The effects of smoking on whisker movements: a quantitative measure of exploratory behaviour in rodents

Nicotine, an important component of cigarette smoke, is a neurotransmitter that contributes to stress, depression and anxiety in smokers. In rodents, it increases anxiety and reduces exploratory behaviours. However, so far, the measurements of exploratory behaviour in rodents have only been semi-quantitative and lacking in sufficient detail to characterise the temporal effect of smoking cessation. As rodents, such as mice and rats, primarily use whiskers to explore their environment, we studied the effect of 3 months smoking with 1 and 2 weeks smoking cessation on whisker movements in mice, using high-speed video camera footage and image analysis. Both protraction and retraction whisker velocities were increased in smoking mice (p<0.001) and returned to normal following just one week of smoking cessation. In addition, locomotion speeds were decreased in smoking mice, and returned to normal following smoking cessation. Lung function was also impacted by smoking and remained impaired even following smoking cessation. We suggest that the increased whisker velocities in the smoking mice reflect reduced exploration and impeded tactile performance. The increase in whisker velocity with smoking, and its reduction following smoking cessation, also lends support to acetylcholine being involved in awareness, attention and alertness pathways. It also shows that smoking-induced behavioural changes can be reversed with smoking cessation, which may have implications for human smokers

Exploring the role of the vitamin D pathway in pulmonary innate immunity in COPD

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease affecting millions of people worldwide. Enhanced inflammatory responses within the airways is one of the key characteristics in the pathophysiology of COPD. Although cigarette smoking is the major risk factor, only around 20% of smokers actually develop COPD. Therefore, other risk factors must be involved in COPD onset and progression. We hypothesize that vitamin D deficiency, which is highly prevalent worldwide and even more so in COPD patients, could be such a risk factor for COPD onset and progression because of its anti-inflammatory and antibacterial potential. The use of our established mouse model of CS-induced COPD allowed us to elucidate whether vitamin D deficiency is a causal contributing factor to COPD onset and progression. In Chapter 3, we demonstrate that vitamin D deficiency greatly enhances airway and parenchymal inflammation in a mouse model of subacute and chronic CS exposure, resulting in early onset of emphysema and consistent lung hyperinflation. Our data further strengthen the epidemiological associations that link vitamin D deficiency to COPD onset and progression (lung function decline, exacerbations). Respiratory bacterial infections, such as nontypeable Haemophilus influenzae (NTHi), are the major trigger for COPD exacerbations and amplify the ongoing inflammation in COPD. In Chapter 4, we have investigated whether vitamin D deficiency may affect bacterial clearance and acute inflammatory response to a respiratory infection with NTHi. Although results are preliminary and additional research is necessary, our results suggest that vitamin D deficiency may amplify acute inflammatory responses directly following NTHi infection, leading to a more rapid clearance of the infection and accompanying inflammation. As vitamin D deficiency is highly prevalent worldwide, our results implicate that vitamin D may be a promising strategy to prevent COPD onset and progression. However, it is currently not known whether the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D), can indeed exert anti-inflammatory and antibacterial functions within CS-compromised airways. By using in vitro cell research, we have demonstrated in Chapter 5 that 1,25(OH)2D dampens levels of important inflammatory mediators (IL-8, TNF-a, MCP-1) released by alveolar macrophages from (non-) smoking subjects and released by cigarette smoke extract (CSE)-treated THP-1 macrophages (cell line model for alveolar macrophages). 1,25(OH)2D furthermore enhanced the release of the important antimicrobial peptide cathelicidin from alveolar macrophages from (non-)smoking subjects and CSE-treated THP-1 macrophages. As we have shown that vitamin D metabolism in THP-1 macrophages is not affected by CS exposure, our results suggest that 1,25(OH)2D can exert its anti-inflammatory and antibacterial functions within the airways of smoking subjects and in this way could potentially decrease susceptibility to COPD in those subjects. Although our data support the use of vitamin D supplementation as a means for reducing COPD onset and progression, (high-dose) vitamin D supplementation may lead to high serum vitamin D levels, which have been previously associated with increased risk of adverse outcomes. In Chapter 6, we demonstrate that high serum vitamin D levels, resulting from high-dose vitamin D supplementation, enhance characteristic disease features of COPD (emphysema, lung hyperinflation, pulmonary inflammation) in our mouse model of subacute and chronic CS exposure. These results together with the results from Chapter 3 suggest that there may be an optimal range for serum vitamin D levels. Taken together, our data demonstrate an important role for the vitamin D pathway in COPD onset and progression and support the need for more well-designed intervention studies with vitamin D supplementation.status: publishe

On the rotation invariance of multi-order parameter models for grain growth

In this paper, the rotation invariance of multi-order parameter or multi-phase field models for grain growth in systems with anisotropic properties is verified. The main conclusion is that these models can be considered to be rotationally invariant, if a sufficient number of discrete orientations (namely phase fields or order parameter fields) is used, which is perfectly feasible when sparse data structure algorithms are used for the numerical solution.status: publishe

