Altered expression of immune-associated genes in first-trimester human decidua of pregnancies later complicated with hypertension or foetal growth restriction

During pregnancy the maternal immune system has to coordinate uterine spiral-artery remodelling, trophoblast invasion, and acceptance of the semi-allogenic fetus simultaneously. As dysregulation of the immune system is associated with adverse pregnancy outcomes, we analysed first-trimester deciduas of pregnancies for immune parameters in later complicated pregnancies. Higher IL6 and macrophage mRNA expression, and lower ratios of regulatory macrophages were found in first-trimester deciduas of pregnancies later complicated with pregnancy-induced hypertension. Lower Gata3 (Th2) mRNA expression was found in deciduas of pregnancies with later foetal growth restriction. Our results suggest that adverse pregnancy outcomes are associated with immunological disturbances in first-trimester deciduas. (C) 2012 Elsevier Ltd. All rights reserved

A Targeted Lipidomic Reveals CYP450-Derived Oxylipin Linked to the Inflammatory Response by Polycyclic Aromatic Hydrocarbon Exposure in Children

Polycyclic aromatic hydrocarbon (PAH) exposure is a cause of chronic inflammation. The effect of PAHs on bioactive lipid mediators involved in the inflammatory process remains largely unknown. This study measured ten urinary monohydroxy-PAHs (OH-PAHs), 54 plasma oxylipins, and inflammation-related markers. Children with high PAH exposure had higher levels of ten OH-PAHs, (±)18-HETE, 19(S)-HETE, 5,6-DiHETrE, 9,10-DiHOME, more monocytes, interleukin (IL)-10, tumor necrosis factor (TNF)-α and IL-6 than those with low PAH exposure (all p &lt; 0.05). The ƩOH-PAHs were inversely correlated to the levels of anti-inflammatory oxylipins, including 5,6-EET (p for trend = 0.007), 11,12-EET (p for trend = 0.035), 14,15-EET (p for trend = 0.022), and 16(17)-EpDPE (p for trend = 0.043), but positively associated with pro-inflammatory 9,10-DiHOME (p for trend &lt; 0.001). Mediation analyses indicated that cytochrome P450 (CYP)-derived 9,10-DiHOME mediated a separate 42.7%, 31.1%, 57.8%, and 38.5% of the associations between OH-PAHs and monocytes, IL-6, IL-10, TNF-α (p = 0.017, 0.014, 0.005 and 0.012, respectively). Our study suggests that CYP-derived oxylipins can be considered sensitive lipid mediators to signal the early inflammation response to PAH exposure.</p

Healthy worker survivor analysis in an occupational cohort study of Dutch agricultural workers

OBJECTIVES: High microbial exposures in farmers and agricultural workers are associated with less atopy. Although it has been speculated that healthy worker survival could be an explanation, this has not been studied so far. Therefore, we investigated the presence of healthy worker survival in a five-year follow-up study of an occupational cohort of Dutch farmers and agricultural industry (company) workers. METHODS: We compared baseline demographic characteristics, respiratory health, atopy and endotoxin exposure of 259 workers followed up with 124 workers lost to follow-up. Additionally, baseline health status of 31 participants who had changed to lower exposure jobs at follow-up was compared to those with similar or higher exposure jobs at follow-up. RESULTS: In general, no major healthy worker survival effect was found. Nonetheless, small differences were observed between subjects included in follow-up and those lost to follow-up. Those lost to follow-up were older, had a lower peak expiratory flow, and were less often raised on a farm. Company workers lost to follow-up with a farm childhood had more often self-reported allergy, but this was not observed for subjects with atopic sensitization or other respiratory symptoms. No differences were found for any of the studied characteristics in participants with lower exposure at follow-up compared to participants with similar or higher exposure at follow-up. CONCLUSIONS: No major healthy worker survival is present in this organic dust exposed cohort. Differences between participants lost to follow-up and participants included in follow-up with regard to health characteristics are small and unlikely to explain the previously reported inverse associations between endotoxin exposure and atopy

The role of endogenous H2S formation in reversible remodeling of lung tissue during hibernation in the Syrian hamster

