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ObjectivesSkull base tumors, can cause oculomotor dysfunction, presenting a management challenge given their proximity to cranial nerves. This study investigated the oculomotor outcomes in patients with skull base tumors presenting cranial nerve palsy due to tumor compression and aimed to identify associated factors.MethodsThis retrospective observational cohort study enrolled patients diagnosed with primary skull base tumors who exhibited cranial nerve palsy due to tumor compression, confirmed by magnetic resonance imaging treated at Asan Medical Center between January 2011 and December 2022. Patients were assessed for oculomotor function pre- and post-treatment, and categorized into recovery and non-recovery groups based on outcomes. Factors associated with oculomotor outcomes were also analyzed.ResultsFifty-six patients were enrolled, with the majority (n = 37, 66.1%) demonstrating recovery in oculomotor function post-treatment. The duration from symptom onset to treatment initiation was short in the recovery group, suggesting that early treatment may contribute to improved oculomotor outcomes. The type of tumor was significantly associated with oculomotor outcomes, with patients with pituitary adenoma exhibiting better outcomes. In the recovery group, 19/37 (51.4%) patients underwent surgical resection alone. In contrast, in the non-recovery group, 17/19 (89.5%) patients received primary or adjuvant radiosurgery or radiation therapy.ConclusionApproximately 70% of patients with skull base tumors experienced recovery in oculomotor function post-treatment. The duration before treatment and the type of tumor were significantly associated with the oculomotor outcome. These findings aid neuro-ophthalmologists in predicting oculomotor outcomes for patients with skull base tumors, guiding management strategies for oculomotor dysfunction.

Social networks often involve the users rating each other based on their beliefs, abilities, and other characteristics. This is particularly common in e-commerce platforms where buyers rate sellers based on their trustworthiness. However, the rating tends to vary between users due to differences in their individual scoring criteria. For example, in a transaction network, a positive user may give a high rating unless the transaction was unsatisfactory while a neutral user may give a mid-rating, consequently giving the same numeric score to different levels of satisfaction. In this paper, we propose a novel method called user tendency-based rating scaling, which adjusts the current rating (its score) based on the pattern of past ratings. We investigate whether this rating scaling method can classify between "good users" and "bad users" in online trade social networks better when compared with using the original rating scores without scaling. Classifying between good users and bad users is especially important for anonymous rating networks like Bitcoin transaction networks, where users' reputations must be recorded to preclude fraudulent and risky users. We evaluate the proposed rating scaling method by performing user classification, link prediction, and clustering tasks, using three real-world online rating network datasets. We use both the original ratings and the scaled ratings as weights of graphs and use a weighted graph embedding method to find node representations that reflect users' positive and negative information. The experimental results showed that using the proposed rating scaling method outperformed using the original (i.e., unscaled) ratings by up to 17% in classification accuracy, and by up to 2.5% in link prediction based on the AUC ROC measure, and by up to 21% in the clustering tasks based on the Dunn-index.

IntroductionPre-emptive therapy for cytomegalovirus (CMV) reactivation has been used in allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is unclear if this strategy has poorer clinical outcomes in CMV-endemic areas and if more aggressive prophylaxis is required.MethodsWe retrospectively analyzed the patterns and survival after CMV reactivation in patients undergoing pre-emptive therapy following allo-HSCT and assessed high-risk patients who could benefit from aggressive CMV prophylaxis in endemic areas.ResultsOf the 292 patients who underwent allo-HSCT, 70.5% (donor+ or recipient+) were CMV seropositive. CMV reactivation occurred in 139 patients (47.6%), with a median of 31.5 days from day 0 of allo-HSCT. The overall survival of patients with CMV reactivation who received pre-emptive therapy did not differ from those without reactivation. Of the 139 patients with CMV reactivation, 78 (56.1%) underwent ≥2 rounds of pre-emptive therapy. In multivariate analysis, the risk of CMV reactivation was higher in patients with multiple myeloma, with CMV seropositivity of the recipient and donor, administered with a higher dose of anti-thymocyte globulin (ATG), and with acute graft-versus-host disease (aGVHD) ≥ grade 2.ConclusionAlthough half of the patients with allo-HSCT were administered with pre-emptive therapy for CMV, CMV reactivation did not affect their survival, indicating the advantages of pre-emptive therapy, even in CMV-endemic areas. The cost-effectiveness of more aggressive CMV prophylaxis should be re-evaluated in patients at a high risk for CMV reactivation.

ObjectivesTo evaluate the effect of inferior oblique (IO) myectomy on ocular torsion according to the absence of the trochlear nerve in unilateral congenital superior oblique palsy (UCSOP).MethodsWe retrospectively reviewed the clinical data of patients who had been diagnosed with UCSOP and underwent ipsilateral IO myectomy (n = 43). Patients were classified into the present and absent groups according to the absence of the trochlear nerve and superior oblique hypoplasia on magnetic resonance imaging (MRI). For quantitative analysis of ocular torsion, disc-fovea angles (DFA) were collected in both eyes using fundus photographs taken within three months before surgery and one month after surgery.ResultsDFA of the paretic eye did not differ according to the absence of the trochlear nerve (9.4±5.6° in the present group vs. 11.0±5.4° in the absent group, p = 0.508). However, the present group had a larger DFA in the non-paretic eye than the absent group (14.1±6.7° in the present group vs. 8.0±5.0° in the absent group, p = 0.003). The change of ocular torsion after IO myectomy in the paretic eye was -5.3±3.7° in the present group and -4.8±3.5° in the absent group, respectively (p = 0.801). In the non-paretic eye, the change in DFA was -1.5±3.0° in the present group, which was larger than that in the absent group (0.7±2.6°, p = 0.047). In the multivariate analysis, the change in DFA was correlated with only the preoperative DFA (standardized β = -0.617, pConclusionsIn the paretic eye, there was no significant difference in the change of ocular torsion between both groups, whereas in the non-paretic eye, the present group had a larger change in DFA after IO myectomy than the absent group. However, in the multivariable analysis, the change in ocular torsion was significantly correlated with preoperative excyclotorsion but not with the presence of the trochlear nerve itself.

We investigated the association of insulin administration method with the achievement of mean glucose ≤ 180 mg/dL and neurological outcomes in out-of-hospital cardiac arrest (OHCA) survivors who had hyperglycemia after the return of spontaneous circulation. From a multicenter prospective registry, we extracted the data of adult OHCA survivors who underwent targeted temperature management (TTM) between 2015 and 2018. Blood glucose levels every 4 h after initiating TTM were obtained for 72 h. We divided insulin administration methods into three categories: subcutaneous (SQI), intravenous bolus (IBI), and continuous intravenous (CII). We calculated the mean glucose and standard deviation (SD) of glucose. The primary outcome was the achievement of mean glucose ≤ 180 mg/dL. The secondary outcomes were the 6-month neurological outcome based on the Cerebral Performance Category (CPC) scale (good, CPC 1-2; poor, CPC 3-5), mean glucose, and SD of glucose. Of the 549 patients, 296 (53.9%) achieved mean glucose ≤ 180 mg/dL, and 438 (79.8%) had poor neurological outcomes, 134 (24.4%), 132 (24.0), and 283 (51.5%) were in the SQI, IBI, and CII groups, respectively. The SQI (adjusted odds ratio [aOR], 0.848; 95% confidence intervals [CIs], 0.493-1.461) and IBI (aOR, 0.673; 95% CIs, 0.415-1.091) groups were not associated with mean glucose ≤ 180 mg/dL and the SQI (aOR, 0.660; 95% CIs, 0.335-1.301) and IBI (aOR, 1.757; 95% CIs, 0.867-3.560) groups were not associated with poor neurological outcomes compared to the CII group. The CII (168 mg/dL [147-202]) group had the lowest mean glucose than the SQI (181 mg/dL [156-218]) and IBI (184 mg/dL [162-216]) groups. The CII (45.0[33.9-63.5]) group had a lower SD of glucose than the IBI (50.8 [39.1-72.0]) group. The insulin administration method was not associated with achieving mean glucose ≤ 180 mg/dL and 6-month neurological outcomes.

