Computed tomography-based visual assessment of chronic obstructive pulmonary disease: comparison with pulmonary function test and quantitative computed tomography

BackgroundChronic obstructive pulmonary disease (COPD) has variable subtypes involving mixture of large airway inflammation, small airway disease, and emphysema. This study evaluated the relationship between visually assessed computed tomography (CT) subtypes and clinical/imaging characteristics.MethodsIn total, 452 participants were enrolled in this study between 2012 and 2017. Seven subtypes were defined by visual evaluation of CT images using Fleischner Society classification: normal, paraseptal emphysema (PSE), bronchial disease, and centrilobular emphysema (trace, mild, moderate and confluent/advanced destructive). The differences in several variables, including clinical, laboratory, spirometric, and quantitative CT features among CT-based visual subtypes, were compared using the chi-square tests and one-way analysis of variance.ResultsSubjects who had PSE had better forced expiratory volume in 1 second (FEV1) (P=0.03) percentage and higher lung density (P<0.05) than those with moderate to confluent/advanced destructive centrilobular emphysema. As the visual grade of centrilobular emphysema worsened, pulmonary function declined and modified Medical Research Council, COPD assessment test (CAT) score, and quantitative assessment (emphysema index and air trapping) increased. The bronchial subtype was associated with higher body mass index (BMI), better lung function and higher lung density. Participants with trace emphysema showed a rapid increase in functional small airway diseaseConclusionsClassifying subtypes using visual CT imaging features can reflect heterogeneity and pathological processes of COPD.     

The role of copper and protons in heme-copper oxidases: kinetic study of an engineered heme-copper center in myoglobin

To probe the role of copper and protons in heme-copper oxidase (HCO), we have performed kinetic studies on an engineered heme-copper center in sperm whale myoglobin (Leu-29 --> HisPhe-43 --> His, called Cu(B)Mb) that closely mimics the heme-copper center in HCO. In the absence of metal ions, the engineered Cu(B) center in Cu(B)Mb decreases the O(2) binding affinity of the heme. However, addition of Ag(I), a redox-inactive mimic of Cu(I), increases the O(2)-binding affinity. More importantly, copper ion in the Cu(B) center is essential for O(2) reduction, as no O(2) reduction can be observed in copper-free, Zn(II), or Ag(I) derivatives of Cu(B)Mb. Instead of producing a ferryl-heme as in HCO, the Cu(B)Mb generates verdoheme because the engineered Cu(B)Mb may lack a hydrogen bonding network that delivers protons to promote the heterolytic OO cleavage necessary for the formation of ferryl-heme. Reaction of oxidized Cu(B)Mb with H(2)O(2), a species equivalent in oxidation state to 2e(-), reduced O(2) but, possessing the extra protons, resulted in ferryl-heme formation, as in HCO. The results showed that the Cu(B) center plays a critical role in O(2) binding and reduction, and that proton delivery during the O(2) reduction is important to avoid heme degradation and to promote the HCO reaction.     

Psychosocial,Physical, and Autonomic Correlates of Depression in Korean Adults: Results from a County-Based Depression Screening Study

Objective

We aimed to investigate the prevalence and psychosocial and neurophysiological correlates of depression in a large county-based cohort of Korean adults.

Methods

We recruited 2355 adults from a rural county-based health promotion program. The following psychometric scales were used: the Center for Epidemiologic Studies Depression scale (CES-D) was used to assess depression, the General Health Questionnaire (GHQ) was used to evaluate stress, and the Medical Outcome Study Social Support Survey (MOS-SSS) was used to determine perceived social support. Heart rate variability (HRV) was used to assess neurophysiological properties. The psychosocial and neurophysiological variables of adults with depression (CES-D score ≥25) and without depression (CES-D score <25) were statistically compared. A logistic regression model was constructed to identify factors independently associated with depression.

Results

We estimated that 17.7% of the subjects had depression, which was associated with old age, being female, being single, less religious affiliation, high education, low body mass index (BMI), low levels of aerobic exercise, low social support, and a low HRV triangular index. The explanatory factors of depression included high education, less religious affiliation, low levels of current aerobic exercise, low BMI, and low social support.

Conclusion

Given the relatively high prevalence of overall depression, subsyndromal depression should also be regarded as an important issue in screening. The independent factors associated with depression suggest that practical psychosocial intervention, including brief psychotherapy, aerobic exercise, and other self-help methods should be considered. In addition, the HRV results suggest that further depression screening accompanied by neurophysiological features would require fine methodological modifications with proactive efforts to prevent depressive symptoms.     