During hibernation, small mammals alternate between periods of metabolic suppression and low body temperature ('torpor') and periods of full metabolic recovery with euthermic temperatures ('arousal'). Previously, we demonstrated marked structural remodeling of the lung during torpor, which is rapidly reversed during arousal. We also found that cooling of hamster cells increased endogenous production of H2S through the enzyme cystathionine-beta-synthase (CBS). H2S suppresses the immune response and increases deposition of collagen. Therefore, we examined inflammatory markers and matrix metalloproteinase (MMP) activity in relation to CBS expression and H2S levels in lungs of euthermic and hibernating Syrian hamsters. Lung remodeling during torpor was confirmed by a strong increase in both collagenous and non-collagenous hydroxyproline content. The number of leukocytes in lung was unchanged in any phase of hibernation, while adhesion molecules VCAM-1 and ICAM-1, and the inflammatory marker NF-kappa B (P65) were modestly upregulated in torpor. Gelatinase activity was decreased in lungs from torpid animals, indicating inhibition of the Zn2+-dependent MMP-2 and MMP-9. Moreover, expression of CBS and tissue levels of H2S were increased in torpor. All changes normalized during arousal. Inhibition of gelatinase activity in torpor is likely caused by quenching of Zn2+ by the sulphide ion of H2S. In accord, inhibition of CBS normalized gelatinase activity in torpid animals. Conversely, NaHS decreased the gelatinase activity of euthermic animals, which was attenuated by excess Zn2+. Similar results were obtained on the activity of the Zn2+-dependent angiotensin converting enzyme. Our data indicate that increased production of H2S through CBS in hamster lungs during torpor contributes to remodeling by inhibition of gelatinase activity and possibly by suppression of the inflammatory response. Although administration of H2S is known to induce metabolic suppression in nonhibernating mammals ('suspended animation'), this is the first report implying endogenous H2S production in natural hibernation

Sexual maturation protects against development of lung inflammation through estrogen.

Increasing levels of estrogen and progesterone are suggested to play a role in the gender switch in asthma prevalence during puberty. We investigated whether the process of sexual maturation in mice affects the development of lung inflammation in adulthood and the contributing roles of estrogen and progesterone during this process. By inducing ovalbumin-induced lung inflammation in sexually mature and immature (ovariectomized before sexual maturation) adult mice, we showed that sexually immature adult mice developed more eosinophilic lung inflammation. This protective effect of \u22puberty\u22 appears to be dependent on estrogen, as estrogen supplementation at the time of ovariectomy protected against development of lung inflammation in adulthood whereas progesterone supplementation did not. Investigating the underlying mechanism of estrogen-mediated protection, we found that estrogen-treated mice had higher expression of the anti-inflammatory mediator secretory leukoprotease inhibitor (SLPI) and lower expression of the proasthmatic cytokine IL-33 in parenchymal lung tissue and that their expressions colocalized with type II alveolar epithelial cells (AECII). Treating AECII directly with SLPI significantly inhibited IL-33 production upon stimulation with ATP. Our data suggest that estrogen during puberty has a protective effect on asthma development, which is accompanied by induction of anti-inflammatory SLPI production and inhibition of proinflammatory IL-33 production by AECII

Beneficial and limiting factors in return to work after primary total knee replacement:Patients' perspective

Return to work (RTW) is an important outcome in Total Knee Arthroplasty (TKA). At present, 70-80%of TKA patients return to work within three to six months. What are patients' perspectives regarding beneficial and limiting factors in RTW after TKA? METHODS: Focus groups were formed in accordance with the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist. Three major topics were explored: 1. What was beneficial for RTW after TKA; 2. What was limiting for RTW after TKA; and 3. What additional care would benefit RTW after TKA? RESULTS: Data saturation was reached after four focus groups, comprising 17 participants - nine men and eight women (median age 58, range 52-65). The focus group study identified four main themes that contributed to a successful RTW namely rehabilitation (medical) like post-operative physical therapy, patient characteristics (personal), like motivation to RTW, occupational characteristics (work-related) like build-up in work tasks and medical support (medical) like availability of a walker or crutches. CONCLUSION: According to participants, factors within the following four themes can contribute to a successful return to work: occupational, patient, rehabilitation and medical care. Incorporating these factors into the integrated care pathway for the 'young' TKA patients may increase the chances of a successful RTW

Про підготовку навчального посібника з краєзнавства для вищих навчальних закладів України

У статті обґрунтовується необхідність підготовки навчального посібника з національного краєзнавства для вищих навчальних закладів України, висвітлено стан його підготовки, концепція та окремі, найбільш важливі і дискусійні аспекти змісту майбутнього посібника.В статье обосновывается необходимость подготовки учебного пособия по национальному краеведению для высших учебных заведений Украины, показана степень его подготовки, концепция и отдельные, наиболее важные и дискуссионные аспекты будущего учебника.In the article the necessity of preparation of the tutorial of local history for higher educational establishments in Ukraine is settled down, the state of its preparation, conception and particular, most essential and debatable aspects of the content of the manual are covered

Aberrant DNA methylation and expression of SPDEF and FOXA2 in airway epithelium of patients with COPD

