Chapter Immune System and Environmental Xenobiotics - The Effect of Selected Mineral Fibers and Particles on the Immune Response

Medical genetic

Immune System and Environmental Xenobiotics - The Effect of Selected Mineral Fibers and Particles on the Immune Response

Medical genetic

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Molecular and morphological delineation of Longidorus poessneckensis Altherr, 1974 (Nematoda: Dorylaimida).

The plant-parasitic nematode Longidorus poessneckensis from the Czech Republic was morphologically and molecularly characterised. Molecular analyses were carried out using mitochondrial DNA (cytochrome c oxidase subunit 1-cox1) and ribosomal DNA (ITS2-second internal transcribed spacer, 18S gene and D2/D3 expansion segments of the 28S gene), which were amplified and sequenced. Phylogenetic relationship of L. poessneckensis with three morphologically closely related species, i.e. L. macrosoma, L. helveticus and L. uroshis, was inferred by using maximum likelihood and maximum parsimony methods, with a female of Xiphinema diversicaudatum and a bivulval female of X. vuittenezi as outgroups. All multiple alignments yielded similar basic trees supporting the uniqueness of L. poessneckensis and the validity of the four Longidorus species identified using morphological characters. Phylogenetic analyses revealed that L. poessneckensis is more closely related to L. macrosoma and L. helveticus than to L. uroshis. High inter-population diversity (19%) was observed across the cox1 gene between two populations of L. poessneckensis

The reverse role of the hypothalamic paraventricular (PVN) and arcuate (ARC) nuclei in the central serotonergic regulation of the liver cytochrome P450 isoform CYP2C11

Our recent work showed that the brain serotonergic system negatively regulated liver cytochrome P450. The aim of our present research was to study the effect of damage to the serotonergic innervation of the paraventricular (PVN) or arcuate nuclei (ARC) of the hypothalamus on the neuroendocrine regulation of cytochrome P450 (CYP). Male rats received bilateral injections of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the PVN or ARC. One week after the injection brain neurotransmitters, serum hormones (growth hormone, testosterone, corticosterone, thyroid hormones), pituitary somatostatin and liver cytochrome P450 expression and activity were measured. Lesion of the serotonergic innervation of the PVN decreased serotonin level in the hypothalamic area containing the PVN, causing an increase in growth hormone and testosterone concentrations in the blood and, subsequently, an increase in the expression (mRNA and protein level) and activity of isoform CYP2C11 in the liver. In contrast, damage to the serotonergic innervation of the ARC, which caused a decrease in serotonin level in the hypothalamic area containing the ARC, reduced the concentration of growth hormone and the expression and activity of CYP2C11. In conclusion, the obtained results show a reverse effect of the serotonergic innervation of the hypothalamic paraventricular (a negative effect) and arcuate nuclei (a positive effect) on growth hormone secretion and growth hormone-dependent CYP2C11 expression. They also suggest that CYP2C11 expression may be changed by drugs acting via the serotonergic system, their effect depending on their mechanism of action, route of administration (intracerebral, peripheral) and distribution pattern within the hypothalamus

Type 1 Sodium Calcium Exchanger Forms a Complex with Carbonic Anhydrase IX and Via Reverse Mode Activity Contributes to pH Control in Hypoxic Tumors

Hypoxia and acidosis are among the key microenvironmental factors that contribute to cancer progression. We have explored a possibility that the type 1Na+/Ca2+ exchanger (NCX1) is involved in pH control in hypoxic tumors. We focused on changes in intracellular pH, co-localization of NCX1, carbonic anhydrase IX (CA IX), and sodium proton exchanger type 1 (NHE1) by proximity ligation assay, immunoprecipitation, spheroid formation assay and migration of cells due to treatment with KB-R7943, a selective inhibitor of the reverse-mode NCX1. In cancer cells exposed to hypoxia, reverse-mode NCX1 forms a membrane complex primarily with CA IX and also with NHE1. NCX1/CA IX/NHE1 assembly operates as a metabolon with a potent ability to extrude protons to the extracellular space and thereby facilitate acidosis. KB-R7943 prevents formation of this metabolon and reduces cell migration. Thus, we have shown that in hypoxic cancer cells, NCX1 operates in a reverse mode and participates in pH regulation in hypoxic tumors via cooperation with CAIX and NHE1