We evaluated the performance of cardiac arrest-specific prognostication scores developed for outcome prediction in the early hours after out-of-hospital cardiac arrest (OHCA) in predicting long-term outcomes using independent data. The following scores were calculated for 1,163 OHCA patients who were treated with targeted temperature management (TTM) at 21 hospitals in South Korea: OHCA, cardiac arrest hospital prognosis (CAHP), C-GRApH (named on the basis of its variables), TTM risk, 5-R, NULL-PLEASE (named on the basis of its variables), Serbian quality of life long-term (SR-QOLl), cardiac arrest survival, revised post-cardiac arrest syndrome for therapeutic hypothermia (rCAST), Polish hypothermia registry (PHR) risk, and PROgnostication using LOGistic regression model for Unselected adult cardiac arrest patients in the Early stages (PROLOGUE) scores and prediction score by Aschauer et al. Their accuracies in predicting poor outcome at 6 months after OHCA were determined using the area under the receiver operating characteristic curve (AUC) and calibration belt. In the complete-case analyses, the PROLOGUE score showed the highest AUC (0.923; 95% confidence interval [CI], 0.904-0.941), whereas the SR-QOLl score had the lowest AUC (0.749; 95% CI, 0.711-0.786). The discrimination performances were similar in the analyses after multiple imputation. The PROLOGUE, TTM risk, CAHP, NULL-PLEASE, 5-R, and cardiac arrest survival scores were well calibrated. The rCAST and PHR risk scores showed acceptable overall calibration, although they showed miscalibration under the 80% CI level at extreme prediction values. The OHCA score, C-GRApH score, prediction score by Aschauer et al., and SR-QOLl score showed significant miscalibration in both complete-case (P = 0.026, 0.013, 0.005, and < 0.001, respectively) and multiple-imputation analyses (P = 0.007, 0.018, < 0.001, and < 0.001, respectively). In conclusion, the discrimination performances of the prognostication scores were all acceptable, but some showed significant miscalibration.

BackgroundAmong comatose survivors of out-of-hospital cardiac arrest (OHCA), targeted temperature management (TTM) has improved neurological outcomes. However, although the target temperature shifted from 33°C to 33°C~36°C, the optimal target temperature is still unclear. The goal of this study was to evaluate neurological outcomes at 6 months at target temperatures of 33°C and 36°C.Materials and methodsWe analyzed OHCA survivors who underwent TTM and were recorded in the Korean Hypothermia Network, a prospective multicenter registry, from October 2015 to December 2018. The primary outcome was good neurological outcome at six months, defined as a cerebral performance category of 1-2, and the secondary outcome was survival at 6 months.ResultsA total of 1339 patients were treated with TTM in twenty-two emergency departments. Of those, 1054 were treated at 33°C, and 285 were treated at 36°C. There was no significant difference in good neurological outcomes at 6 months (30.6% vs. 31.2%, p = 0.850, adjusted OR 0.97, 95% CI = 0.73-1.29]) and survival at six months (41.4% vs. 38.7%, p = 0.401, adjusted HR 1.08, 95% CI = 0.91-1.28]) between TTM 33°C and TTM 36°C. After propensity score matching, good neurological outcomes at 6 months (OR 0.93, 95% CI = 0.74-1.18) and survival at 6 months (HR 1.05, 95% CI = 0.92-1.21) were still not associated with TTM 33°C and TTM 36°C.ConclusionIn this study, patients treated with a target temperature of 33°C had similar good neurological outcomes and survival at six months compared with those treated with a target temperature of 36°C.

The current cut-off value for diagnosing exercise-induced bronchoconstriction (EIB) in adults-percent fall in FEV1 (ΔFEV1) ≥ 10% after exercise challenge test (ECT)-has low specificity and weak evidences. Therefore, this study aimed to identify the cut-off value for EIB that provides the highest diagnostic sensitivity and specificity. Participants who underwent the ECT between 2007 and 2018 were categorized according to ΔFEV1: definite EIB (ΔFEV1 ≥ 15%), borderline (10% ≤ ΔFEV1 < 15%), and normal (ΔFEV1 < 10%). Distinct characteristics of the definite EIB group were identified and explored in the borderline EIB group. A receiver operating characteristic curve was plotted to determine the optimal cut-off value. Of 128 patients, 60 were grouped as the definite EIB group, 23 as the borderline group, and 45 as the normal group. All participants were men, with a median age of 20 years (interquartile range [IQR:] 19-23 years). The definite EIB group exhibited wheezing on auscultation (P < 0.001), ΔFEV1/FVC ≥ 10% (P < 0.001), and ΔFEF25-75% ≥ 25% (P < 0.001) compared to other groups. Eight (8/23, 34.8%) patients in the borderline group had at least one of these features, but the trend was more similar to that of the normal group than the definite EIB group. A cut-off value of ΔFEV1 ≥ 13.5% had a sensitivity of 98.5% and specificity of 93.5% for EIB. Wheezing on auscultation, ΔFEV1/FVC ≥ 10%, and ΔFEF25-75% ≥ 25% after ECT may be useful for the diagnosis of EIB, particularly in individuals with a ΔFEV1 of 10-15%. For EIB, a higher cut-off value, possibly ΔFEV1 ≥ 13.5%, should be considered as the diagnostic criterion.

Brain tissue oxygen tension (PbtO2)-guided care, a therapeutic strategy to treat or prevent cerebral hypoxia through modifying determinants of cerebral oxygen delivery, including arterial oxygen tension (PaO2), end-tidal carbon dioxide (ETCO2), and mean arterial pressure (MAP), has recently been introduced. Studies have reported that cerebral hypoxia occurs after cardiac arrest in the absence of hypoxemia or hypotension. To obtain preliminary information on the degree to which PbtO2 is responsive to changes in the common target variables for PbtO2-guided care in conditions without hypoxemia or hypotension, we investigated the relationships between the common target variables for PbtO2-guided care and PbtO2 using data from an experimental study in which the animals did not experience hypoxemia or hypotension after resuscitation. We retrospectively analyzed 170 sets of MAP, ETCO2, PaO2, PbtO2, and cerebral microcirculation parameters obtained during the 60-min post-resuscitation period in 10 pigs resuscitated from ventricular fibrillation cardiac arrest. PbtO2 and cerebral microcirculation parameters were measured on parietal cortices exposed through burr holes. Multiple linear mixed effect models were used to test the independent effects of each variable on PbtO2. Despite the absence of arterial hypoxemia or hypotension, seven (70%) animals experienced cerebral hypoxia (defined as PbtO2

