3B and ATG5. The expression of BCL-2, BAX, cleaved caspase-3, phospho-AKT, and mTOR was assessed simultaneously through Western blotting. EPO administration after burn injury attenuated neuroinflammation through various mechanisms, including the reduction of microglia activity as well as iNOS and COX-2 expression in the spinal cord ventral horn. In addition, the expression of phospho-AKT, mTOR and apoptotic indicators, such as BAX, BCL-2, and cleaved caspase-3, was modulated. Furthermore, the activity of burn-induced autophagy in the spinal cord ventral horn characterized by the expression of autophagic biomarkers, LC3B and ATG5, was reduced after EPO administration. The present results indicate that EPO inhibits the AKT-mTOR pathway to attenuate burn-induced motor neuron programmed cell death and microglia activation. EPO can modulate neuroinflammation and programmed cell death and may be a therapeutic candidate for neuroprotection.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract illness in infants, young children and the elderly. However, there is no licensed vaccine available against RSV infection. In this study, we generated virus-like particle (VLP) vaccine and investigated the vaccine efficacy in a mouse model. For VLP vaccines, tandem gene (1-780 bp) for V1 VLPs and tandem repeat gene (repeated 450-780 bp) for V5 VLPs were constructed in pFastBacTM vectors, respectively. Influenza matrix protein 1 (M1) was used as a core protein in the VLPs. Notably, upon challenge infection, significantly lower virus loads were measured in the lung of mice immunized with V1 or V5 VLPs compared to those of naïve mice and formalin-inactivated RSV immunized control mice. In particular, V5 VLPs immunization showed significantly lower virus titers than V1 VLPs immunization. Furthermore, V5 VLPs immunization elicited increased memory B cells responses in the spleen. These results indicated that V5 VLP vaccine containing tandem repeat gene protein provided better protection than V1 VLPs with significantly decreased inflammation in the lungs. Thus, V5 VLPs could be a potential vaccine candidate against RSV.

BackgroundIncidental pulmonary embolism (IPE) is frequently detected in of cancer patients undergoing CT scans for staging work up or treatment response evaluation. Nevertheless, the optimal management of IPE remains unknown. Thus, we aimed to evaluate the clinical manifestations of IPE in cancer patients and to compare the clinical prognosis according to anticoagulation therapy.MethodsWe retrospectively analyzed medical records of cancer patients with newly diagnosed PE between March 2010 and December 2013. Baseline demographics, comorbidities, cancer status and clinical presentation of PE were recorded. We compared all cause death, recurrent venous thromboembolism and clinically relevant bleeding events in those with PE. Survival analysis was performed to assess effect of anticoagulation on IPE.ResultsAmong 703 cancer patients diagnosed with PE, IPE was identified in 474 (67.3%) patients. Compared to symptomatic patients, those with IPE had more advanced malignancy, were more likely to be on current chemotherapy at the time of IPE diagnosis. These patients tend to have smaller embolic burden, as demonstrated by the lower rate of bilateral lung involvement and RV dysfunction. While symptomatic PE showed better survival with anticoagulation (median survival 6.0 vs. 17.3 months, p = 0.003), anticoagulation did not result in significant survival benefit in IPE (median survival 15.1 vs. 21.3, p = 0.225). However, in subgroup analysis, there was significant improvement in survival with anticoagulation in patients with proximal IPE (median survival 12.2 vs. 23.4 months, p = 0.023), but not in patients with distal IPE (21.2 vs. 15.1, p = 0.906).ConclusionsIn cancer patients who were diagnosed with IPE, the overall survival was different according to the embolic burden and anticoagulation therapy.

Despite the ability to induce a broad range of cross protection, M2e5x virus-like particles (VLPs) alone provide limited vaccine efficacy and confer low efficacy of protection against highly pathogenic avian influenza virus (HPAIV) infection in chickens. Avian influenza hemagglutinin (HA) has been a major antigenic target that enhances humoral immunity, but the efficacy of avian HA-based vaccines against HPAIV needs to be further improved. In this study, we evaluated the vaccine efficacy induced by combination of conserved tandem repeat M2e5x VLPs and HA VLPs against an avian influenza virus. We found that combinatorial vaccine elicited higher levels of reassortant H5N1 (rgH5N1) virus-specific IgG, IgG1, IgG2a and IgA antibody responses compared to M2e5x VLPs in sera and lungs of mice. Combinatorial VLPs vaccination induced higher levels of CD8+ T cell and germinal center B cell responses in lung and spleen compared to M2e5x VLPs. Combinatorial VLPs vaccination showed significantly reduced inflammatory responses and lung viral loads upon rgH5N1 virus challenge infection, resulting in less body weight loss compared to M2e5x VLPs alone. These results indicate that immune responses to both M2e and HA might provide a strategy of vaccination inducing enhanced protection against avian influenza virus.

