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Cigarette smoke (CS) is a highly complex mixture and many of its components are known carcinogens, mutagens, and other toxic substances. CS induces oxidative stress and cell death, and this cell toxicity plays a key role in the pathogenesis of several pulmonary diseases.We studied the effect of cigarette smoke extract (CSE) in human alveolar epithelial type I-like (ATI-like) cells. These are isolated type II cells that are differentiating toward the type I cell phenotype in vitro and have lost many type II cell markers and express type I cell markers. ATI-like cells were more sensitive to CSE than alveolar type II cells, which maintained their differentiated phenotype in vitro. We observed disruption of mitochondrial membrane potential, apoptosis and necrosis that were detected by double staining with acridine orange and ethidium bromide or Hoechst 33342 and propidium iodide and TUNEL assay after treatment with CSE. We also detected caspase 3 and caspase 7 activities and lipid peroxidation. CSE induced nuclear translocation of Nrf2 and increased expression of Nrf2, HO-1, Hsp70 and Fra1. Moreover, we found that Nrf2 knockdown sensitized ATI-like cells to CSE and Nrf2 overexpression provided protection against CSE-induced cell death. We also observed that two antioxidant compounds N-acetylcysteine and trolox protected ATI-like cells against injury by CSE.Our study indicates that Nrf2 activation is a major factor in cellular defense of the human alveolar epithelium against CSE-induced toxicity and oxidative stress. Therefore, antioxidant agents that modulate Nrf2 would be expected to restore antioxidant and detoxifying enzymes and to prevent CS-related lung injury and perhaps lessen the development of emphysema.

Small interfering RNA (siRNA) has been used widely to induce gene silencing in cells. To predict the efficacy of an siRNA with respect to inhibition of its target mRNA, we developed a two layer system, siPRED, which is based on various characteristic methods in the first layer and fusion mechanisms in the second layer. Characteristic methods were constructed by support vector regression from three categories of characteristics, namely sequence, features, and rules. Fusion mechanisms considered combinations of characteristic methods in different categories and were implemented by support vector regression and neural networks to yield integrated methods. In siPRED, the prediction of siRNA efficacy through integrated methods was better than through any method that utilized only a single method. Moreover, the weighting of each characteristic method in the context of integrated methods was established by genetic algorithms so that the effect of each characteristic method could be revealed. Using a validation dataset, siPRED performed better than other predictive systems that used the scoring method, neural networks, or linear regression. Finally, siPRED can be improved to achieve a correlation coefficient of 0.777 when the threshold of the whole stacking energy is ≥-34.6 kcal/mol. siPRED is freely available on the web at http://predictor.nchu.edu.tw/siPRED.

The aim of this study was to compare the health-related quality of life of fathers under different infant feeding type scenarios. The Medical Outcomes Study 36-item Short-Form was used to measure the health-related quality of life of 1,699 fathers, and the scores were used to look for associations with different infant feeding methods. Multivariable linear regression analysis was used to explore the contribution of the other potential related factors on fathers’ quality of life. After controlling for confounding factors, fathers whose infants were ever being breast-fed reported lower scores than fathers whose infants were bottle-fed. Except for the infant feeding pattern, having a job, higher family income, and being the major caregiver were positively related to the father’s quality of life. Fathers may not benefit during breast-feeding process. Because fathers’ involvement plays an important role in the success of breast-feeding, the development of interventions that enable fathers to support their breast-feeding partner is very important.

In the title salt, C9H12NO2+·NO3−, the cation and anion are linked by a bifurcated N—H...(O,O) hydrogen bond. The crystal packing is stabilized by intermolecular N—H...O, O—H...O and C—H...O hydrogen bonds, which connect neighbouring cations and anions, resulting in a two-dimensional network.

The title compound, C8H8N4, possesses crystallographic mirror symmetry, with four C atoms lying on the reflecting plane, which bisects the phenyl and tetrazole rings. It is composed of a planar r.m.s. deviation (0.0012 Å) tetrazole ring which is nearly coplanar with the benzene ring, the dihedral angle being 2.67 (9)°. In the crystal, symmetry-related molecules are linked by intermolecular N—H...N hydrogen bonds. The molecules stack along [100] with a π...π interaction involving the phenyl and tetrazole rings of adjacent molecules [centroid–centroid distance = 3.5639 (15) Å]. The H atom of the N—H group is disordered over two sites of equal occupancy. The methyl H atoms were modelled as disordered over two sets of sites of equal occupancy rotated by 60° with respect to each other.