Several studies have suggested that sympathetic overstimulation causes deleterious effects in septic shock. A previous study suggested that pralidoxime exerted a pressor effect through a mechanism unrelated to the sympathetic nervous system; this effect was buffered by the vasodepressor action of pralidoxime mediated through sympathoinhibition. In this study, we explored the effects of pralidoxime on hemodynamics and survival in rats with peritonitis-induced sepsis. This study consisted of two sub-studies: survival and hemodynamic studies. In the survival study, 66 rats, which survived for 10 hours after cecal ligation and puncture (CLP), randomly received saline placebo, pralidoxime, or norepinephrine treatment and were monitored for up to 24 hours. In the hemodynamic study, 44 rats were randomly assigned to sham, CLP-saline placebo, CLP-pralidoxime, or CLP-norepinephrine groups, and hemodynamic measurements were performed using a conductance catheter placed in the left ventricle. In the survival study, 6 (27.2%), 15 (68.1%), and 5 (22.7%) animals survived the entire 24-hour monitoring period in the saline, pralidoxime, and norepinephrine groups, respectively (log-rank test P = 0.006). In the hemodynamic study, pralidoxime but not norepinephrine increased end-diastolic volume (P

Large-scale conformational changes are essential for proteins to function properly. Given that these transition events rarely occur, however, it is challenging to comprehend their underlying mechanisms through experimental and theoretical approaches. In this study, we propose a new computational methodology called internal coordinate normal mode-guided elastic network interpolation (ICONGENI) to predict conformational transition pathways in proteins. Its basic approach is to sample intermediate conformations by interpolating the interatomic distance between two end-point conformations with the degrees of freedom constrained by the low-frequency dynamics afforded by normal mode analysis in internal coordinates. For validation of ICONGENI, it is applied to proteins that undergo open-closed transitions, and the simulation results (i.e., simulated transition pathways) are compared with those of another technique, to demonstrate that ICONGENI can explore highly reliable pathways in terms of thermal and chemical stability. Furthermore, we generate an ensemble of transition pathways through ICONGENI and investigate the possibility of using this method to reveal the transition mechanisms even when there are unknown metastable states on rough energy landscapes.

BackgroundThere is currently no validated risk prediction model for recurrent events among patients with acute ischemic stroke (AIS) and atrial fibrillation (AF). Considering that the application of conventional risk scores has contextual limitations, new strategies are needed to develop such a model. Here, we set out to develop and validate a comprehensive risk prediction model for stroke recurrence in AIS patients with AF.MethodsAIS patients with AF were collected from multicenter registries in South Korea and Japan. A developmental dataset was constructed with 5648 registered cases from both countries for the period 2011‒2014. An external validation dataset was also created, consisting of Korean AIS subjects with AF registered between 2015 and 2018. Event outcomes were collected during 1 year after the index stroke. A multivariable prediction model was developed using the Fine-Gray subdistribution hazard model with non-stroke mortality as a competing risk. The model incorporated 21 clinical variables and was further validated, calibrated, and revised using the external validation dataset.ResultsThe developmental dataset consisted of 4483 Korean and 1165 Japanese patients (mean age, 74.3 ± 10.2 years; male 53%); 338 patients (6%) had recurrent stroke and 903 (16%) died. The clinical profiles of the external validation set (n = 3668) were comparable to those of the developmental dataset. The c-statistics of the final model was 0.68 (95% confidence interval, 0.66 ‒0.71). The developed prediction model did not show better discriminative ability for predicting stroke recurrence than the conventional risk prediction tools (CHADS2, CHA2DS2-VASc, and ATRIA).ConclusionsNeither conventional risk stratification tools nor our newly developed comprehensive prediction model using available clinical factors seemed to be suitable for identifying patients at high risk of recurrent ischemic stroke among AIS patients with AF in this modern direct oral anticoagulant era. Detailed individual information, including imaging, may be warranted to build a more robust and precise risk prediction model for stroke survivors with AF.

BACKGROUND:Identifying acute ischemic stroke (AIS) among potential stroke cases is crucial for stroke research based on claims data. However, the accuracy of using the diagnostic codes of the International Classification of Diseases 10th revision was less than expected. METHODS:From the National Health Insurance Service (NHIS) claims data, stroke cases admitted to the hospitals participating in the multicenter stroke registry (Clinical Research Collaboration for Stroke in Korea, CRCS-K) during the study period with principal or additional diagnosis codes of I60-I64 on the 10th revision of International Classification of Diseases were extracted. The datasets were randomly divided into development and validation sets with a ratio of 7:3. A stroke identification algorithm using the claims data was developed and validated through the linkage between the extracted datasets and the registry database. RESULTS:Altogether, 40,443 potential cases were extracted from the NHIS claims data, of which 31.7% were certified as AIS through linkage with the CRCS-K database. We selected 17 key identifiers from the claims data and developed 37 conditions through combinations of those key identifiers. The key identifiers comprised brain CT, MRI, use of tissue plasminogen activator, endovascular treatment, carotid endarterectomy or stenting, antithrombotics, anticoagulants, etc. The sensitivity, specificity, and diagnostic accuracy of the algorithm were 81.2%, 82.9%, and 82.4% in the development set, and 80.2%, 82.0%, and 81.4% in the validation set, respectively. CONCLUSIONS:Our stroke identification algorithm may be useful to grasp stroke burden in Korea. However, further efforts to refine the algorithm are necessary.

Aquaporins are water-permeable membrane-channel proteins found in biological cell membranes that selectively exclude ions and large molecules and have high water permeability, which makes them promising candidates for water desalination systems. To effectively apply the properties of aquaporins in the desalination process, many studies have been conducted on aquaporin-lipid membrane systems using phospholipids, which are the main component of cell membranes. Many parametric studies have evaluated the permeability of such systems with various aquaporin types and lipid compositions. In this study, we performed molecular dynamics simulations for four cases with different protein-lipid molar ratios (1:50, 1:75, 1:100, and 1:150) between aquaporin Z and the phospholipids, and we propose a possibility of the existence of optimal protein-lipid molar ratio to maximize water permeability. Elucidating these simulation results from a structural viewpoint suggests that there is a relationship between the permeability and changes in the hydrophobic thickness of the lipid membrane adjacent to the aquaporin as a structural parameter. The results of this study can help optimize the design of an aquaporin-lipid membrane by considering its molar ratio at an early stage of development.

