Air pollution, genetic susceptibility and inflammation - Focusing on cardiovascular effects in adults and respiratory effects in children

Air pollution exposure can induce low-grade systemic inflammation with consequences for both cardiovascular and respiratory systems. The overall aim of this thesis was to investigate the effects of air pollutants on the development of complex inflammatory diseases (myocardial infarction and respiratory disease), and genetically determined susceptibility for these effects, using epidemiologic methodology. The two study populations were drawn from a case-control study of myocardial infarction (SHEEP) and a birth cohort (BAMSE). From SHEEP, the present study population included 1192 first-time myocardial infarction (MI) cases aged 45-70 years identified in Stockholm County during 1992-1994, and 1536 matched population controls from the study base. Participants completed questionnaires and underwent medical examination as well as blood sampling. Their air pollution exposure was assessed retrospectively both long-term (1-30 years) and short-term (12 h - 5 days). NO2 was used as an indicator of emissions from road traffic and SO2 as an indicator of emissions from residential heating. From the BAMSE cohort, which recruited 4089 new-born children during 1994-1996 in four municipalities in Stockholm County, this study included 497 wheezers and 485 non-wheezing controls at 4 years, and 198 asthma cases and 192 non-asthma controls at 8 years. Questionnaires were completed by the parents when the children were 2 months, 1, 2, 4, and 8 years of age. The children were also invited for medical examination and blood sampling at 4 and 8 years. In adults, long-term exposure to both traffic- NO2 and heating-SO2 emissions showed an association with IL-6 levels. For instance, 30-year traffic-NO2 exposure was associated with a 64.5% (95%CI 6.7-153.8%) increase in serum IL-6 per 28.8 μg/m3 (corresponding to the difference between the 5th and the 95th percentile exposure value). There was also suggested association between short-term exposure to trafficrelated air pollutants and inflammatory markers (IL-6, TNF-α). Gene-environment interaction was observed for several IL6 and TNF single nucleotide polymorphisms (SNPs) in relation to inflammation blood marker levels. For example, 1-year traffic- NO2 exposure interacted with IL6 -174G/C in an additive way, where each additional IL6-174C allele was associated with an increased air pollution effect on IL-6 levels, and 1-year heating-SO2 exposure was associated with higher TNF-α levels in TNF-308AA homozygotes but not in -308G carriers. Also short-term air pollution exposure interacted with IL6 and TNF SNPs in relation to marker levels. The risk of MI followed the pattern of effect on blood markers across genotype groups. In children, interaction with early maternal smoking was seen for 3 TNF SNPs with respect to early wheeze. The odds ratio for developing early wheeze related to maternal smoking was 2.4 (95%CI 1.6-3.7) in TNF -857CC homozygote children, while no tobacco-related risk was seen in children with the rare -857T allele. Suggestive interaction with early maternal smoking was also seen for 3 GSTP1 SNPs with respect to transient wheeze. SNPs in TNS1, ADAM19, THSD4 and ADCY2 identified through genome-wide analyses on lung function in adults showed association also with lung function in children; DAAM2 rs2395730 showed suggestive interaction with current tobacco smoke exposure at 8 years. In summary, the results indicate that air pollutants affect levels of inflammatory blood markers, and this effect appears to be modified by genetic variants, affecting both blood marker levels and consequent MI risk. Polymorphisms in genes related to inflammation (TNF) and antioxidant defense (GSTP1) seem to modify the effect of early tobacco smoke exposure on childhood wheezing. Several gene variants of importance for lung function in adults also seem to affect lung function in children

The valveless horn and its use in chamber music, 1700-1865

Thesis (M.A.)--Boston UniversityIt has been the intention of the author to discuss in some detail the history and development of the French Hor n and its use in Chamber Music, up to the time when its position as an orchestral and chamber instrument was usurped by the valved horn. This covers a period of its use as an art instrument from the 17th century to the mid-19th century. These are of course the outward limits of the instrument's employment. [TRUNCATED

Effects of potato fiber and soluble corn fiber on the fecal microbiome of dogs with implications to inflammation