Aim To compare the risks of hospitalization for heart failure (HHF) associated with sulfonylurea (SU), dipeptidyl peptidase-4 inhibitor (DPP-4i), and thiazolidinedione (TZD) as add-on medications to metformin (MET) therapy using the data of Korean adults with type-2 diabetes from the Korean National Health Insurance database. Methods We identified 98,383 people who received SU (n = 42,683), DPP-4i (n = 50,310), or TZD (n = 5,390) added to initial treatment of MET monotherapy in patients with type-2 diabetes. The main outcome was the hospitalization for HHF. Hazard ratios for HHF by type of second-line glucose-lowering medication were estimated by Cox-proportional hazard models. Sex, age, duration of MET monotherapy, Charlson Comorbidity Index and additional comorbidities, and calendar year were controlled as potential confounders. Results The observed numbers (rate per 100,000 person-years) of HHF events were 1,129 (658) for MET+SU users, 710 (455) for MET+DPP-4i users, and 110 (570) for MET+TZD users. Compared to that for MET+SU users (reference group), the adjusted hazard ratios for HHF events were 0.76 (95% confidence interval 0.69-0.84) for MET+DPP-4i users and 0.96 (95% confidence interval 0.79-1.17) for MET+TZD users. Conclusion DPP-4i as an add-on therapy to MET may lower the risks of HHF compared with SU.

Background Fluid overload is not only the characteristic but also an important complication in chronic kidney disease (CKD) patients. Angiopoietin-2 (Angpt2) disturbs endothelium and vessel permeability, which may induce fluid overload. The aim of this study is to examine the interaction between fluid status and Angpt2 in adverse renal outcomes of CKD. Methods This cohort study enrolled 290 patients with CKD stages 3–5 from January 2011 to December 2011 and followed up until December 2015. Fluid status was presented as overhydration (OH) value measured by body composition monitor, while OH>1.1L was defined as fluid overload. Renal outcomes were defined as commencing dialysis and rapid renal function decline (the slope of estimated glomerular filtration rate < -5 ml/min/1.73 m2/y). Results During a mean follow-up of 38.6±18.3 months, 125 (43.1%) patients progressed to commencing dialysis and 99(34.7%) patients presented rapid renal function decline. All patients were stratified by OH of 1.1L and the median of circulating Angpt2. These patients with both OH>1.1L and high circulating Angpt2 were more likely to reach commencing dialysis compared to other groups. The risks for commencing dialysis and rapid renal function decline were significantly higher in patients with OH>1.1L and high circulating Angpt2 level compared to those with OH≦1.1L and low circulating Angpt2 (2.14, 1.21–3.78, P = 0.009; 4.96, 1.45–16.97, P = 0.01). There was a significant interaction between OH level and circulating Angpt2 in entering dialysis (P-interaction = 0.02). Conclusions Fluid overload and Angpt2 might have a synergistic effect on adverse renal outcomes in CKD patients.

Carfilzomib (CFZ) is a peptide epoxyketone proteasome inhibitor approved for the treatment of multiple myeloma (MM). Despite the remarkable efficacy of CFZ against MM, the clinical trials in patients with solid cancers yielded rather disappointing results with minimal clinical benefits. Rapid degradation of CFZ in vivo and its poor penetration to tumor sites are considered to be major factors limiting its efficacy against solid cancers. We previously reported that polymer micelles (PMs) composed of biodegradable block copolymers poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) can improve the metabolic stability of CFZ in vitro. Here, we prepared the CFZ-loaded PM, PEG-PCL-deoxycholic acid (CFZ-PM) and assessed its in vivo anticancer efficacy and pharmacokinetic profiles. Despite in vitro metabolic protection of CFZ, CFZ-PM did not display in vivo anticancer efficacy in mice bearing human lung cancer xenograft (H460) superior to that of the clinically used cyclodextrin-based CFZ (CFZ-CD) formulation. The plasma pharmacokinetic profiles of CFZ-PM were also comparable to those of CFZ-CD and the residual tumors that persisted in xenograft mice receiving CFZ-PM displayed an incomplete proteasome inhibition. In summary, our results showed that despite its favorable in vitro performances, the current CFZ-PM formulation did not improve in vivo anticancer efficacy and accessibility of active CFZ to solid cancer tissues over CFZ-CD. Careful consideration of the current results and potential confounding factors may provide valuable insights into the future efforts to validate the potential of CFZ-based therapy for solid cancer and to develop effective CFZ delivery strategies that can be used to treat solid cancers.