BackgroundPrognostication after cardiac arrest (CA) needs a multimodal approach, but the optimal method is not known. We tested the hypothesis that the combination of neuron-specific enolase (NSE) and neuroimaging could improve outcome prediction after CA treated with targeted temperature management (TTM).MethodsA retrospective observational cohort study was performed on patients who underwent at least one NSE measurement between 48 and 72 hr; received both a brain computed tomography (CT) scan within 24 hr and diffusion-weighted magnetic resonance imaging (DW-MRI) within 7 days after return of spontaneous circulation (ROSC); and were treated with TTM after out-of-hospital CA between 2009 and 2017 at the Seoul St. Mary's Hospital in Korea. The primary outcome was a poor neurological outcome at 6 months after CA, defined as a cerebral performance category of 3-5.ResultsA total of 109 subjects underwent all three tests and were ultimately included in this study. Thirty-four subjects (31.2%) experienced good neurological outcomes at 6 months after CA. The gray matter to white matter attenuation ratio (GWR) was weakly correlated with the mean apparent diffusion coefficient (ADC), PV400 and NSE (Spearman's rho: 0.359, -0.362 and -0.263, respectively). NSE was strongly correlated with the mean ADC and PV400 (Spearman's rho: -0.623 and 0.666, respectively). Serum NSE had the highest predictive value among the single parameters (area under the curve (AUC) 0.912, sensitivity 70.7% for maintaining 100% specificity). The combination of a DWI parameter (mean ADC or PV400) and NSE had better prognostic performance than the combination of the CT parameter (GWR) and NSE. The addition of the GWR to a DWI parameter and NSE did not improve the prediction of neurological outcomes.ConclusionThe GWR (≤ 24 hr) is weakly correlated with the mean ADC (≤ 7 days) and NSE (highest between 48 and 72 hr). The combination of a DWI parameter and NSE has better prognostic performance than the combination of the GWR and NSE. The addition of the GWR to a DWI parameter and NSE does not improve the prediction of neurological outcomes after CA treatment with TTM.

Background and purposeNon-contrast computed tomography (NCCT) Alberta Stroke Program Early CT Score (ASPECTS) and assessment of collateral flow with multiphase computed tomography angiography (CTA) have been investigated as predictors of clinical outcome in patients with acute ischemic stroke. This study assessed the value of multiphase CTA ASPECTS in predicting final infarction core and clinical outcome in patients undergoing endovascular treatment of acute ischemic stroke.MethodsWe retrospectively studied consecutive patients who underwent multiphase CTA prior to endovascular treatment of acute stroke due to anterior circulation large artery occlusion. Multiphase CTA and final diffusion-weighted imaging (DWI) scans were evaluated by two independent observers for NCCT ASPECTS, acute phase CTA (CTA-AP) ASPECTS, delayed phase CTA (CTA-DP) ASPECTS, and final DWI ASPECTS. Modified Rankin Scale score ≤2 at 3 months was considered a favorable outcome.ResultsA total of 74 patients were analyzed. We found that CTA-DP ASPECTS (r = 0.82; 95% CI, 0.73-0.91; p < 0.001) correlated with final DWI ASPECTS better than NCCT ASPECTS (r = 0.49; 95% CI, 0.39-0.59) and CTA-AP ASPECTS (r = 0.71; 95% CI, 0.64-0.78). Interobserver agreement was higher for CTA-DP ASPECTS (k = 0.84). Good CTA-DP ASPECTS was an independent predictor of favorable outcome (odds ratio, 8.71; 95% CI, 3.71-17.3; p < 0.001).ConclusionCTA-DP ASPECTS is a reliable predictor of final infarction core and neurological outcome.

ObjectiveThe aim of this study in out-of-hospital cardiac arrest (OHCA) patients treated with targeted temperature management (TTM) was to evaluate the prognostic value of OHCA, C-GRApH, and CAHP scores with initial neurologic examinations for predicting neurologic outcomes.MethodsThis retrospective study included OHCA patients treated with TTM from 2009 to 2017. We calculated three cardiac arrest (CA)-specific risk scores (OHCA, C-GRApH, and CAHP) at the time of admission. The initial neurologic examination included an evaluation of the Full Outline of UnResponsiveness brainstem reflexes (FOUR_B) and Glasgow Coma Scale motor (GCS_M) scores. The primary outcome was the neurologic outcome at hospital discharge.ResultsOf 311 subjects, 99 (31.8%) had a good neurologic outcome at hospital discharge. The OHCA score had an area under the receiver operating characteristic curve (AUROC) of 0.844 (95% confidence interval (CI): 0.798-0.884), the C-GRApH score had an AUROC of 0.779 (95% CI: 0.728-0.824), and the CAHP score had an AUROC of 0.872 (95% CI: 0.830-0.907). The addition of the FOUR_B or GCS_M score to the OHCA score improved the prediction of poor neurologic outcome (with FOUR_B: AUROC = 0.899, p = 0.001; with GCS_M: AUROC = 0.880, p = 0.004). The results were similar with the C-GRApH and CAHP scores in predicting poor neurologic outcome.ConclusionsThis study confirms the good prognostic performance of CA-specific scores to predict neurologic outcomes in OHCA patients treated with TTM. By adding new variables associated with the initial neurologic examinations, the prognoses of neurologic outcomes improved compared to the existing scoring models.

BACKGROUND:There have been many efforts to find modifiable risk factors for venous thromboembolism (VTE) in the perioperative period of total knee arthroplasty (TKA), while no study has investigated the relationship between the muscle mass and deep vein thrombosis (DVT) or pulmonary embolism frequency following TKA. This study aimed to evaluate the relationship between muscle volume and the prevalence of symptomatic and radiologically confirmed venous thromboembolism (VTE) after total knee arthroplasty (TKA). METHODS:A total of 261 consecutive patients who underwent primary TKA between 2013 and 2015 were enrolled. Computed tomographic venography with pulmonary angiography (CTVPA) was performed between the 5th and 7th postoperative days to assess the presence of VTE. Four parameters of muscle volume at three levels were evaluated on CTVPA: (i) the cross-sectional area of all skeletal muscles (skeletal muscle index) and total psoas area at the level of the third lumbar vertebrae; (ii) the vastus lateralis muscle at the thigh level; and (iii) the posterior crural muscle at the lower leg level. The relationship between the muscle volume at each level and the prevalence of VTE after TKA was evaluated with multivariate adjusted logistic regression models. RESULTS:The CTVPA scan showed no proximal DVT, and all thrombi were located in muscular, peroneal, and posterior tibial veins. In unilateral TKA, patients with lower muscle volume of the vastus lateralis at the thigh level in the nonoperated limb had significantly higher prevalence of distal DVT in the operated limb (adjusted OR: 2.97 at subclinical DVT revealed by CTVPA and adjusted OR: 2.68 at symptomatic DVT). This finding was also discovered in patients who underwent simultaneous bilateral TKA (adjusted OR: 1.73-2.97 at subclinical DVT and adjusted OR:1.76-1.86 at symptomatic DVT). CONCLUSIONS:The relative muscle volume of the vastus lateralis at the thigh level was negatively associated with the prevalence of symptomatic and radiologically confirmed DVT, suggesting that low thigh muscle mass is an independent risk factor for VTE in the postoperative period of TKA.