Outcomes of acute lymphoblastic leukaemia in adolescent and young adult Korean patients

This study used Korean national data to investigate the relationship between treatment patterns and outcomes in Korean adolescent and young-adult (AYA) acute lymphoblastic leukaemia (ALL) patients. Chemotherapy incorporating L-asparaginase was considered paediatric-inspired (PI), as opposed to adult protocols. In total, 65·3% of patients received PI therapy. Five-year overall survival (OS) of PI-treated patients outperformed adult protocols (63·1% vs. 40·4%; P < 0·0001); this trend was maintained within various age subgroups. Younger age, L-asparaginase therapy, and radiotherapy corresponded with superior OS by multivariable analysis. OS tends to improve with PI protocols that include L-asparaginase in AYA ALL, suggesting that therapy protocol is critical in the treatment performance of this group.     

Quantitative Prediction of Oral Bioavailability of a Lipophilic Antineoplastic Drug Bexarotene Administered in Lipidic Formulation Using a Combined In Vitro Lipolysis/Microsomal Metabolism Approach

For performance assessment of the lipid-based drug delivery systems (LBDDSs), in vitro lipolysis is commonly applied because traditional dissolution tests do not reflect the complicated in vivo micellar formation and solubilization processes. Much of previous research on in vitro lipolysis has mostly focused on rank-ordering formulations for their predicted performances. In this study, we have incorporated in vitro lipolysis with microsomal stability to quantitatively predict the oral bioavailability of a lipophilic antineoplastic drug bexarotene (BEX) administered in LBDDS. Two types of LBDDS were applied: lipid solution and lipid suspension. The predicted oral bioavailability values of BEX from linking in vitro lipolysis with microsomal stability for lipid solution and lipid suspension were 34.2 ± 1.6% and 36.2 ± 2.6%, respectively, whereas the in vivo oral bioavailability of BEX was tested as 31.5 ± 13.4% and 31.4 ± 5.2%, respectively. The predicted oral bioavailability corresponded well with the oral bioavailability for both formulations, demonstrating that the combination of in vitro lipolysis and microsomal stability can quantitatively predict oral bioavailability of BEX. In vivo intestinal lymphatic uptake was also assessed for the formulations and resulted in <1% of the dose, which confirmed that liver microsomal stability was necessary for correct prediction of the bioavailability.     

LPS and IL‐1 differentially activate mouse and human astrocytes: Role of CD14

Treatment of cultures with toll‐like receptor (TLR) ligands or cytokines has become a popular approach to investigate astrocyte neuroinflammatory responses and to simulate the neural environment in various CNS disorders. However, despite much effort, the mechanism of astrocyte activation such as their responses to the TLR ligands and IL‐1 remain highly debated. We compared highly pure primary mouse and human astrocyte cultures in their ability to produce proinflammatory mediators (termed “A1”) and immunoregulatory mediators (termed “A2”) in response to LPS, poly IC, and IL‐1 stimulation. In human astrocytes, IL‐1 induced both A1 and A2 responses, poly IC induced mostly A2, and LPS induced neither. In mouse astrocytes, LPS induced mostly an A1‐predominant response, poly IC induced both A1 and A2, and IL‐1 neither. In addition, mouse astrocytes produce abundant IL‐1 protein, whereas human astrocytes did not, despite robust IL‐1 mRNA expression. Of the TLR4 receptor complex proteins, human astrocytes expressed TLR4 and MD2 but not CD14, whereas mouse astrocytes expressed all three. Mouse astrocyte CD14 (cell‐associated and soluble) was potently upregulated by LPS. Silencing TLR4 or CD14 by siRNA suppressed LPS responses in mouse astrocytes. In vivo, astrocytes in LPS‐injected mouse brains also expressed CD14. Our results show striking differences between human and mouse astrocytes in the use of TLR/IL‐1R and subsequent downstream signaling and immune activation. IL‐1 translational block in human astrocytes may be a built‐in mechanism to prevent autocrine and paracrine cell activation and neuroinflammation. These results have important implications for translational research of human CNS diseases. GLIA 2014;62:999–1013     

Variable selection in subdistribution hazard frailty models with competing risks data

The proportional subdistribution hazards model (i.e. Fine‐Gray model) has been widely used for analyzing univariate competing risks data. Recently, this model has been extended to clustered competing risks data via frailty. To the best of our knowledge, however, there has been no literature on variable selection method for such competing risks frailty models. In this paper, we propose a simple but unified procedure via a penalized h‐likelihood (HL) for variable selection of fixed effects in a general class of subdistribution hazard frailty models, in which random effects may be shared or correlated. We consider three penalty functions, least absolute shrinkage and selection operator (LASSO), smoothly clipped absolute deviation (SCAD) and HL, in our variable selection procedure. We show that the proposed method can be easily implemented using a slight modification to existing h‐likelihood estimation approaches. Numerical studies demonstrate that the proposed procedure using the HL penalty performs well, providing a higher probability of choosing the true model than LASSO and SCAD methods without losing prediction accuracy. The usefulness of the new method is illustrated using two actual datasets from multi‐center clinical trials. Copyright © 2014 John Wiley & Sons, Ltd.