Dietary fiber provides numerous benefits to the health of both companion animals and humans including improved digestive health (increases stool weight and promotes normal laxation) and systemic health (promotes satiety and decreases incidences of obesity and type II diabetes). Novel dietary fibers often are evaluated for their ability to induce prebiotic effects. Prebiotics are defined as non-digestible food ingredients that, when consumed in sufficient amounts, are fermented and selectively stimulate the growth, activity, or both, of one or a limited number of microbial genera or species in the gut microbiota that ultimately benefits health of the host. Not all dietary fibers are the same in terms of their physico-chemical properties, which ultimately affects their fermentability. The overarching objectives of this thesis were to assess two novel dietary fiber sources, potato fiber (PF) and soluble corn fiber (SCF), for their inclusion in commercial dog diets, and ultimately, their prebiotic potential and implications for host health. Specifically, PF and SCF were evaluated for their chemical composition, in vitro fermentability, in vivo characteristics (nutrient digestibility and fecal fermentation characteristics), and ability to change fecal microbiota concentrations. Previous research in our laboratory found that feeding graded concentrations of dietary PF to dogs elicited linear increases (P < 0.05) in fecal acetate, propionate, butyrate, and total short-chain fatty acids (SCFA) without causing detriments to nutrient digestibility. We investigated this further by studying the prebiotic potential of PF by analyzing the fecal microbiome. We predicted that our previous results on fecal fermentation characteristics would be associated with shifts in the fecal microbiome. Based on previous studies involving dietary fiber in pets and humans, we expected that at the phylum level, an increase in fecal Firmicutes and a decrease in fecal Fusobacteria would occur. More specifically, we also predicted increases in bifidobacteria and other SCFA-producing genera (e.g., Blautia, Lachnospira, and Faecalibacterium spp.) with increasing dietary PF concentrations. As anticipated, with increasing concentrations of dietary PF, there were significant (P < 0.05) changes in fecal concentrations of key SCFA-producing bacteria. Butyrate-producing genera, such as Blautia and Faecalibacterium spp. increased (P < 0.05) with increasing dietary PF concentrations, which was confirmed by qPCR. Our sequencing data also confirmed an increase (P < 0.05) in Firmicutes and a decrease in Fusobacteria (P < 0.05) with increased dietary PF consumption. Prebiotics often are evaluated by their ability to produce butyrate (a butyrogenic effect) or to stimulate the growth of bifidobacteria (a bifidogenic effect); however, the definition of a prebiotic is not limited to this genus. We found that with ingestion of PF, Bifidobacterium spp. were positively correlated with butyrate (R = 0.49; P < 0.05) and lactobacilli (R = 0.82; P < 0.05) concentrations. Bifidobacteria’s main carbohydrate fermentation products are acetate and lactate when substrate is available, while lactobacilli produce lactic acid. This has previously been explained by bacterial cross-feeding where primary fermenters of carbohydrate will produce secondary metabolites (acetate and lactate) or hydrolyzed substrate that can be utilized by other bacteria. Overall, this research suggests to us that PF is beneficial to gut health and should be investigated as a novel functional ingredient in dog diets. Soluble corn fiber (NUTRIOSE®) also was evaluated for its efficacy as a fiber source in dog foods; however, the objective was to determine a minimum dose to elicit a prebiotic effect. We found that SCF was highly fermentable in vitro showing increases (P < 0.05) in acetate, propionate, and butyrate concentrations over 12 h. When tested in vivo from 0-1.25% of the diet, we found no detrimental effects on nutrient digestibility or fecal consistency; however, no changes were shown in fecal fermentation characteristics. Furthermore, this