Viral myocarditis is a common cardiovascular disease, which has greatly threatened human health. However, up to now, the pathogenesis of viral myocarditis has been unclear, which leads to the lack of its effective treatments. To investigate the role of chemokines in pathogenesis of viral myocarditis, mRNA expression for a panel of 19 chemokines detected by RT-PCR in myocardial tissue of BALB/c mice that were inoculated intraperitoneally with coxsackievirus B3. Moreover primary cultured cardiac myocytes were infected with coxsackievirus B3 following extraction of RNA, from myocytes the expression of 19 chemokines was detected by by RT-PCR. Our results showed that there was much difference in the expression pattern of chemokines in myocardial tissue between infected mice with viral myocarditis and uninfected control mice. The expression of chemokines was varied significantly in clusters in myocardium post coxsackievirus B3 infection. There were also complexity and imbalance in the change of the expression of chemokines. In the meantime, Coxsackievirus B3 infection also influenced the expression pattern of chemokines in cardiac myocytes in vitro. However the expression of monocyte chemoattractant protein-1 alone was upregulated in cardiac myocytes post coxsackievirus B3 infection in the 19 detected chemokines. The chemokine expression pattern changed in complexity and imbalance manner both in myocardium and in primary cultured cardiac myocytes after coxsackievirus B3 infection. Coxsackievirus B3 infection may start viral myocarditis by regulating the expression pattern of chemokines in cardiac myocytes. MCP-1 may be one of key chemokines in the initial stage of viral myocarditis.

BACKGROUND: Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD) and lung cancer. Respiratory bacterial infections have been shown to be involved in the development of COPD along with impaired airway innate immunity. METHODOLOGY/PRINCIPAL FINDINGS: To address the in vivo impact of cigarette smoke (CS) exclusively on host innate defense mechanisms, we took advantage of Caenorhabditis elegans (C. elegans), which has an innate immune system but lacks adaptive immune function. Pseudomonas aeruginosa (PA) clearance from intestines of C. elegans was dampened by CS. Microarray analysis identified 6 candidate genes with a 2-fold or greater reduction after CS exposure, that have a human orthologue, and that may participate in innate immunity. To confirm a role of CS-down-regulated genes in the innate immune response to PA, RNA interference (RNAi) by feeding was carried out in C. elegans to inhibit the gene of interest, followed by PA infection to determine if the gene affected innate immunity. Inhibition of lbp-7, which encodes a lipid binding protein, resulted in increased levels of intestinal PA. Primary human bronchial epithelial cells were shown to express mRNA of human Fatty Acid Binding Protein 5 (FABP-5), the human orthologue of lpb-7. Interestingly, FABP-5 mRNA levels from human smokers with COPD were significantly lower (p = 0.036) than those from smokers without COPD. Furthermore, FABP-5 mRNA levels were up-regulated (7-fold) after bacterial (i.e., Mycoplasma pneumoniae) infection in primary human bronchial epithelial cell culture (air-liquid interface culture). CONCLUSIONS: Our results suggest that the C. elegans model offers a novel in vivo approach to specifically study innate immune deficiencies resulting from exposure to cigarette smoke, and that results from the nematode may provide insight into human airway epithelial cell biology and cigarette smoke exposure.

We experimentally investigate generation of backward 357 nm N _2 laser in a gas mixture of N _2 /Ar using 800 nm femtosecond laser pulses, and examine the involved gain dynamics based on pump-probe measurements. Our findings show that a minimum duration of gain in the excited N _2 molecules is required for generating intense backward nitrogen lasers, which is ∼0.8 ns under our experimental conditions. The results shed new light on the mechanism for generating intense backward lasers from nitrogen molecules, which are highly in demand for high sensitivity remote atmospheric sensing application.

We investigate lasing action in aligned nitrogen molecular ions (N_{2}^{+}) produced in an intense laser field. We find that, besides the population inversion between the B^{2}Σ_{u}^{+}-X^{2}Σ_{g}^{+} states, which is responsible for the observed simulated amplification of a seed pulse, a rotational wave packet in the ground vibrational state (v=0) of the excited electronic B^{2}Σ_{u}^{+} state has been created in N_{2}^{+}. The rotational coherence can faithfully encode its characteristics into the amplified seed pulses, enabling reconstruction of rotational wave packets of molecules in a single-shot detection manner from the frequency-resolved laser spectrum. Our results suggest that the air laser can potentially provide a promising tool for remote characterization of coherent molecular rotational wave packets.