Picroside II isolated from Pseudolysimachion rotundum var. subintegrum has been used as traditional medicine to treat inflammatory diseases. In this study, we assessed whether picroside II has inhibitory effects on airway inflammation in a mouse model of house dust mite (HDM)-induced asthma. In the HDM-induced asthmatic model, picroside II significantly reduced inflammatory cell counts in the bronchoalveolar lavage fluid (BALF), the levels of total immunoglobulin (Ig) E and HDM-specific IgE and IgG1 in serum, airway inflammation, and mucus hypersecretion in the lung tissues. ELISA analysis showed that picroside II down-regulated the levels of Th2-related cytokines (including IL-4, IL-5, and IL-13) and asthma-related mediators, but it up-regulated Th1-related cytokine, IFNγ in BALF. Picroside II also inhibited the expression of Th2 type cytokine genes and the transcription factor GATA3 in the lung tissues of HDM-induced mice. Finally, we demonstrated that picroside II significantly decreased the expression of GATA3 and Th2 cytokines in developing Th2 cells, consistent with in vivo results. Taken together, these results indicate that picroside II has protective effects on allergic asthma by reducing GATA3 expression and Th2 cytokine bias.

Background The effectiveness of dialysis on the incidence of cancer in patients with end-stage renal disease (ESRD) remains to be clarified. In this study, we evaluated the incidence rate and type of cancer among patients with ESRD, compared to the general population, through a prospective 7-year follow-up. We also calculated the cumulative incidence rate of cancer associated with ESRD, with stratification to control for the competing risk of death. Methods This prospective observational cohort study was conducted using data from a nationwide study on patients with ESRD in Korea. A total of 5,235 patients, ≥18 years old, with ESRD were identified from the national registry as being treated by dialysis between August 2008 and December 2014. The standardized incidence ratio (SIR) and cumulative incidence rate of specific cancers were evaluated and compared to the general population. Results A total of 5,235 participants were included. During the 7 year observation period, 116 (2.2%) participants had been diagnosed as cancer. The SIR of overall cancer was 0.94 [95% confidence interval (CI), 0.72–1.19] and was comparable to the rate for the general population. Although the digestive organs were the most frequent site of a primary site cancer (N = 39, 33.6%), the SIR was highest for urinary tract cancer [4.7, 95% CI, 2.42–8.19]. The five year standardized cumulative incidence of cancer was higher for females than for males, and for non-diabetic compared to diabetic causes of ESRD. We estimated that the five year standardized cumulative incidence was highest [8.4, 95% CI, 5.07–13.75] in patients with ESRD, caused by glomerulonephritis. Conclusion A screening program should be necessary for urinary tract cancer in Korean patients with ESRD. Cancer screening programs for patients with ESRD in Korea should be emphasized on female patients and patients with non-diabetic ESRD.

Toxoplasma gondii (T. gondii) microneme protein 8 (MIC8) represents a novel, functional distinct invasion factor. In this study, we generated virus-like particles (VLPs) targeting Toxoplasma gondii MIC8 for the first time, and investigated the protection against highly virulent RH strain of T. gondii in a mouse model. We found that VLP vaccination induced Toxoplasma gondii-specific IgG and IgG1 antibody responses in the sera. Upon challenge infection with RH strain of T. gondii tachyzoites, vaccinated mice showed a significant increase of both IgG antibodies in sera and IgA antibodies in feces compared to those before challenge, and a rapid expansion of both germinal center B cell (B220(+), GL7(+)) and T cell (CD4(+), CD8(+)) populations. Importantly, intranasally immunized mice showed higher neutralizing antibodies and displayed no proinflammatory cytokine IFN-gamma in the spleen. Mice were completely protected from a lethal challenge infection with the highly virulent T. gondii (RH) showing no body weight loss (100% survival). Our study shows the effective protection against T. gondii infection provided by VLPs containing microneme protein 8 of T. gondii, thus indicating a potential T. gondii vaccine candidate.

Background Hereditary thrombophilia (HT) is a genetic predisposition to thrombosis. Asian mutation spectrum of HT is different from Western ones. We investigated the incidence and clinical characteristics of HT in Korean patients with unprovoked venous thromboembolism (VTE). Methods Among 369 consecutive patients with thromboembolic event who underwent thrombophilia tests, we enrolled 222 patients diagnosed with unprovoked VTE. The presence of HT was confirmed by DNA sequencing of the genes that cause deficits in natural anticoagulants (NAs). Median follow-up duration was 40±38 months. Results Among the 222 patients with unprovoked VTE, 66 (29.7%) demonstrated decreased NA level, and 33 (14.9%) were finally confirmed to have HT in a genetic molecular test. Antithrombin III deficiency (6.3%) was most frequently detected, followed by protein C deficiency (5.4%), protein S deficiency (1.8%), and dysplasminogenemia (1.4%). The HT group was significantly younger (37 [32–50] vs. 52 [43–65] years; P < 0.001) and had a higher proportion of male (69.7% vs. 47%; P = 0.013), more previous VTE events (57.6% vs. 31.7%; P = 0.004), and a greater family history of VTE (43.8% vs. 1.9%; P < 0.001) than the non-HT group. Age

