326 research outputs found
Sputum tumour necrosis factor-alpha and leukotriene concentrations in cystic fibrosis.
No full textIt is postulated that a vigorous host inflammatory response in the cystic fibrosis lung contributes to lung injury. Tumour necrosis factor-α (TNF-α) may play a part in that process and in the generation of leukotrienes. Therefore, the relationships between sputum TNF-α, leukotriene concentration, and lung function abnormalities in 16 children with cystic fibrosis were investigated. Each subject provided sputum samples and performed spirometry. TNF-α was measured by enzyme linked immunosorbent assay; individual leukotrienes were separated using high performance liquid chromatography and quantified by radioimmunoassay. The geometric mean concentration of TNF-α was 129.7 pg/ml and 95% confidence interval 48.2 to 348.3. Mean (SEM) leukotriene B4 (LTB4) was 97.8 (22.9) pmol/g and total cysteinyl leukotrienes were 60.9 (14.8) pmol/g. Mean (SD) forced expiratory volume in one second (FEV1) of the group was 53 (15)% of predicted and forced vital capacity (FVC) was 65 (14)% of predicted. There was a significant positive correlation between TNF-α and both LTB4 and the total cysteinyl leukotriene sputum content. An inverse relationship existed between TNF-α and FEV1 and FVC. Moreover, a negative correlation was observed between sputum LTB4 and FEV1 and FVC. These results suggest that TNF-α and the leukotrienes may participate in the airways inflammation and airflow obstruction observed in cystic fibrosis subjects and support the hypothesis that TNF-α. upregulates the 5-lipoxygenase pathway in vivo.</p
High concentrations of pepsin in bronchoalveolar lavage fluid from children with cystic fibrosis are associated with high interleukin-8 concentrations
No full textBackground. Gastro-oesophageal reflux is common in children with cystic fibrosis (CF) and is thought to be associated with pulmonary aspiration of gastric contents. The measurement of pepsin in bronchoalveolar lavage (BAL) fluid has recently been suggested to be a reliable indicator of aspiration. The prevalence of pulmonary aspiration in a group of children with CF was assessed and its association with lung inflammation investigated.Methods. This was a cross-sectional case-control study. BAL fluid was collected from individuals with CF (n¼31) and healthy controls (n¼7). Interleukin-8 (IL-8), pepsin, neutrophil numbers and neutrophil elastase activity levels were measured in all samples. Clinical, microbiological and lung function data were collected from medical notes.Results. The pepsin concentration in BAL fluid was higher in the CF group than in controls (mean (SD) 24.4 (27.4) ng/ml vs 4.3 (4.0) ng/ml, p¼0.03). Those with CF who had raised pepsin concentrations had higher levels of IL-8 in the BAL fluid than those with a concentration comparable to controls (3.7 (2.7) ng/ml vs 1.4 (0.9) ng/ml, p¼0.004). Within the CF group there was a moderate positive correlation between pepsin concentration and IL-8 in BAL fluid (r¼0.48, p¼0.04). There was no association between BAL fluid pepsin concentrations and age, sex, body mass index z score, forced expiratory volume in 1 s or Pseudomonas aeruginosa colonisation status.Conclusions. Many children with CF have increased levels of pepsin in the BAL fluid compared with normal controls. Increased pepsin levels were associated with higher IL-8 concentrations in BAL fluid. These data suggest that aspiration of gastric contents occurs in a subset of patients with CF and is associated with more pronounced lung inflammation
Atopic children with cystic fibrosis have increased urinary leukotriene E<sub>4</sub> concentrations and more severe pulmonary disease
No full textBackground: We investigated the hypothesis that cysteinyl leukotriene (LT) production is altered in atopic patients with cystic fibrosis (CF). Methods: Urinary LTE4 was measured in two groups of children with CF: atopic (ACF group, n = 22) and nonatopic (NACF group, n = 13); and in two groups of unaffected children, those with atopic asthma (AA group, n = 11) and nonatopic normal control subjects (NN group, n = 12). Results: Atopic groups excreted significantly more urinary LTE4 (geometric means [95% confidence intervals] in picomoles per millimole creatinine), ACF group: 104 (73-147) and AA group: 195 (136-282) compared with NACF group: 19 (9-39) and NN group: 27 (15-48). The ACF group had significantly more airflow obstruction than the NACF group, with forced expiratory volume in 1 second (percent predicted, mean ± SD) in ACF: 58 ± 21 versus NACF: 81 ± 23, and forced vital capacity (percent predicted, mean ± SD) 72 ± 17 versus 87 ± 23, respectively. There were significant correlations between the degree of airflow obstruction, bronchodilator responsiveness, and urinary LTE4 concentration within the entire CF group. We used multiple regression analysis to assess the respective influence of age, atopy, sensitization to Aspergillus fumigatus, and colonization with Pseudomonas aeruginosa on urinary LTE4 concentration. The atopic state was the only significant variable associated with urinary LTE4 production in subjects with CF. Conclusions: The similarities in urinary LTE4 between ACF and AA groups suggest that the atopic state is the prime determinant of urinary LTE4 excretion. Enhanced cysteinyl LT production associated with atopy in CF may increase the severity of pulmonary disease.</p