BACKGROUND:Severe centrum semiovale perivascular spaces (CSO-PVSs) are associated with the onset of brain atrophy and dementia. This study explored the relationship between severity of CSO-PVS and development of subdural fluid (SDF) in patients with mild traumatic brain injury (TBI), with the aim of investigating independent radiological risk factors for development of SDF. METHODS:The study cohort comprised 222 patients with a mean age of 51 years (64.0% men) who presented with mild TBI from January 2013 to November 2016. In this study, mild TBI was defined as a Glasgow Coma Scale (GCS) of ≥ 13, Post-Traumatic Amnesia (PTA) of

INTRODUCTION:The aim of this trial was to investigate the effect of a continuous infusion of a neuromuscular blockade (NMB) in comatose out-of-hospital cardiac arrest (OHCA) subjects who underwent targeted temperature management (TTM). METHODS:In this open-label, multicenter trial, subjects resuscitated from OHCA were randomly assigned to receive either NMB (38 subjects) or placebo (43 subjects) for 24 hours. Sedatives and analgesics were given according to the protocol of each hospital during TTM. The primary outcome was serum lactate levels at 24 hours after drug infusion. The secondary outcomes included in-hospital mortality, a poor neurological outcome at hospital discharge, changes in lactate levels, changes in the PaO2:FiO2 ratio over time and muscle weakness as assessed by the Medical Research Council (MRC) scale. RESULTS:Eighty-one subjects (NMB group: median age, 65.5 years, 30 male patients; placebo group: median age, 61.0 years, 29 male patients) were enrolled in this trial. No difference in the serum lactate level at 24 hours was observed between the NMB (2.8 [1.2-4.0]) and placebo (3.6 [1.8-5.2]) groups (p = 0.238). In-hospital mortality and a poor neurologic outcome at discharge did not differ between the two groups. No significant difference in the PaO2:FiO2 ratio over time (p = 0.321) nor the MRC score (p = 0.474) was demonstrated. CONCLUSIONS:In OHCA subjects who underwent TTM, a continuous infusion of NMB did not reduce lactate levels and did not improve survival or neurological outcome at hospital discharge. Our results indicated a limited potential for the routine use of NMB during early TTM. However, this trial may be underpowered to detect clinical differences, and future research should be conducted.

Unrecognized endobronchial intubation frequently occurs after emergency intubation. However, no study has evaluated the effect of one-lung ventilation on end-tidal carbon dioxide (ETCO2) during cardiopulmonary resuscitation (CPR). We compared the hemodynamic parameters, blood gases, and ETCO2 during one-lung ventilation with those during conventional two-lung ventilation in a pig model of CPR, to determine the effect of the former on ETCO2. A randomized crossover study was conducted in 12 pigs intubated with double-lumen endobronchial tube to achieve lung separation. During CPR, the animals underwent three 5-min ventilation trials based on a randomized crossover design: left-lung, right-lung, or two-lung ventilation. Arterial blood gases were measured at the end of each ventilation trial. Ventilation was provided using the same tidal volume throughout the ventilation trials. Comparison using generalized linear mixed model revealed no significant group effects with respect to aortic pressure, coronary perfusion pressure, and carotid blood flow; however, significant group effect in terms of ETCO2 was found (P < 0.001). In the post hoc analyses, ETCO2 was lower during the right-lung ventilation than during the two-lung (P = 0.006) or left-lung ventilation (P < 0.001). However, no difference in ETCO2 was detected between the left-lung and two-lung ventilations. The partial pressure of arterial carbon dioxide (PaCO2), partial pressure of arterial oxygen (PaO2), and oxygen saturation (SaO2) differed among the three types of ventilation (P = 0.003, P = 0.001, and P = 0.001, respectively). The post hoc analyses revealed a higher PaCO2, lower PaO2, and lower SaO2 during right-lung ventilation than during two-lung or left-lung ventilation. However, the levels of these blood gases did not differ between the left-lung and two-lung ventilations. In a pig model of CPR, ETCO2 was significantly lower during right-lung ventilation than during two-lung ventilation. However, interestingly, ETCO2 during left-lung ventilation was comparable to that during two-lung ventilation.

[This corrects the article DOI: 10.1371/journal.pone.0070358.].

α-Flavone glycosides have beneficial properties for applications in the pharmaceutical, cosmetic, and food industries. However, their chemical syntheses are often limited by a low efficiency or scarcity of substrates. In this study, α-flavone glucosides were enzymatically synthesized by amylosucrase from Deinococcus geothermalis (DGAS) using sucrose and various flavones as a donor for glucosyl units and acceptors, respectively. Luteolin was the most effective acceptor in the transglucosylation reaction using DGAS among nine flavone materials (apigenin, chrysin, 6,7-dihydroxyflavone, homoorientin, 7-hydroxyflavone, isorhoifolin, luteolin, luteolin-3',7-diglucoside, and orientin). The highest production yield of luteolin glucoside was 86%, with a 7:1 molar ratio of donor to acceptor molecules, in 50 mM Tris-HCl buffer (pH 7) at 37°C for 24 h using 2 U of DGAS. The synthesized luteolin glucoside was identified as luteolin-4'-O-α-D-glucopyranoside with a glucose molecule linked to the C-4' position on the B-ring of luteolin via an α-glucosidic bond, as determined by 1H and 13C nuclear magnetic resonance. This result clearly confirmed that the glucosylated luteolin was successfully synthesized by DGAS and it can be applied as a functional ingredient. Furthermore, this approach using DGAS has the potential to be utilized for the synthesis of various glucosylated products using different types of polyphenols to enhance their functionalities.

[This corrects the article DOI: 10.1371/journal.pone.0152611.].

d-Tagatose has gained substantial interest due to its potential functionalities as a sucrose substitute. In this study, the gene araA, encoding l-arabinose isomerase (l-AI) from Clostridium hylemonae (DSM 15053), was cloned and expressed in Escherichia coli BL21 (DE3). This gene consists of 1,506 nucleotides and encodes a protein of 501 amino acid residues with a calculated molecular mass of 56,554 Da. Since l-AI was expressed as an intracellular inclusion body, this enzyme was solubilized with guanidine hydrochloride, refolded, and activated with a descending concentration gradient of urea. The purified enzyme exhibited the greatest activity at 50°C, pH 7-7.5, and required 1 mM of Mg2+ as a cofactor. Notably, the catalytic efficiency (3.69 mM-1sec-1) of l-AI from C. hylemonae on galactose was significantly greater than that of other previously reported enzymes. The bioconversion yield of d-tagatose using the C. hylemonae l-arabinose isomerase at 60°C reached approximately 46% from 10 mM of d-galactose after 2 h. From these results, it is suggested that the l-arabinose isomerase from C. hylemonae could be utilized as a potential enzyme for d-tagatose production due to its high conversion yield at an industrially competitive temperature.

[This corrects the article DOI: 10.1371/journal.pone.0148165.].

Porous starch granules (PSGs) with various pores and cavity sizes were prepared by amylolysis enzymes. The greatest hydrolysis rate on corn starch granule was observed with α-amylase, followed by gluco- and β-amylases. Temperature increase enhanced glucoamylase reaction rate more drastically than other enzyme treatments. Final hydrolysis level with glucoamylase reached to 66.9%, close to 67.5% of α-amylolysis. The α-amylase-treated PSGs displayed the greatest pore size and ratio of cavity-to-granule diameters. Gelatinization onset temperatures of PSGs increased to 72.1 (α-), 68.7 (β-), and 68.1°C (gluco-amylolysis) after 8 h; enthalpy changes of β- and gluco-amylase-treated PSGs increased to 13.4, and 13.1 J/g but α-amylase-treated one showed slightly reduced value of 8.5 J/g. Water holding capacities of PSGs were 209.7 (α-), 94.6 (β-), and 133.8% (gluco-amylolysis), and the untreated control had 89.1%; oil holding capacities of them showed 304.5, 182.7, and 211.5%, respectively, while the untreated control had 161.8%. Thus, enzyme types and their reaction conditions can be applied to generate desirable cavity and pore sizes in starch granules. This biocatalytic approach could contribute to develop tailor-made PSGs with distinct internal structure for specific uses in wide range of food, pharmaceutical and other industrial applications.