The inner membrane complex (IMC) of Toxoplasma gondii as a peripheral membrane system has unique and critical roles in parasite replication, motility and invasion. Disruption of IMC sub-compartment protein produces a severe defect in T. gondii endodyogeny, the form of internal cell budding. In this study, we generated T. gondii virus-like particle particles (VLPs) containing proteins derived from IMC, and investigated their efficacy as a vaccine in mice. VLP vaccination induced Toxoplasma gondii-specific total IgG, IgG1 and IgG2a antibody responses in the sera and IgA antibody responses in the feces. Upon challenge infection with a lethal dose of T. gondii (ME49), all vaccinated mice survived, whereas all naive control mice died. Vaccinated mice showed significantly reduced cyst load and cyst size in the brain. VLP vaccination also induced IgA and IgG antibody responses in feces and intestines, and antibody-secreting plasma cells, mixed Th1/Th2 cytokines and CD4(+)/CD8(+) T cells from spleen. Taken together, these results indicate that non-replicating VLPs containing inner membrane complex of T. gondii represent a promising strategy for the development of a safe and effective vaccine to control the spread of Toxoplasma gondii infection.

The use of awkward wrist postures and unskilled techniques might induce lateral epicondylitis. This study thus investigated the effects of wrist deviation combined with extension and movement velocity on the dynamic performances of the wrist muscles during the coupling posture via a custom-made bi-planar isokinetic dynamometer. Thirty subjects were recruited to perform the isokinetic testing. We measured the muscle strengths and activities for the wrist extensors and flexors during concentric and eccentric contractions at three movement velocities, 30°s(-1), 90°s(-1), and 180°s(-1), combined with three wrist postures, neutral position (NP), radial deviation (RD), and ulnar deviation (UD). The root mean square (RMS) of the electromyographic signal in the extensor digitorum communis (EDC), normalized peak torque of extensors, and ratio of normalized peak torque between wrist extensors and flexors, were all greater in the NP than RD and UD in both contractions. The ratio of RMS between EDC and flexor digitorum superficialis (FDS) had a significantly greater value in RD than UD during the concentric contraction. The EDC showed significantly higher activity at the fast velocity in both contractions. Nevertheless, a significantly higher RMS of the electromyographic signal between EDC and FDS and the ratio of strength between wrist extensors and flexors were found at slow velocity in both contractions. The wrist deviation combined with extension and movement velocity of the wrist joint should thus be considered as influential factors which might alter the dynamic performances, and may result in further injury of the elbow joint.

BackgroundGiven the complexity of managing hepatocellular carcinoma (HCC), a multidisciplinary approach (MDT) is recommended to optimize management of HCC patients. However, evidence suggesting that MDT improves patient outcome is limited.MethodsWe performed a retrospective cohort study of all patients newly-diagnosed with HCC between 2005 and 2013 (n = 6,619). The overall survival (OS) rates between the patients who were and were not managed via MDT were compared in the entire cohort (n = 6,619), and in the exactly matched cohort (n = 1,396).ResultsIn the entire cohort, the 5-year survival rate was significantly higher in the patients who were managed via MDT compared to that of the patients who were not (71.2% vs. 49.4%, P < 0.001), with an adjusted hazard ratio (HR) of 0.47 (95% confidence interval [CI]; 0.41-0.53). In the exactly matched cohort, the 5-year survival rate was higher in patients who were managed via MDT (71.4% vs. 58.7%, P < 0.001; HR [95% CI] = 0.67 [0.56-0.80]). The survival benefit of MDT management was observed in most pre-defined subgroups, and was especially significant in patients with poor liver function (ALBI grade 2 or 3), intermediate or advanced tumor stage (BCLC stage B or C), or high alphafetoprotein levels (≥200 ng/ml).ConclusionMDT management was associated with improved overall survival in HCC patients, indicating that MDT management can be a valuable option to improve outcome of HCC patients. This warrants prospective evaluations.

Background Guidelines recommend a break-in period of 2 weeks before starting peritoneal dialysis (PD), but PD within 14 days is also an acceptable and safe alternative to hemodialysis (HD) in patients with an urgent need. However, the effect of the break-in period within 48 hours or later had not been evaluated for early technical complications, long-term maintenance, and survival in patients starting urgent PD. Methods Of 360 patients with a surgically inserted PD catheter, we evaluated 190 patients who needed urgent PD and 29 patients who received conventional PD at a single center between January 2007 and December 2014 in this retrospective observational study. Enrolled patients were divided according to break-in period of