Histone lactylation: a new epigenetic mark in the malaria parasite Plasmodium
No full textEpigenetic processes play important roles in the biology of the malaria parasite Plasmodium falciparum. Here, we characterised a new epigenetic mark, histone lactylation, for the first time in Plasmodium: it was found in two human malaria parasites, P. falciparum and P. knowlesi, and also in vivo in two rodent malaria models, P. yoelii and P. berghei. Histones were increasingly lactylated in response to elevated lactate levels in vitro and in vivo, making this mark uniquely well-placed to act as a metabolic sensor, since severe falciparum malaria characteristically leads to hyperlactataemia in the human host. Mass spectrometry showed that lysines on several parasite histones could be lactylated, as well as many non-histone chromatin proteins. Histone lactylation was less abundant and less inducible in P. knowlesi than P. falciparum, suggesting that P. falciparum may have evolved particular epigenetic responses to this characteristic feature of its pathology. Finally, in the rodent model P. yoelii, hyperlactataemia correlated with parasite transcriptomic programmes that suggested metabolic ‘dormancy’
The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations
No full textEpidemiological research suggests that paternal obesity may increase the risk of fathering small for gestational age offspring. Studies in non-human mammals indicate that such associations could be mediated by DNA methylation changes in spermatozoa that influence offspring development in utero. Human obesity is associated with differential DNA methylation in peripheral blood. It is unclear, however, whether this differential DNA methylation is reflected in spermatozoa. We profiled genome-wide DNA methylation using the Illumina MethylationEPIC array in a cross-sectional study of matched human blood and sperm from lean (discovery n = 47; replication n = 21) and obese (n = 22) males to analyse tissue covariation of DNA methylation, and identify obesity-associated methylomic signatures. We found that DNA methylation signatures of human blood and spermatozoa are highly discordant, and methylation levels are correlated at only a minority of CpG sites (~1%). At the majority of these sites, DNA methylation appears to be influenced by genetic variation. Obesity-associated DNA methylation in blood was not generally reflected in spermatozoa, and obesity was not associated with altered covariation patterns or accelerated epigenetic ageing in the two tissues. However, one cross-tissue obesity-specific hypermethylated site (cg19357369; chr4:2429884; P = 8.95 × 10^{-8}; 2% DNA methylation difference) was identified, warranting replication and further investigation. When compared to a wide range of human somatic tissue samples (n = 5,917), spermatozoa displayed differential DNA methylation across pathways enriched in transcriptional regulation. Overall, human sperm displays a unique DNA methylation profile that is highly discordant to, and practically uncorrelated with, that of matched peripheral blood. We observed that obesity was only nominally associated with differential DNA methylation in sperm, and therefore suggest that spermatozoal DNA methylation is an unlikely mediator of intergenerational effects of metabolic traits
Use of EP3533-Enhanced Magnetic Resonance Imaging as a Measure of Disease Progression in Skeletal Muscle of <em>mdx </em>Mice
No full text\ua9 Copyright \ua9 2021 Murphy, Greally, O\u27Hogain, Blamire, Caravan and Straub.As putative treatments are developed for Duchenne muscular dystrophy (DMD), sensitive, non-invasive measures are increasingly important to quantify disease progression. Fibrosis is one of the histological hallmarks of muscular dystrophy and has been directly linked to prognosis. EP3533 is a novel contrast agent with an affinity to collagen 1 that has demonstrated a significant and high correlation to ex vivo fibrosis quantification. Halofuginone is an established anti-fibrotic compound shown to reduce collagen skeletal muscle fibrosis in murine models of DMD. This experiment explored whether EP3533 could be used to detect signal change in skeletal muscle of mdx mice before and after a 12 week course of halofuginone compared to controls. Four age-matched groups of treated and untreated mice were evaluated: 2 groups of mdx (n = 8 and n = 13, respectively), and 2 groups of BL10 mice (n = 5 and n = 3, respectively). Treated mice received an intraperitoneal injection with halofuginone three times per week for 12 weeks, with the remaining mice being given vehicle. Both mdx groups and the untreated BL10 were scanned at