translated into no appreciable differences in the fecal microbiome. Overall, SCF was fermentable in vitro; however, more research is needed to evaluate a more effective dose to elicit in vivo effects. The changes we observed with increasing dietary PF in the dog presented the most intriguing results. Faecalibacterium, and more specifically, Faecalibacterium prausnitzii, a well-characterized butyrate-producing species, was increased by feeding graded dietary levels of PF to dogs. This bacteria is often found in low concentrations in humans and dogs with inflammatory bowel diseases (IBD). These previous results led us to investigate whether PF, with its in vivo fermentation characteristics and ability to modulate the microbiome, would be efficacious in attenuating the inflammatory response in the dextran-sodium sulfate (DSS)-induced colitis mouse model. We hypothesized that a moderately fermentable PF would be more effective at attenuating the symptoms and inflammatory response in DSS colitis than non-fermentable cellulose (Cell). Mice provided the PF/DSS treatment exhibited decreased (P < 0.05) symptoms of DSS colitis by showing a delayed loss in body weight compared with mice provided the Cell/DSS treatment. Furthermore, fermentation of PF during DSS colitis was found to be anti-inflammatory by showing suppression (P < 0.05) of distal colon gene expression of inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-17A). What was particularly interesting were the changes in distal colon gene expression of CXCL1, which is a neutrophil chemoattractant. Mice provided non-fermentable Cell had a 7-fold increase (P < 0.05) in CXCL1 expression compared with all other treatment groups. Pathology scores from an independent observer also showed decreases (P < 0.05) in leukocyte infiltration scores in distal colon. In this acute-colitis model, neutrophils would be the predominant innate immune cell type at the site of inflammation. Therefore, this suggests that fermentation of PF to produce SCFA may be a driving force in controlling leukocyte recruitment to the site of inflammation. As a potential mechanism linking SCFA concentrations and leukocyte recruitment, we analyzed free fatty acid receptor 2 (FFAR2) expression in distal colon. Leukocytes, and in particular neutrophils, have FFAR2 on their cell surface. Short-chain fatty acids can bind to this receptor, causing changes in chemotaxis and reactive oxygen species concentrations. We found that DSS caused an increase (P < 0.05) in FFAR2 expression in distal colon; however, there was no main effect of diet or an interactive effect. One alternative mechanism proposed was the role of SCFA suppressing innate T-helper 17 (Th17) cells, which recruit neutrophils and monocytes through the concentrations of IL-17A and chemokines. Short-chain fatty acids have been found to induce both effector and regulatory T cells by suppression of histone deacetylases that is independent of FFAR2 or 3. Inhibition of histone deacetylases by SCFA and, in particular, acetate, has been shown to regulate the mTOR pathway required for the generation of Th17 cells. Collectively, these data show that moderately fermentable fiber intake during DSS colitis is anti-inflammatory, which could potentially be due to SCFA decreasing leukocyte recruitment. Overall, the ability of a dietary fiber to elicit positive effects on fermentation and health benefits is due to the physico-chemical properties of the fiber. Here, we found that ingestion of a moderately fermentable fiber elicited increases in fecal SCFA concentrations, and modulated the microbiome. This dietary fiber elicited anti-inflammatory effects in the DSS-model, which may have been a result of SCFA affecting leukocyte recruitment to the site of inflammation. These data show that ingestion of a moderately fermentable prebiotic fiber could affect the acute inflammatory response through controlling leukocyte recruitment. More studies are needed to assess the importance of moderately fermentable fibers in the diet during in controlling inflammatory bouts noted in IBD