Introduction Fluid overload is one of the major characteristics and complications in patients with chronic kidney disease (CKD). N-terminal pro-brain natriuretic peptide (NT-proBNP) is related to fluid status and fluid distribution. The aim of this study is to investigate the interaction between NT-proBNP and fluid status in adverse clinical outcomes of late stages of CKD. Methods We enrolled 239 patients with CKD stages 4–5 from January 2011 to December 2011 and followed up until June 2017. Fluid status was presented as hydration status (HS) value measured by body composition monitor, while HS>7% was defined as fluid overload. Clinical outcomes included renal outcomes (commencing dialysis and estimated glomerular filtration rate decline>3 ml/min/1.73 m2/year), all-cause mortality and major adverse cardiovascular events (MACEs). Results During a mean follow-up of 3.3±2.0 years, 129(54.7%) patients commenced dialysis, 88(37.3%) patients presented rapid renal function decline, and 48(20.3%) had MACEs or died. All patients were stratified by HS of 7% and the median of plasma NT-proBNP. The adjusted risks for commencing dialysis was significantly higher in patients with high plasma NT-proBNP and HS>7% compared to those with low plasma NT-proBNP and HS≦7%. There was a significant interaction between plasma NT-proBNP and HS in commencing dialysis (P-interaction = 0.047). Besides, patients with high plasma NT-proBNP and HS>7% had greater risks for MACEs or all-cause mortality than others with either high plasma NT-proBNP or HS>7%. Conclusion NT-proBNP and fluid overload might have a synergistic association of adverse clinical outcomes in patients with late stages of CKD.

The effects of spiramycin on adipogenesis and high fat diet (HFD)-induced obesity were investigated. Potential mechanisms contributing to these effects were elucidated. The inhibitory effect of spiramycin on adipocyte differentiation was assessed using 3T3-L1 preadipocyte cells, in which several parameters involved in AMPK signal pathways and lipid metabolism were examined. To further investigate the pharmacological effects of spiramycin in vivo, we examined several obesity-related parameters in HFD-induced obese mice. Spiramycin significantly inhibited preadipocyte differentiation by attenuating intracellular lipid accumulation. Spiramycin also reduced the expression of adipogenic master regulators (PPAR gamma, C/EBP alpha, and SREBP1c) and their downstream target genes (FAS, aP2, and GLUT4) in 3T3-L1 cells. In addition, AMPK phosphorylation was increased by spiramycin treatment in 3T3-L1 cells during early differentiation. Notably, HFD-induced obese mice administered spiramycin showed substantial decreases in body weight gain, serum leptin levels, adipose tissue mass, and hepatic lipid accumulation. Moreover, the decreased levels of GPT and GOT in the serum indicated that spiramycin attenuated hepatic injury caused by HFD. Taken together, these results demonstrate for the first time that spiramycin effectively attenuates HFD-induced obesity and hepatic steatosis by inhibiting adipogenesis.

Picroside II isolated from Pseudolysimachion rotundum var. subintegrum has been used as traditional medicine to treat inflammatory diseases. In this study, we assessed whether picroside II has inhibitory effects on airway inflammation in a mouse model of house dust mite (HDM)-induced asthma. In the HDM-induced asthmatic model, picroside II significantly reduced inflammatory cell counts in the bronchoalveolar lavage fluid (BALF), the levels of total immunoglobulin (Ig) E and HDM-specific IgE and IgG1 in serum, airway inflammation, and mucus hypersecretion in the lung tissues. ELISA analysis showed that picroside II down-regulated the levels of Th2-related cytokines (including IL-4, IL-5, and IL-13) and asthma-related mediators, but it up-regulated Th1-related cytokine, IFNγ in BALF. Picroside II also inhibited the expression of Th2 type cytokine genes and the transcription factor GATA3 in the lung tissues of HDM-induced mice. Finally, we demonstrated that picroside II significantly decreased the expression of GATA3 and Th2 cytokines in developing Th2 cells, consistent with in vivo results. Taken together, these results indicate that picroside II has protective effects on allergic asthma by reducing GATA3 expression and Th2 cytokine bias.

Background Little is known about the epidemiology on human papillomavirus (HPV) infection among HIV-infected men in Korea. The objective of this study was to determine the prevalence, genotype distribution and risk factors associated with anal HPV infection among HIV-infected men in Korea. Methods A single-center cross-sectional study was conducted with HIV-infected men in Korea. Participants completed a detailed sexual behavior risk factor questionnaire. Anal samples were collected for cytology and HPV genotyping. Factors associated with anal HPV infection were assessed using multivariable logistic regression, stratifying by sexual behaviour. Results A total of 201 HIV-infected men were included in the study: 133 were from men who have sex with men (MSM) and 68 from men who have sex with women (MSW). Any anal HPV infection was detected in 82.7% of HIV-infected MSM and in 51.5% of HIV- infected MSW (P < 0.001). High-risk HPV (HR-HPV) prevalence was higher among MSM (47.4%) than MSW (25.0%; P = 0.002). The HR-HPV types identified most frequently were HPV 16 (11%), HPV 18 (9.9%), and HPV 58 (5%) in MSM, and HPV 58(11%) and HPV 16 (8.9%) in MSW. Prevalence of any HPV types in 9-valent vaccine types was higher among MSM than MSW (47.4% vs 22.1%. P = 0.001). Abnormal anal cytology was more commonly detected in MSM than MSW (42.9% vs.19.1%, P < 0.001). In HIV-infected MSM, higher number of lifetime male sex partners was significantly associated with any anal HPV infection, but age was a significant risk factor associated with anal HR-HPV infection. Conclusion Anal HPV infection was highly prevalent in HIV-infected MSM in Korea, and also commonly found in HIV-infected MSW. In HIV-infected MSM, the significant risk factor for being infected with any HPV infection was lifetime number of male sexual partners, and with anal oncogenic HPV infection was age.