baseline, then all groups were scanned on week 13. All subjects were scanned using a 7T Varian scanner before and after administration of EP3533 using a T1 mapping technique. Mice underwent grip testing in week 13 prior to dissection. Skeletal muscle was used for Masson\u27s trichrome quantification, hydroxyproline assay, and immunofluorescent antibody staining. Untreated mdx mice demonstrated a significant increase in R1 signal from pre- to post-treatment scan in three out of four muscles (gastrocnemius p = 0.04, hamstrings p = 0.009, and tibialis anterior p = 0.01), which was not seen in either the treated mdx or the BL10 groups. Histological quantification of fibrosis also demonstrated significantly higher levels in the untreated mdx mice with significant correlation seen between histology and EP3533 signal change. Forelimb weight adjusted-grip strength was significantly lower in the untreated mdx group, compared to the treated group. EP3533 can be used over time as an outcome measure to quantify treatment effect of an established anti-fibrotic drug. Further studies are needed to evaluate the use of this contrast agent in humans
Analysis of 3-year observations of CFC-11, CFC-12 and CFC-113 from a semi-rural site in China
No full textIn-situ measurements of atmospheric chlorofluorocarbons (CFCs) can be used to the assess their global and regional emissions and to check for compliance with phase-out schedules under Montreal protocol and its amendments. The atmospheric mixing ratios of CFC-11 (CCl3F), CFC-12 (CCl2F2) and CFC-113 (CCl2F-CClF2) have been measured by an automated in-situ GC-ECDs system at the regional Chinese Global Atmosphere Watch (GAW) station Shangdianzi (SDZ), from November 2006 to October 2009. The time series for these three principal CFCs showed large episodic events and background conditions occurred for approximately 30% (CFC-11), 52% (CFC-12) and 56% (CFC-113) of the measurements. The mean background mixing ratios for CFC-11, CFC-12 and CFC-113 were 244.8 ppt (parts per trillion, 10(-12), molar) 539.6 ppt and 76.8 ppt, respectively, for 2006-2009. The enhanced CFC mixing ratios compared to AGAGE sites such as Trinidad Head (THD), US and Mace Head (MHD), Ireland suggest regional influences even during background conditions at SDZ, which is much closer to highly-populated areas. Between 2006 and 2009 background CFCs exhibited downward trends at rates of -2.0 ppt yr(-1) for CFC-11, -2.5 ppt yr(-1) for CFC-12 and -0.7 ppt yr(-1) for CFC-113. De-trended 3-year average background seasonal cycles displayed small fluctuations with peak-to-trough amplitudes of 1.0 +/- 0.02 ppt (0.4%) for background CFC-11, 1.3 +/- 2.1 ppt (0.3%) for CFC-12 and 0.2 +/- 0.4 ppt (0.3%) for CFC-113. On the other hand, during pollution periods these CFCs showed much larger seasonal cycles of 11.2 +/- 10.7 ppt (5%) for CFC-11, 7.5 +/- 6.5 ppt (2%) for CFC-12 and 1.0 +/- 1.2 ppt (1.2%) for CFC-113, with apparent winter minima and early summer maxima. This enhancement was attributed to prevailing wind directions from urban regions in summer and to enhanced anthropogenic sources during the warm season. In general, horizontal winds from northeast showed negative contribution to atmospheric CFCs loading, whereas South Western advection (urban sector: Beijing) had positive contributions. (C) 2010 Elsevier Ltd. All rights reserved
Novel DNA methylation profiles associated with key gene regulation and transcription pathways in blood and placenta of growth-restricted neonates
No full textFetal growth is determined by the feto-placental genome interacting with the maternal in utero environment. Failure of this interplay leads to poor placental development and fetal growth restriction (FGR), which is associated with future metabolic disease. We investigated whether whole genome methylation differences existed in umbilical cord blood and placenta, between gestational-matched, FGR, and appropriately grown (AGA) neonates. Using the Infinium HumanMethylation450 BeadChip®, we found that DNA from umbilical cord blood of FGR born at term (n = 19) had 839 differentially methylated positions (DMPs) that reached genome-wide significance compared with AGA (n = 18). Using gestational age as a continuous variable, we identified 76,249 DMPs in cord blood (adj. P 10% and 25 genes were co-methylated more than twice within 1000 base pairs. Gene Ontology (GO) analysis of DMPs supported their involvement in gene regulation and transcription pathways related to organ development and metabolic function. A similar profile of DMPs was found across different cell types in the cord blood. At term, no DMPs between FGR and AGA placentae reached genome-wide significance, validated with an external dataset. GO analysis of 284 pre-term, placental DMPs associated with autophagy, oxidative stress and hormonal responses. Growth restricted neonates have distinct DNA methylation profiles in pre-term placenta and in cord blood at birth, which may predispose to future adult disease
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