A phase field model for isothermal crystallization of oxide melts

We present a multicomponent multi-phase field model for isothermal crystallization of oxide melts. The bulk thermodynamic properties of the liquid as a function of composition are retrieved from the FACT thermodynamic database for oxide systems. For solid phases modeled as stoichiometric in the thermodynamic database, a paraboloid Gibbs energy is introduced with specific constraints to ensure correct phase equilibria and minimal solubility in the stoichiometric phase. The interfacial mobility can show strong anisotropy and the interfacial energy can have weak anisotropy, since both faceted and dendritic growth morphologies are important for crystallization in oxide systems. The possibilities of the model are illustrated with three case studies considering crystallizing and dissolving solid phases in a CaO-Al2O3-SiO2 melt. These case studies show the influence of the diffusion mobilities on the diffusion path, the tie-line selection in a ternary system and the effect of the surface energy on dendritic growth. (C) 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.status: publishe

Innate immune modulation in chronic obstructive pulmonary disease: moving closer toward vitamin D therapy

Chronic obstructive pulmonary disease (COPD) is one of the most common respiratory diseases and a major cause of morbidity and mortality worldwide. Disturbed innate immune processes characterize the pathogenesis of COPD. Vitamin D deficiency is very common in COPD patients and has been associated with disease severity. Interestingly, mechanistic evidence from animal and in vitro studies has demonstrated important innate immunomodulatory functions of vitamin D, including anti-inflammatory, antioxidative, and antimicrobial functions. This review discusses in detail how the innate immunomodulatory functions of vitamin D may have therapeutic potential in COPD patients. The remaining challenges associated with vitamin D therapy in COPD patients are also discussed.status: publishe

Phase field modeling of the crystallization of FeOx–SiO2 melts in contact with an oxygen-containing atmosphere

In this work, we present a phase field model to simulate the crystallization of Fe3O4 in FeOx–SiO2 melts under oxidizing conditions. The diffusion of FeO and Fe2O3 is considered, because the FeO/Fe2O3 ratio in the melt can be related to the local oxygen potential of the melt. A boundary condition is developed to ensure conservation of Fe while the ratio of FeO/Fe2O3 is in equilibrium with the oxygen fugacity of the atmosphere. Two-dimensional simulations are performed with different nucleation densities of Fe3O4 and varying oxygen fugacity in the atmosphere. The results show that, for the considered nucleation densities, the crystallization of the melt has a larger effect on the oxidation state than the oxygen fugacity of the atmosphere. Furthermore, for the considered composition range, the growth velocities of the spinel crystals increase with decreasing oxygen fugacity.status: publishe

Isothermal crystal growth behavior of CaSiO3 in ternary oxide melts

The process of isothermal Wollastonite (CaSiO3) crystallization in the CaO-Al2O3-SiO2 system is simulated using a phase field model coupled with the FACTSage Toxide thermodynamic database. The effects of composition and temperature on the crystallization behaviour were studied. The simulations show that for the considered cases, the Wollastonite morphology is mainly determined by anisotropy in the interface energy and hardly affected by anisotropy in the interface kinetics. In agreement with the observations from in-situ experiments, the simulations show a transition from planar to dendritic growth with decreasing temperature and the dendritic structure becomes finer when the temperature is decreased further. The growth rates and dendrite tip radii obtained in the simulations agree well with Ivanstov’s theory and are of the same orders of magnitude as those measured experimentally.status: publishe

Interaction Between Physical Activity and Smoking on Lung, Muscle and Bone in Mice

Physical inactivity is an important contributor to skeletal muscle weakness, osteoporosis and weight loss in chronic obstructive pulmonary disease. However, the effects of physical inactivity, in interaction with smoking, on lung, muscle and bone are poorly understood. To address this issue, male mice were randomly assigned into an active (daily running), moderately inactive (space restriction) or extremely inactive group (space restriction followed by hindlimb suspension to mimic bed rest) during 24 weeks and simultaneously exposed to either cigarette smoke or room air. The effects of different physical activity levels and smoking status and their respective interaction were examined on lung function, body composition, in vitro limb muscle function and bone parameters. Smoking caused emphysema, reduced food intake with subsequent loss of body weight, fat, lean and muscle mass but increased trabecular bone volume. Smoking induced muscle fiber atrophy which did not result in force impairment. Moderate inactivity only affected lung volumes and compliance, whereas extreme inactivity increased lung inflammation, lowered body and fat mass, induced fiber atrophy with soleus muscle dysfunction and reduced exercise capacity and all bone parameters. When combined with smoking, extreme inactivity also aggravated lung inflammation and emphysema, and accelerated body and muscle weight loss. This study shows that extreme inactivity, especially when imposed by absolute rest, accelerates lung damage and inflammation. When combined with smoking, extreme inactivity is deleterious for muscle bulk, bone and lungs. These data highlight that the consequences of physical inactivity during the course of COPD should not be neglected.status: publishe