Paratuberculosis or Johne's disease is a chronic granulomatous enteropathy in ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP) infection. In the present study, we examined the host response to MAP infection in spleens of mice in order to investigate the host immunopathology accompanying host-pathogen interaction. Transcriptional profiles of the MAP-infected mice at 3 and 6 weeks p.i. showed severe histopathological changes, whereas those at 12 weeks p.i. displayed reduced lesion severity in the spleen and liver. MAP-infected mice at 3 and 6 weeks p.i. showed up-regulation of interferon-related genes, scavenger receptor, and complement components, suggesting an initial innate immune reaction, such as macrophage activation, bactericidal activity, and macrophage invasion of MAP. Concurrently, MAP-infected mice at 3 and 6 weeks p.i. were also suggested to express M2 macrophage phenotype with up-regulation of Mrc1, and Marco and down-regulation of MHC class II, Ccr7, and Irf5, and canonical pathways related to the T cell response including ICOS-ICOSL signaling in T helper cells, calcium-induced T lymphocyte apoptosis, and CD28 signaling in T helper cell. These results provide information which furthers the understanding of the immunopathologic response to MAP infection in mice, thereby providing insights valuable for research into the pathogenesis for MAP infection.

Burn-induced neuropathic pain is complex, and fat grafting has reportedly improved neuropathic pain. However, the mechanism of fat grafting in improving neuropathic pain is unclear. Previous investigations have found that neuroinflammation causes neuropathic pain, and anti-inflammatory targeting may provide potential therapeutic opportunities in neuropathic pain. We hypothesized that fat grafting in burn scars improves the neuropathic pain through anti-inflammation. Burn-induced scar pain was confirmed using a mechanical response test 4 weeks after burn injuries, and autologous fat grafting in the scar area was performed simultaneously. After 4 weeks, the animals were sacrificed, and specimens were collected for the inflammation test, including COX-2, iNOS, and nNOS in the injured skin and spinal cord dorsal horns through immunohistochemistry and Western assays. Furthermore, pro-inflammatory cytokines (IL-1 β and TNF-α) in the spinal cord were collected. Double immunofluorescent staining images for measuring p-IκB, p-NFκB, p-JNK, and TUNEL as well as Western blots of AKT, Bax/Bcl-2 for the inflammatory process, and apoptosis were analyzed. Fat grafting significantly reduced COX2, nNOS, and iNOS in the skin and spinal cord dorsal horns, as well as IL-1β and TNF-α, compared with the burn group. Moreover, regarding the anti-inflammatory effect, the apoptosis cells in the spinal cord significantly decreased after the fat grafting in the burn injury group. Fat grafting was effective in treating burn-induced neuropathic pain through the alleviation of neuroinflammation and ameliorated spinal neuronal apoptosis.

Background Chronic kidney disease (CKD) patients have higher prevalence of major adverse cardiovascular events (MACE) and all-cause mortality. Endothelial damage and dysfunction have been regarded as early portents of MACE in CKD patients. Angiopoietin-2 (Ang-2) impairs endothelial function and promotes aberrant neovascularization. The aim of the study was to assess the relationship between circulating Ang-2 and MACE or all-cause mortality in a CKD cohort. Methods A total of 621 pre-dialysis stage 3–5 CKD patients were enrolled from January 2006 to December 2011 and were followed up till October 2014. Plasma Ang-2 was measured in duplicate using commercial enzyme-linked immunosorbent assays (ELISA). Clinical outcomes included MACE or all-cause mortality Results Of all patients, 122 (19.8%) reached MACE or all-cause mortality. Seventy-two had MACE, 79 died, and 29 had both MACE and all-cause mortality during the follow-up period of 41.5±28.3 months. Ang-2 quintile was divided at 1405.0, 1730.0, 2160.9, and 2829.9 pg/ml. The adjusted HR of MACE or all-cause mortality for every single higher log Ang-2 was 5.69 (95% CI: 2.00–16.20, P = 0.001). The adjusted HR of MACE or all-cause mortality was 2.48 (95% CI: 1.25–4.90) for patients of quintile 5 compared with those of quintile 1. A longitudinal association between MACE or all-cause mortality and stepwise increases in Ang-2 levels was found (P-trend = 0.008). Conclusions Ang-2 is an independent predictor of MACE or all-cause mortality in CKD patients. Additional study is necessary in order to explore the mechanism of the association of Ang-2 with adverse outcomes in patients with CKD.