Ontogenetic Development of Neurophysiological Mechanisms Underlying Language Processing

During the last 20 years, new data on the neurophysiological mechanisms underlying different types of cognitive activity, especially speech and its ontogenetic formation, were obtained in the Laboratory of Children’s Neurophysiology headed by Prof. M.N. Tsitseroshin. Using the analysis of the spatial-temporal structure of regional interactions of cortical bioelectric potentials (so-called functional connectivity), we investigated how specific language levels, such as phonology, grammar, and semantics, are represented in the brain. The data obtained in children vs. adults indicate that the speech perception and production require joint and extremely coordinated activities of both hemispheres, along with the obligatory and differentiated involvement of “classic” speech centers in the left hemisphere, especially Wernicke’s area. Another line of our research is to explore the differences, which arise during verbal processing in adults and children with impaired vs. non-impaired speech, particularly with alalia, dysarthria and stuttering, using behavioral and EEG data. Our data obtained in children vs. adults allow assessing the degree of maturity in the organization of the central processes of maintaining the studied types of verbal activity in children of different ages. These data allow expanding modern concepts about the brain mechanisms of verbal activity in children in the norm and pathology

ФАЗОВЫЕ ПРЕВРАЩЕНИЯ ПРИ КРИСТАЛЛИЗАЦИИ Sr2FeMoO6–δ ИЗ ПРОСТЫХ ОКСИДОВ

The sequence of phase transformations during Sr2FeMoO6–δ crystallization by the solid phase method was studied for powders synthesized from the stoichiometric mixture of SrCO3 Fe2O3, MoO3 oxides. It is found that the synthesis of a strontium ferromolybdate solid solution proceeds through a series of parallel chemical reactions. It is revealed that at the beginning stage of interaction, the initially formed Sr2FeMoO6–δ powder is enriched with iron. During the annealing process, the composition of strontium ferromolybdate changes and the molybdenum content increases upon further heating. It is shown that in the process of crystallization of double perovskite in the temperature range T = (300–1420) K, there is the following sequence of phase transformations Fe2O3, MoO3, SrCO3} (300 К) → {SrMoO4, Fe2O3, SrCO3} (770 К) → {SrMoO4, SrFeO3–х (traces), Sr2FeMoO6–δ (traces)} (970 K) → {SrMoO4, Sr2FeMoO6–δ } (1170 К) → { Sr2FeMoO6–δ } (1420 К)..На основании изучения последовательности фазовых превращений при кристаллизации Sr2FeMoO6–δ установлено, что синтез двойного перовскита в смеси простых оксидов протекает через ряд последовательно-параллельных стадий. На начальном этапе взаимодействия образующийся ферромолибдат стронция обогащен железом и его состав в ходе реакции изменяется в сторону увеличения содержания молибдена. Оксид молибдена в тройной смеси состава 2SrCO3+ + MoO3 + 0,5Fe2O3 вступает в реакцию несколько быстрее с карбонатом стронция, чем оксид железа. Показано, что в процессе кристаллизации двойного перовскита ферромолибдата стронция в интервале температур Т = (300–1420)К имеет место следующая последовательность фазовых превращений: {Fe2O3, MoO3, SrCO3} (300 К) → {SrMoO4, Fe2O3, SrCO3} (770 К) → {SrMoO4, SrFeO3–х (следы), Sr2FeMoO6–δ (следы)} (970 К) → {SrMoO4, Sr2FeMoO6–δ } (1170 К) → { Sr2FeMoO6–δ } (1420 К)

Associations between outdoor temperature and markers of inflammation: a cohort study

<p>Abstract</p> <p>Background</p> <p>Associations between ambient temperature and cardiovascular mortality are well established. This study investigated whether inflammation could be part of the mechanism leading to temperature-related cardiovascular deaths.</p> <p>Methods</p> <p>The study population consisted of a cohort of 673 men with mean age of 74.6 years, living in the greater Boston area. They were seen for examination roughly every 4 years, and blood samples for inflammation marker analyses were drawn in 2000-2008 (total of 1254 visits). We used a mixed effects model to estimate the associations between ambient temperature and a variety of inflammation markers (C-reactive protein, white blood cell count, soluble Vascular Cell Adhesion Molecule-1, soluble Intercellular Adhesion Molecule-1, tumor necrosis factor alpha, and interleukins -1β, -6 and -8). Random intercept for each subject and several possible confounders, including combustion-related air pollution and ozone, were used in the models.</p> <p>Results</p> <p>We found a 0 to 1 day lagged and up to 4 weeks cumulative responses in C-reactive protein in association with temperature. We observed a 24.9% increase [95% Confidence interval (CI): 7.36, 45.2] in C-reactive protein for a 5°C decrease in the 4 weeks' moving average of temperature. We observed similar associations also between temperature and soluble Intercellular Adhesion Molecule-1 (4.52%, 95% CI: 1.05, 8.10, over 4 weeks' moving average), and between temperature and soluble Vascular Cell Adhesion Molecule-1 (6.60%, 95% CI: 1.31, 12.2 over 4 weeks' moving average). Penalized spline models showed no deviation from linearity. There were no associations between temperature and other inflammation markers.</p> <p>Conclusions</p> <p>Cumulative exposure to decreased temperature is associated with an increase in inflammation marker levels among elderly men. This suggests that inflammation markers are part of intermediate processes, which may lead to cold-, but not heat-, related cardiovascular deaths.</p