We propose an energy efficient combination design for OFDM systems based on selected mapping (SLM) and clipping peak-to-average power ratio (PAPR) reduction techniques, and show the related energy efficiency (EE) performance analysis. The combination of two different PAPR reduction techniques can provide a significant benefit in increasing EE, because it can take advantages of both techniques. For the combination, we choose the clipping and SLM techniques, since the former technique is quite simple and effective, and the latter technique does not cause any signal distortion. We provide the structure and the systematic operating method, and show the various analyzes to derive the EE gain based on the combined technique. Our analysis show that the combined technique increases the EE by 69% compared to no PAPR reduction, and by 19.34% compared to only using SLM technique.

To evaluate choroidal changes in eyes with acute anterior uveitis associated with human leukocyte antigen (HLA)-B27.In 44 patients with first-onset, unilateral, acute-onset (

BACKGROUND:We performed this retrospective study to identify predictors of right paraesophageal lymph node metastasis, and reviewed previous studies related to this topic. METHODS:Between June 2005 and March 2015, 1107 patients were diagnosed with papillary thyroid carcinoma and underwent surgery at Pusan National University Hospital. RESULTS:Right paraesophageal lymph node metastasis was observed in 171 (15.4%) patients. Multivariate analyses showed that the risk of right paraesophageal metastasis was significantly associated with tumor size, location, a higher number of metastatic central lymph nodes, and lateral lymph node metastasis. In a meta-analysis of the eligible studies, tumor size, number of metastatic central lymph nodes, and lateral lymph node metastasis showed significant relationships with the risk of right paraesophageal metastasis. CONCLUSIONS:In patients with risk factors such as those identified in our study, the possibility of right paraesophageal metastasis should be kept in mind, and careful inspection and dissection are required.

The biological function of proteins is closely related to its structural motion. For instance, structurally misfolded proteins do not function properly. Although we are able to experimentally obtain structural information on proteins, it is still challenging to capture their dynamics, such as transition processes. Therefore, we need a simulation method to predict the transition pathways of a protein in order to understand and study large functional deformations. Here, we present a new simulation method called normal mode-guided elastic network interpolation (NGENI) that performs normal modes analysis iteratively to predict transition pathways of proteins. To be more specific, NGENI obtains displacement vectors that determine intermediate structures by interpolating the distance between two end-point conformations, similar to a morphing method called elastic network interpolation. However, the displacement vector is regarded as a linear combination of the normal mode vectors of each intermediate structure, in order to enhance the physical sense of the proposed pathways. As a result, we can generate more reasonable transition pathways geometrically and thermodynamically. By using not only all normal modes, but also in part using only the lowest normal modes, NGENI can still generate reasonable pathways for large deformations in proteins. This study shows that global protein transitions are dominated by collective motion, which means that a few lowest normal modes play an important role in this process. NGENI has considerable merit in terms of computational cost because it is possible to generate transition pathways by partial degrees of freedom, while conventional methods are not capable of this.

Photographs of skin wounds have the most important information during the secondary intention healing (SIH). However, there is no standard method for handling those images and analyzing them efficiently and conveniently.To investigate the sequential changes of SIH depending on the body sites using a color patch method.We performed retrospective reviews of 30 patients (11 facial and 19 non-facial areas) who underwent SIH for the restoration of skin defects and captured sequential photographs with a color patch which is specially designed for automatically calculating defect and scar sizes.Using a novel image analysis method with a color patch, skin defects were calculated more accurately (range of error rate: -3.39% ~ + 3.05%). All patients had smaller scar size than the original defect size after SIH treatment (rates of decrease: 18.8% ~ 86.1%), and facial area showed significantly higher decrease rate compared with the non-facial area such as scalp and extremities (67.05 ± 12.48 vs. 53.29 ± 18.11, P < 0.05). From the result of estimating the date corresponding to the half of the final decrement, all of the facial area showed improvements within two weeks (8.45 ± 3.91), and non-facial area needed 14.33 ± 9.78 days.From the results of sequential changes of skin defects, SIH can be recommended as an alternative treatment method for restoration with more careful dressing for initial two weeks.

Oxidative stress has been proposed as a potential factor associated with the establishment and progression of endometriosis. Although a few studies have shown possible mechanisms which may play roles in development, progression of endometriosis, few are known in regards of initiation of the disease, especially in the relationship with endometrium. The aim of our study was to investigate whether normal endometrium may be changed by Damage-associated molecular patterns (DAMPs), which may contribute developing pathologic endometrium to induce endometriosis. Endometrial tissues were obtained from 10 patients with fibroids undergoing hysterectomy at a university hospital. High mobility group box-1 (HMGB-1), which is a representative DAMP, has been chosen that may induce alteration in endometrium. In preceding immunohistochemistry experiments using paraffin-block sections from endometriosis (N = 33) and control (N = 27) group, retrospectively, HMGB-1 expression was shown in both epithelial and stromal cell. HMGB-1 expression was significantly increased in secretory phase of endometriosis group, comparing to the controls. To examine the alteration of endometrial stromal cell (HESC) by oxidative stress in terms of HMGB-1, cell proliferation and expression of its receptor, TLR4 was measured according to recombinant HMGB-1 use. Cell proliferation was assessed by CCK-8 assay; real-time PCR and western blotting were used to quantify Toll like receptor 4 (TLR4) mRNA and protein expression respectively. A TLR4 antagonist (LPS-RS) and an inhibitor of the NF-κB pathway (TPCA-1, an IKK-2 inhibitor) were used to confirm the relationships between HMGB-1, TLR4, and the NF-κB pathway. Passive release of HMGB-1 was significantly proportional to the increase in cell death (P

To investigate the prevalence, mortalities, and patient characteristics of Acute-on-chronic liver failure (ACLF) according to the AARC (Asian Pacific Association for the Study of the Liver ACLF Research Consortium) and European Association for the Study of the Liver CLIF-C (Chronic Liver Failure Consortium) definitions.We collected retrospective data for 1470 hospitalized patients with chronic liver disease (CLD) and acute deterioration between January 2013 and December 2013 from 21 university hospitals in Korea.Of the patients assessed, the prevalence of ACLF based on the AARC and CLIF-C definitions was 9.5% and 18.6%, respectively. The 28-day and 90-day mortality rates were higher in patients with ACLF than in those without ACLF. Patients who only met the CLIF-C definition had significantly lower 28-day and 90-day survival rates than those who only met the AARC definition (68.0% vs. 93.9%, P

BACKGROUND:Serum ferritin levels increase in postmenopausal women, and they are reported to be linked to major health problems. Here, we investigated the association between serum ferritin levels and insulin resistance (IR) in postmenopausal women. METHODS:A total of 6632 healthy Korean women (4357 premenopausal and 2275 postmenopausal) who participated in the Korean National Health and Nutrition Examination Survey (KNHANES) in 2007-2010 were enrolled in the study. Serum ferritin values were divided into six groups for the premenopausal and postmenopausal groups. IR and obesity indices were evaluated according to the six serum ferritin groups. Statistical analysis was carried out using SAS software, version 9.2 (SAS Institute Inc., Cary, NC, USA). RESULTS:The association between the IR indices and ferritin groups had a higher level of statistical significance in the postmenopausal group than in the premenopausal group. In addition, for the postmenopausal group, the estimates increased significantly in the sixth ferritin group compared to those in the first ferritin group. However, the association between the obesity indices and ferritin levels was not significantly different between the premenopausal and postmenopausal groups. CONCLUSION:Elevated serum ferritin levels were associated with an increased risk of insulin resistance in postmenopausal women.