In a previous report, we identified Sebox as a new candidate maternal effect gene that is essential for embryonic development and primarily impacts the two-cell (2C) stage. The present study was conducted to determine the mechanism of action for Sebox in this capacity, as shown by changes in the expression levels of other known MEG mRNAs after Sebox RNA interference (RNAi) in oocytes. Sebox-knockdown metaphase II (Mll) oocytes displayed normal morphology, but among the 23 MEGs monitored, 8 genes were upregulated, and 15 genes were unchanged. We hypothesized that the perturbed gene expression of these MEGs may cause the arrest of embryo development at the 2C stage and examined the expression of several marker genes for the degradation of maternal factors and zygotic genome activation. We found that some maternal mRNAs, c-mos, Gbx2, and Gdf9, were not fully degraded in Sebox-knockdown 2C embryos, and that several zygotic genome activation markers, Mt1a, Rpl23, Ube2a and Wee1, were not fully expressed in conjunction with diminished embryonic transcriptional activity. In addition, Sebox may be involved in the formation of the subcortical maternal complex through its regulation of the upstream regulator, Figla. Therefore, we concluded that Sebox is important in preparing oocytes for embryonic development by orchestrating the expression of other important MEGs.

Introduction Initial lactate level, lactate clearance, C-reactive protein, and procalcitonin in critically ill patients with sepsis are associated with hospital mortality. However, no study has yet discovered which factor is most important for mortality in severe sepsis patients with lactic acidosis. We sought to clarify this issue in patients with lactic acidosis who were supplementing with sodium bicarbonate. Materials and Methods Data were collected from a single center between May 2011 and April 2014. One hundred nine patients with severe sepsis and lactic acidosis who were supplementing with sodium bicarbonate were included. Results The 7-day mortality rate was 71.6%. The survivors had higher albumin levels and lower SOFA, APACHE II scores, vasopressor use, and follow-up lactate levels at an elapsed time after their initial lactate levels were checked. In particular, a decrement in lactate clearance of at least 10% for the first 6 hours, 24 hours, and 48 hours of treatment was more dominant among survivors than non-survivors. Although the patients who were treated with broad-spectrum antibiotics showed higher illness severity than those who received conventional antibiotics, there was no significant mortality difference. 6-hour, 24-hour, and 48-hour lactate clearance (HR: 4.000, 95% CI: 1.309–12.219, P = 0.015) and vasopressor use (HR: 4.156, 95% CI: 1.461–11.824, P = 0.008) were significantly associated with mortality after adjusting for confounding variables. Conclusions Lactate clearance at a discrete time point seems to be a more reliable prognostic index than initial lactate value in severe sepsis patients with lactic acidosis who were supplementing with sodium bicarbonate. Careful consideration of vasopressor use and the initial application of broad-spectrum antibiotics within the first 48 hours may be helpful for improving survival, and further study is warranted.

The mechanisms underlying the progression of simple steatosis to steatohepatitis are yet to be elucidated. To identify the proteins involved in the development of liver tissue inflammation, we performed comparative proteomic analysis of non-alcoholic steatohepatitis (NASH). Mice fed a methionine and choline deficient diet (MCD) developed hepatic steatosis characterized by increased free fatty acid (FFA) and triglyceride levels as well as alpha-SMA. Two-dimensional proteomic analysis revealed that the change from the normal diet to the MCD diet affected the expressions of 50 proteins. The most-pronounced changes were observed in the expression of proteins involved in Met metabolism and oxidative stress, most of which were significantly downregulated in NASH model animals. Peroxiredoxin (Prx) is the most interesting among the modulated proteins identified in this study. In particular, cross-regulated Prx1 and Prx6 are likely to participate in cellular defense against the development of hepatitis. Thus, these Prx isoforms may be a useful new marker for early stage steatohepatitis. Moreover, curcumin treatment results in alleviation of the severity of hepatic inflammation in steatohepatitis. Notably, curcumin administration in MCD-fed mice dramatically reduced CYP2E1 as well as Prx1 expression, while upregulating Prx6 expression. These findings suggest that curcumin may have a protective role against MCD fed-induced oxidative stress.