We experimentally demonstrate the generation of narrow-bandwidth emissions with excellent coherent properties at ∼391 and ∼428 nm from N _2 ^+ (B ^2 Σ _u ^+ ( v ′ = 0) → X ^2 Σ _g ^+ ( v = 0, 1)) inside a femtosecond filament in air by an orthogonally polarized two-color driver field (i.e. 800 nm laser pulse and its second harmonic). The durations of the coherent emissions at 391 and 428 nm are measured to be ∼2.4 and ∼7.8 ps, respectively, both of which are much longer than the duration of the pump and its second harmonic pulses. Furthermore, the measured temporal decay characteristics of the excited molecular systems suggest an ‘instantaneous’ population inversion mechanism that may be achieved in molecular nitrogen ions at an ultrafast time scale comparable to the 800 nm pump pulse.

This paper presents results of a case study on cliff recession mechanism and progressive development of talus deposits around Xiangshan of the Sishou Hills in the southeast of the Taipei Basin. Based on photogrammetric analysis and physical modeling, the geomorphologic changes of talus deposits are carefully examined and the cliff recession rates from 1904 to 2005 are thus measured and tabulated. Our study identified the fundamental control factors on mechanisms of cliff recession and proposed a possible scenario of cliff recession and progressive development of talus deposits around the Xiangshan region from 1904 to 2005.

Abstract Background In recent years, the creation of supportive environments for encouraging mothers to breastfeed their children has emerged as a key health issue for women and children. The provision of lactation rooms and breast pumping breaks have helped mothers to continue breastfeeding after returning to work, but their effectiveness is uncertain. The aim of this study was to assess the effects of worksite breastfeeding-friendly policies and work-related factors on the behaviour of working mothers. Methods This study was conducted at a large Taiwanese semiconductor manufacturer in August-September 2003. Questionnaires were used to collect data on female employees' breastfeeding behaviour, child rearing and work status when raising their most recently born child. A total of 998 valid questionnaires were collected, giving a response rate of 75.3%. Results The results showed that 66.9% of survey respondents breastfed initially during their maternity leave, which averaged 56 days. Despite the provision of lactation rooms and breast pumping breaks, only 10.6% mothers continued to breastfeed after returning to work, primarily office workers and those who were aware of their company's breastfeeding-friendly policies. Conclusion In conclusion, breastfeeding-friendly policies can significantly affect breastfeeding behaviour. However, an unfavourable working environment, especially for fab workers, can make it difficult to implement breastfeeding measures. With health professionals emphasizing that the importance of breastfeeding for infant health, and as only females can perform lactation, it is vital that women's work "productive role" and family "reproductive role" be respected and accommodated by society.

Shaan Gellatly, Nicole Pavelka, Taylor Crue, Kelly S Schweitzer, Brian J Day, Elysia Min, Mari Numata, Dennis R Voelker, April Scruggs, Irina Petrache, Hong Wei Chu Department of Medicine, National Jewish Health, Denver, CO 80206, USACorrespondence: Hong Wei Chu; Irina Petrache Tel +1 303-398-1689; +1 303-398-2080Fax +1 303-270-2319; +1 303-270-1780Email chuhw@njhealth.org; petrachei@njhealth.orgPurpose: Electronic cigarettes (e-cigs) are relatively new devices that allow the user to inhale a heated and aerosolized solution. At present, little is known about their health effects in the human lung, particularly in the small airways (< 2 mm in diameter), a key site of airway obstruction and destruction in chronic obstructive pulmonary disease and other acute and chronic lung conditions. The aim of this study was to investigate the effect of e-cigarettes on human distal airway inflammation and remodeling.Methods: We isolated primary small airway epithelial cells from donor lungs without known lung disease. Small airway epithelial cells were cultured at air–liquid interface and exposed to 15 puffs vapor obtained by heating a commercially available e-cigarette solution (e-vapor) with or without nicotine. After 24 hrs of e-vapor exposure, basolateral and apical media as well as cell lysates were collected to measure the pleiotropic cytokine interleukin 6 (IL6) and MUC5AC, one of the major components in mucus.Results: Unlike the nicotine-containing e-vapor, nicotine-free e-vapor significantly increased the amount of IL6, which was coupled with increased levels of intracellular MUC5AC protein. Importantly, a neutralizing IL6 antibody (vs an IgG isotype control) significantly inhibited the production of MUC5AC induced by nicotine-free e-vapor.Conclusion: Our results suggest that human small airway epithelial cells exposed to nicotine-free e-vapor increase the inflammatory response and mucin production, which may contribute to distal lung airflow limitation and airway obstruction.Keywords: electronic cigarette, small airway epithelial cells, inflammation, interleukin 6, mucus