Background: Goblet cell metaplasia, a common feature of chronic obstructive pulmonary disease (COPD), is associated with mucus hypersecretion which contributes to the morbidity and mortality among patients. Transcription factors SAM-pointed domain-containing Ets-like factor (SPDEF) and forkhead box protein A2 (FOXA2) regulate goblet cell differentiation. This study aimed to (1) investigate DNA methylation and expression of SPDEF and FOXA2 during goblet cell differentiation and (2) compare this in airway epithelial cells from patients with COPD and controls during mucociliary differentiation. Methods: To assess DNA methylation and expression of SPDEF and FOXA2 during goblet cell differentiation, primary airway epithelial cells, isolated from trachea (non-COPD controls) and bronchial tissue (patients with COPD), were differentiated by culture at the air-liquid interface (ALI) in the presence of cytokine interleukin (IL)-13 to promote goblet cell differentiation. Results: We found that SPDEF expression was induced during goblet cell differentiation, while FOXA2 expression was decreased. Importantly, CpG number 8 in the SPDEF promoter was hypermethylated upon differentiation, whereas DNA methylation of FOXA2 promoter was not changed. In the absence of IL-13, COPD-derived ALI-cultured cells displayed higher SPDEF expression than control-derived ALI cultures, whereas no difference was found for FOXA2 expression. This was accompanied with hypomethylation of CpG number 6 in the SPDEF promoter and also hypomethylation of CpG numbers 10 and 11 in the FOXA2 promoter. Conclusions: These findings suggest that aberrant DNA methylation of SPDEF and FOXA2 is one of the factors underlying mucus hypersecretion in COPD, opening new avenues for epigenetic-based inhibition of mucus hypersecretion

Prenatal smoke exposure induces persistent Cyp2a5 methylation and increases nicotine metabolism in the liver of neonatal and adult male offspring

Prenatal smoke exposure (PSE) is a risk factor for nicotine dependence. One susceptibility gene for nicotine dependence is Cytochrome P450 (CYP) 2A6, an enzyme responsible for the conversion of nicotine to cotinine and nicotine clearance in the liver. Higher activity of the CYP2A6 enzyme is associated with nicotine dependence, but no research has addressed the PSE effects on the CYP2A6 gene or its mouse homologue Cyp2a5. We hypothesized that PSE affects Cyp2a5 promoter methylation, Cyp2a5 mRNA levels, and nicotine metabolism in offspring. We used a smoke-exposed pregnant mouse model. RNA, DNA, and microsomal protein were isolated from liver tissue of foetal, neonatal, and adult offspring. Enzyme activity, Cyp2a5 mRNA levels, and Cyp2a5 methylation status of six CpG sites within the promoter region were analysed via HPLC, RT-PCR, and bisulphite pyrosequencing. Our data show that PSE induced higher cotinine levels in livers of male neonatal and adult offspring compared to controls. PSE-induced cotinine levels in neonates correlated with Cyp2a5 mRNA expression and promoter methylation at CpG-7 and CpG+45. PSE increased methylation in almost all CpG sites in foetal offspring, and this effect persisted at CpG-74 in male neonatal and adult offspring. Our results indicate that male offspring of mothers which were exposed to cigarette smoke during pregnancy have a higher hepatic nicotine metabolism, which could be regulated by DNA methylation. Given the detected persistence into adulthood, extrapolation to the human situation suggests that sons born from smoking mothers could be more susceptible to nicotine dependence later in life

Postnatal Smoke Exposure Further Increases the Hepatic Nicotine Metabolism in Prenatally Smoke Exposed Male Offspring and Is Linked with Aberrant Cyp2a5 Methylation

Prenatal smoke exposure (PreSE) is a risk factor for nicotine dependence, which is further enhanced by postnatal smoke exposure (PostSE). One susceptibility gene to nicotine dependence is Cytochrome P450 (CYP) 2A6, an enzyme responsible for the conversion of nicotine to cotinine in the liver. Higher CYP2A6 activity is associated with nicotine dependence and could be regulated through DNA methylation. In this study we investigated whether PostSE further impaired PreSE-induced effects on nicotine metabolism, along with Cyp2a5, orthologue of CYP2A6, mRNA expression and DNA methylation. Using a mouse model where prenatally smoke-exposed adult offspring were exposed to cigarette smoke for 3 months, enzyme activity, mRNA levels, and promoter methylation of hepatic Cyp2a5 were evaluated. We found that in male offspring, PostSE increased PreSE-induced cotinine levels and Cyp2a5 mRNA expression. In addition, both PostSE and PreSE changed Cyp2a5 DNA methylation in male groups. PreSE however decreased cotinine levels whereas it had no effect on Cyp2a5 mRNA expression or methylation. These adverse outcomes of PreSE and PostSE were most prominent in males. When considered in the context of the human health aspects, the combined effect of prenatal and adolescent smoke exposure could lead to an accelerated risk for nicotine dependence later in life.</p