Background The pathophysiological mechanisms of renal function progression in chronic kidney disease (CKD) have still not been completely explored. In addition to well-known traditional risk factors, non-traditional risk factors, such as endothelial dysfunction, have gradually attracted physicians' attention. Angiopoietin-2 (Ang-2) impairs endothelial function through preventing angiopoietin-1 from binding to Tie2 receptor. Whether Ang-2 is associated with renal function progression in CKD is unknown. Methods This study enrolled 621 patients with stages 3–5 CKD to assess the association of circulating Ang-2 with commencing dialysis, doubling creatinine and rapid decline in renal function (the slope of estimated glomerular filtration rate (eGFR) greater than 5 ml/min per 1.73 m2/y) over follow-up of more than 3 years. Results Of all patients, 224 patients (36.1%) progressed to commencing dialysis and 165 (26.6%) reached doubling creatinine. 85 subjects (13.9%) had rapid decline in renal function. Ang-2 quartile was divided at 1494.1, 1948.8, and 2593.1 pg/ml. The adjusted HR of composite outcomes, either commencing dialysis or doubling creatinine was 1.53 (95% CI: 1.06–2.23) for subjects of quartile 4 compared with those of quartile 1. The adjusted OR for rapid decline in renal function was 2.96 (95% CI: 1.13–7.76) for subjects of quartile 4 compared with those of quartile 1. The linear mixed-effects model shows a more rapid decrease in eGFR over time in patients with quartile 3 or more of Ang-2 than those with the lowest quartile of Ang-2. Conclusions Ang-2 is an independent predictor of adverse renal outcome in CKD. Further study is needed to identify the pathogenic role of Ang-2 in CKD progression.

Natural killer (NK) cells are innate immune effector cells that protect against cancer and some viral infections. Until recently, most studies have investigated the molecular signatures of human or mouse NK cells to identify genes that are specifically expressed during NK cell development. However, the mechanism regulating NK cell development remains unclear. Here, we report a regulatory network of potential interactions during in vitro differentiation of human NK cells, identified using genome-wide mRNA and miRNA databases through hierarchical clustering analysis, gene ontology analysis and a miRNA target prediction program. The microRNA (miR)-583, which demonstrated the largest ratio change in mature NK cells, was highly correlated with IL2 receptor gamma (IL2R gamma) expression. The overexpression of miR-583 had an inhibitory effect on NK cell differentiation. In a reporter assay, the suppressive effect of miR-583 was ablated by mutating the putative miR-583 binding site of the IL2R gamma 3' UTR. Therefore, we show that miR-583 acts as a negative regulator of NK cell differentiation by silencing IL2R gamma. Additionally, we provide a comprehensive database of genome-wide mRNA and miRNA expression during human NK cell differentiation, offering a better understanding of basic human NK cell biology for the application of human NK cells in immunotherapy.

BACKGROUND: Climate change affects the survival and transmission of arthropod vectors as well as the development rates of vector-borne pathogens. Increased international travel is also an important factor in the spread of vector-borne diseases (VBDs) such as dengue, West Nile, yellow fever, chikungunya, and malaria. Dengue is the most important vector-borne viral disease. An estimated 2.5 billion people are at risk of infection in the world and there are approximately 50 million dengue infections and an estimated 500,000 individuals are hospitalized with dengue haemorrhagic fever annually. The Asian tiger mosquito (Aedes albopictus) is one of the vectors of dengue virus, and populations already exist on Jeju Island, South Korea. Currently, colder winter temperatures kill off Asian tiger mosquito populations and there is no evidence of the mosquitos being vectors for the dengue virus in this location. However, dengue virus-bearing mosquito vectors can inflow to Jeju Island from endemic area such as Vietnam by increased international travel, and this mosquito vector's survival during colder winter months will likely occur due to the effects of climate change. METHODS AND RESULTS: In this section, we show the geographical distribution of medically important mosquito vectors such as Ae. albopictus, a vector of both dengue and chikungunya viruses; Culex pipiens, a vector of West Nile virus; and Anopheles sinensis, a vector of Plasmodium vivax, within Jeju Island, South Korea. We found a significant association between the mean temperature, amount of precipitation, and density of mosquitoes. The phylogenetic analyses show that an Ae. albopictus, collected in southern area of Jeju Island, was identical to specimens found in Ho Chi Minh, Vietnam, and not Nagasaki, Japan. CONCLUSION: Our results suggest that mosquito vectors or virus-bearing vectors can transmit from epidemic regions of Southeast Asia to Jeju Island and can survive during colder winter months. Therefore, Jeju Island is no longer safe from vector borne diseases (VBDs) due to the effects of globalization and climate change, and we should immediately monitor regional climate change to identify newly emerging VBDs.

Specificity protein 1 (SP1) is an essential transcription factor that regulates multiple cancer-related genes. Because aberrant expression of SP1 is related to cancer development and progression, we focused on SP1 expression in gastric carcinoma and its correlation with disease outcomes. Although patient survival decreased as SP1 expression increased (P