Hai-Liang Yuan,1 Xian Zhang,2 Dong-Zhu Peng,1 Guan-Bin Lin,1 Hui-Hui Li,1 Fang-Xian Li,1 Jing-Jing Lu,1 Wei-Wei Chu1 1Department of Gastroenterology, Beilun Branch of the First Affiliated Hospital of Zhejiang University, Ningbo, Zhejiang, People’s Republic of China; 2Department of Endocrinology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of ChinaCorrespondence: Wei-Wei Chu, Department of Gastroenterology, Beilun Branch of the First Affiliated Hospital of Zhejiang University, No. 1288, Lushan East Road, Beilun District, Ningbo, Zhejiang Province, People’s Republic of China, Tel +86-134 56123811, Fax +86- 574 86100266, Email chuweiwei920@163.comPurpose: Constipation is a common complication of diabetic patients, which has a negative impact on their own health. This study aims to establish and internally validate the risk nomogram of constipation in patients with type 2 diabetes mellitus (T2DM) and to test its predictive ability.Patients and Methods: This retrospective study included 746 patients with T2DM at two medical centers. Among the 746 patients with T2DM, 382 and 163 patients in the Beilun branch of the First Affiliated Hospital of Zhejiang University were enrolled in the training cohort and the validation cohort, respectively. A total of 201 patients in the First Affiliated Hospital of Nanchang University were enrolled in external validation cohorts. The nomogram was established by optimizing the predictive factors through univariate and multivariable logistic regression analysis. The prediction performance of the nomogram was measured by the area under the receiver operating characteristic curve (AUROC), the calibration curve, and the decision curve analysis (DCA). Furthermore, its applicability was internally and independently validated.Results: Among the 16 clinicopathological features, five variables were selected to develop the prediction nomogram, including age, glycated hemoglobin (HbA1c), calcium, anxiety, and regular exercise. The nomogram revealed good discrimination with an area under the receiver operating characteristic curve (AUROC) of 0.908 (95% CI = 0.865– 0.950) in the training cohort, and 0.867 (95% CI = 0.790– 0.944) and 0.816 (95% CI = 0.751– 0.881) in the internal and external validation cohorts, respectively. The calibration curve presented a good agreement between the prediction by the nomogram and the actual observation. The DCA revealed that the nomogram had a high clinical application value.Conclusion: In this study, the nomogram for pretreatment risk management of constipation in patients with T2DM was developed which could help in making timely personalized clinical decisions for different risk populations.Keywords: constipation, type 2 diabetes mellitus, model, nomogram, prediction

Reena Berman, Di Jiang, Qun Wu, Hong Wei Chu Department of Medicine, National Jewish Health, Denver, CO, USA Abstract: Human rhinovirus (HRV) infections target airway epithelium and are the leading cause of acute exacerbations of COPD. Cigarette smoke (CS) increases the severity of viral infections, but there is no effective therapy for HRV infection. We determined whether α1-antitrypsin (A1AT) reduces HRV-16 infection in CS-exposed primary human airway epithelial cells. Brushed bronchial epithelial cells from normal subjects and patients diagnosed with COPD were cultured at air–liquid interface to induce mucociliary differentiation. These cells were treated with A1AT or bovine serum albumin for 2 hours and then exposed to air or whole cigarette smoke (WCS) with or without HRV-16 (5×104 50% Tissue Culture Infective Dose [TCID50]/transwell) infection for 24 hours. WCS exposure significantly increased viral load by an average of fivefold and decreased the expression of antiviral genes interferon-λ1, OAS1, and MX1. When A1AT was added to WCS-exposed cells, viral load significantly decreased by an average of 29-fold. HRV-16 infection significantly increased HRV-16 receptor intercellular adhesion molecule-1 messenger RNA expression in air-exposed cells, which was decreased by A1AT. A1AT-mediated reduction of viral load was not accompanied by increased epithelial antiviral gene expression or by inhibiting the activity of 3C protease involved in viral replication or maturation. Our findings demonstrate that A1AT treatment prevents a WCS-induced increase in viral load and for the first time suggest a therapeutic effect of A1AT on HRV infection. Keywords: α1-antitrypsin, rhinovirus, COPD, cigarette smoke, ICAM-1