Myotubularin-related protein 1 (MTMR1) is a phosphatase that belongs to the tyrosine/dual-specificity phosphatase superfamily. MTMR1 has been shown to use phosphatidylinositol 3-monophosphate (PI(3)P) and/or phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) as substrates. Here, we determined the crystal structure of human MTMR1. The refined model consists of the Pleckstrin homology (PH)-GRAM and phosphatase (PTP) domains. The overall structure was highly similar to the previously reported MTMR2 structure. Interestingly, two phosphate molecules were coordinated by strictly conserved residues located in the C(X)5R motif of the active site. Additionally, our biochemical studies confirmed the substrate specificity of MTMR1 for PI(3)P and PI(3,5)P2 over other phosphatidylinositol phosphates. Our structural and enzymatic analyses provide insight into the catalytic mechanism and biochemical properties of MTMR1.

[This corrects the article DOI: 10.1371/journal.pone.0157934.].

Beneficial effects of omega-3 fatty acid (O3FA) supplementation in a wide range of disease condition have been well studied. However, there is limited information regarding the effects of O3FAs on chronic kidney disease (CKD), especially in diabetic nephropathy (DN) with hypertriglyceridemia. We investigate whether O3FA supplementation could help maintain renal function in patients with diabetes and hypertriglyceridemia. Total 344 type 2 diabetic patients with a history of O3FA supplementation for managing hypertriglyceridemia were included. Reduction in urine albumin to creatinine ratio (ACR) and glomerular filtrate rate (GFR) were examined. Subgroup analyses were stratified according to the daily O3FA doses. Serum total cholesterol, triglyceride, and urine ACR significantly reduced after O3FA supplementation. Overall, 172 (50.0%) patients did not experience renal function loss, and 125 (36.3%) patients had a GFR with a positive slope. The patients treated with O3FAs at 4g/day showed greater maintenance in renal function than those treated with lower dosages (p < 0.001). This dose dependent effect remains significant after adjustment for multiple variables. O3FA supplementation in diabetic patients with hypertriglyceridemia shows benefits of reducing albuminuria and maintaining renal function. The effects are dependent on the dose of daily O3FA supplementation.

BackgroundWhether diabetic patients without a history of coronary heart disease (CHD) have the same risk of CHD events as non-diabetic patients with a history of CHD remains controversial. This study aimed to determine whether type 2 diabetes mellitus (T2DM) is a coronary heart disease (CHD) equivalent in the need for coronary revascularization procedures (RVs) in the Korean population.Methodology/principal findingsWe followed 2,168,698 subjects who had oral anti-diabetic drugs (OADs)-taking T2DM in 2008 and/or CHD in 2007-2008 (i.e., recent CHD). We used systematic datasets from the nationwide claims database of the Health Insurance Review and Assessment service of Korea, which is representative of the whole population of Korea, from January 2007 to December 2012. The primary study endpoint was the development of need for RVs (i.e., incident CHD) after January 2009 among three groups based on their status of T2DM and recent CHD, i.e., T2DM only, recent CHD only, and both T2DM and recent CHD. After adjustment for age and sex, patients with recent CHD only had 2.14 times the risk of incident CHD (95% CI, 2.11-2.18, PConclusions/significanceThis analysis of data from the nationwide claims database revealed that T2DM did not have a recent CHD equivalent risk in the Korean population. These results suggest that an appropriate strategy for the CHD risk stratification in diabetic patients should be adopted to manage this population.

Glycogen expressed by the lower genital tract epithelium is believed to support Lactobacillus growth in vivo, although most genital isolates of Lactobacillus are not able to use glycogen as an energy source in vitro. We recently reported that α-amylase is present in the genital fluid of women and that it breaks down glycogen into small carbohydrates that support growth of lactobacilli. Since the pH of the lower genital tract can be very low, we determined how low pH affects glycogen processing by α-amylase. α-amylase in saliva degraded glycogen similarly at pH 6 and 7, but activity was reduced by 52% at pH 4. The glycogen degrading activity in nine genital samples from seven women showed a similar profile with an average reduction of more than 50% at pH 4. However, two samples collected from one woman at different times had a strikingly different pH profile with increased glycogen degradation at pH 4, 5 and 6 compared to pH 7. This second pH profile did not correlate with levels of human α-acid glucosidase or human intestinal maltase glucoamylase. High-performance anion-exchange chromatography showed that mostly maltose was produced from glycogen by samples with the second pH profile in contrast to genital α-amylase that yielded maltose, maltotriose and maltotetraose. These studies show that at low pH, α-amylase activity is reduced to low but detectable levels, which we speculate helps maintain Lactobacillus growth at a limited but sustained rate. Additionally, some women have a genital enzyme distinct from α-amylase with higher activity at low pH. Further studies are needed to determine the identity and distribution of this second enzyme, and whether its presence influences the makeup of genital microbiota.

PURPOSE:To use novel confocal scanning ophthalmoscopy technology to test hypothesis that HIV-seropositive patients without history of retinitis with a history of a low CD4 count are more likely to have damage to their retinal nerve fiber layer (RNFL) when compared to patients with high CD4 count. In addition, we compared optic disc morphologic changes with glaucoma. DESIGN:Cross-sectional study. PARTICIPANTS AND CONTROLS:171 patients were divided into four groups. The control group consisted of 40 eyes of 20 HIV-seronegative patients. The second group consisted of 80 eyes of 41 HIV-positive patients whose CD4 cell count never dropped below 100 (1.0 x 10(9)/L). The third group consisted of 44 eyes of 26 HIV-positive patients with a history of low CD4 counts

The purpose of this study was to investigate if multi-domain cognitive training, especially robot-assisted training, alters cortical thickness in the brains of elderly participants. A controlled trial was conducted with 85 volunteers without cognitive impairment who were 60 years old or older. Participants were first randomized into two groups. One group consisted of 48 participants who would receive cognitive training and 37 who would not receive training. The cognitive training group was randomly divided into two groups, 24 who received traditional cognitive training and 24 who received robot-assisted cognitive training. The training for both groups consisted of daily 90-min-session, five days a week for a total of 12 weeks. The primary outcome was the changes in cortical thickness. When compared to the control group, both groups who underwent cognitive training demonstrated attenuation of age related cortical thinning in the frontotemporal association cortices. When the robot and the traditional interventions were directly compared, the robot group showed less cortical thinning in the anterior cingulate cortices. Our results suggest that cognitive training can mitigate age-associated structural brain changes in the elderly.ClnicalTrials.gov NCT01596205.

Airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are characterized by excessive inflammation and are exacerbated by nontypeable Haemophilus influenzae (NTHi). Airway epithelial cells mount the initial innate immune responses to invading pathogens and thus modulate inflammation. While inflammation is necessary to eliminate a pathogen, excessive inflammation can cause damage to the host tissue. Therefore, the inflammatory response must be tightly regulated and deciphering the signaling pathways involved in this response will enhance our understanding of the regulation of the host inflammatory response. NTHi binds to TLR2 and signal propagation requires the adaptor molecule myeloid differentiation factor 88 (MyD88). An alternative spliced form of MyD88 is called MyD88 short (MyD88s) and has been identified in macrophages and embryonic cell lines as a negative regulator of inflammation. However, the role of MyD88s in NTHi-induced inflammation in airway epithelial cells remains unknown. Here we show that NTHi induces MyD88s expression and MyD88s is a negative regulator of inflammation in airway epithelial cells. We further demonstrate that MyD88s is positively regulated by IKKβ and CREB and negatively regulated by ERK1/2 signaling pathways. Taken together these data indicate that airway inflammation is controlled in a negative feedback manner involving MyD88s and suggest that airway epithelial cells are essential to maintain immune homeostasis.

In certain image acquisitions processes, like in fluorescence microscopy or astronomy, only a limited number of photons can be collected due to various physical constraints. The resulting images suffer from signal dependent noise, which can be modeled as a Poisson distribution, and a low signal-to-noise ratio. However, the majority of research on noise reduction algorithms focuses on signal independent Gaussian noise. In this paper, we model noise as a combination of Poisson and Gaussian probability distributions to construct a more accurate model and adopt the contourlet transform which provides a sparse representation of the directional components in images. We also apply hidden Markov models with a framework that neatly describes the spatial and interscale dependencies which are the properties of transformation coefficients of natural images. In this paper, an effective denoising algorithm for Poisson-Gaussian noise is proposed using the contourlet transform, hidden Markov models and noise estimation in the transform domain. We supplement the algorithm by cycle spinning and Wiener filtering for further improvements. We finally show experimental results with simulations and fluorescence microscopy images which demonstrate the improved performance of the proposed approach.

A number of peptide-based indicators have been identified and reported as potential apoptosis probes, offering great promise for early assessment of therapeutic efficacy in several types of cancer. Direct comparison of the newly developed probes with previously used ones would be an important step in assessing possible applications. Here, we compared the newly identified peptide-based phosphatidylserine (PS) indicator PSP1 (CLSYYPSYC) with annexin V, a common probe for molecular imaging of apoptotic cells, with respect to PS binding kinetics, apoptotic cell-targeting ability, and the efficacy of homing to apoptotic tumor cells in a mouse model after treatment with the anticancer agent camptothecin. Our results indicate that PSP1 efficiently targeted apoptotic cells and generated apoptosis/tumor-specific signals after cancer treatment in the animal model, whereas a similar dose of annexin V showed weak signals. The formation of a stable complex of PSP1 with PS might be one reason for the efficient in vivo targeting. We suggest that PSP1 has potential advantages for in vivo apoptotic cell imaging and could serve as a platform for the development of de novo peptide-based probes for apoptosis.

Tissue inhibitors of metalloproteinases (TIMPs) are multifaceted molecules that exhibit properties beyond their classical proteinase inhibitory function. Although TIMP-1 is a known inhibitor of apoptosis in mammalian cells, the mechanisms by which it exerts its effects are not well-established. Our earlier studies using H2009 lung adenocarcinoma cells, implanted in the CNS, showed that TIMP-1 overexpressing H2009 cells (HB-1), resulted in more aggressive tumor kinetics and increased vasculature. The present study was undertaken to elucidate the role of TIMP-1 in the context of apoptosis, using the same lung cancer cell lines. Overexpressing TIMP-1 in a lung adenocarcinoma cell line H2009 resulted in an approximately 3-fold increased expression of Bcl-2, with a marked reduction in apoptosis upon staurosporine treatment. This was an MMP-independent function as a clone expressing TIMP-1 mutant T2G, lacking MMP inhibition activity, inhibited apoptosis as strongly as TIMP1 overexpressing clones, as determined by inhibition of PARP cleavage. Immunoprecipitation of Bcl-2 from cell lysates also co-immunoprecipitated TIMP-1, indicative of an interaction between these two proteins. This interaction was specific for TIMP-1 as TIMP-2 was not present in the Bcl-2 pull-down. Additionally, we show a co-dependency of TIMP-1 and Bcl-2 RNA and protein levels, such that abrogating Bcl-2 causes a downregulation of TIMP-1 but not TIMP-2. Finally, we demonstrate that TIMP-1 dependent inhibition of apoptosis occurs through p90RSK, with phosphorylation of the pro-apoptotic protein BAD at serine 112, ultimately reducing Bax levels and increasing mitochondrial permeability. Together, these studies define TIMP-1 as an important cancer biomarker and demonstrate the potential TIMP-1 as a crucial therapeutic target.

We developed and tested a multicomponent peptide-woven siRNA nanocomplex (PwSN) comprising different peptides designed for efficient cellular targeting, endosomal escape, and release of siRNA. To enhance tumor-specific cellular uptake, we connected an interleukin-4 receptor-targeting peptide (I4R) to a nine-arginine peptide (9r), yielding I4R-9r. To facilitate endosomal escape, we blended endosomolytic peptides into the I4R-9r to form a multicomponent nanocomplex. Lastly, we modified 9r peptides by varying the number and positions of positive charges to obtain efficient release of siRNA from the nanocomplex in the cytosol. Using this step-wise approach for overcoming the biological challenges of siRNA delivery, we obtained an optimized PwSN with significant biological activity in vitro and in vivo. Interestingly, surface plasmon resonance analyses and three-dimensional peptide models demonstrated that our designed peptide adopted a unique structure that was correlated with faster complex disassembly and a better gene-silencing effect. These studies further elucidate the siRNA nanocomplex delivery pathway and demonstrate the applicability of our stepwise strategy to the design of siRNA carriers capable of overcoming multiple challenges and achieving efficient delivery.

It has been reported in several studies that there may be a significant correlation between reproductive history and the risk of osteoporosis due to the effect of estrogen. Under this hypothesis, however, it is unclear whether the age at first delivery has any major influences on the risk of osteoporosis. Therefore, this study aimed to investigate the relationship between the age at first delivery and the risk of osteoporosis in Korean menopausal women. This study was performed using data from the 2008-2011 Korea National Health and Nutrition Examination Survey and included 2,530 Korean postmenopausal women. The diagnosis of osteoporosis was made using the World Health Organization T-score criteria (T-score ≤ -2.5, at the femoral neck or lumbar spine). Participants were categorized into 3 groups according to age at first delivery: ≤ 23, 24-29, and ≥ 30 years. Older age, lower body mass index, lower calcium intake, later menarche, and earlier menopause increased the risk of osteoporosis, whereas hormone therapy and oral contraceptive use were associated with a decreased risk of osteoporosis. Postmenopausal women whose first delivery occurred at age 24-29 years were shown to have a significantly increased risk of osteoporosis (odds ratio, 2.124; 95% confidence interval, 1.096-4.113; P = 0.026) compared to those who first gave birth after the age of 30 years. These findings suggest that postmenopausal women whose first delivery occurred in their mid to late 20s, a period during which bone mass slowly accumulates to the peak, are at an increased risk of osteoporosis.