Immunotoxicity and genotoxicity testing of PLGA-PEO nanoparticles in human blood cell model

A human blood cell model for immunotoxicity and genotoxicity testing was used to measure the response to polylactic-co-glycolic acid (PLGA-PEO) nanoparticle (NP) (0.12, 3, 15 and 75 μg/cm² exposure in fresh peripheral whole blood cultures/isolated peripheral blood mononuclear cell cultures from human volunteers (n = 9-13). PLGA-PEO NPs were not toxic up to dose 3 μg/cm²; dose of 75 μg/cm² displays significant decrease in [³H]-thymidine incorporation into DNA of proliferating cells after 4 h (70% of control) and 48 h (84%) exposure to NPs. In non-cytotoxic concentrations, in vitro assessment of the immunotoxic effects displayed moderate but significant suppression of proliferative activity of T-lymphocytes and T-dependent B-cell response in cultures stimulated with PWM > CON A, and no changes in PHA cultures. Decrease in proliferative function was the most significant in T-cells stimulated with CD3 antigen (up to 84%). Cytotoxicity of natural killer cells was suppressed moderately (92%) but significantly in middle-dosed cultures (4 h exposure). On the other hand, in low PLGA-PEO NPs dosed cultures, significant stimulation of phagocytic activity of granulocytes (119%) > monocytes (117%) and respiratory burst of phagocytes (122%) was recorded. Genotoxicity assessment revealed no increase in the number of micronucleated binucleated cells and no induction of SBs or oxidised DNA bases in PLGA-PEO-treated cells. To conclude on immuno- and genotoxicity of PLGA-PEO NPs, more experiments with various particle size, charge and composition need to be done

Association of Sex With Frequent and Mild ABCA4 Alleles in Stargardt Disease

IMPORTANCE The mechanisms behind the phenotypic variability and reduced penetrance in autosomal recessive Stargardt disease (STGD1), often a blinding disease, are poorly understood. Identification of the unknown disease modifiers can improve patient and family counseling and provide valuable information for disease management. OBJECTIVE To assess the association of incompletely penetrant ABCA4 alleles with sex in STGD1. DESIGN, SETTING, AND PARTICIPANTS Genetic data for this cross-sectional study were obtained from 2 multicenter genetic studies of 1162 patients with clinically suspected STGD1. Unrelated patients with genetically confirmed STGD1 were selected. The data were collected from June 2016 to June 2019, and post hoc analysis was performed between July 2019 and January 2020. MAIN OUTCOMES AND MEASURES Penetrance of reported mild ABCA4 variants was calculated by comparing the allele frequencies in the general population (obtained from the Genome Aggregation Database) with the genotyping data in the patient population (obtained from the ABCA4 Leiden Open Variation Database). The sex ratio among patients with and patients without an ABCA4 allele with incomplete penetrance was assessed. RESULTS A total of 550 patients were included in the study, among which the mean (SD) age was 45.7 (18.0) years and most patients were women (311 [57%]). Five of the 5 mild ABCA4 alleles, including c.5603A>T and c.5882G>A, were calculated to have incomplete penetrance. The women to men ratio in the subgroup carrying c.5603A>T was 1.7 to 1; the proportion of women in this group was higher compared with the subgroup not carrying a mild allele (difference, 13%; 95% CI, 3%-23%; P=.02). The women to men ratio in the c.5882G>A subgroup was 2.1 to 1, and the women were overrepresented compared with the group carrying no mild allele (difference, 18%; 95% CI, 6%-30%; P=.005). CONCLUSIONS AND RELEVANCE This study found an imbalance in observed sex ratio among patients harboring a mild ABCA4 allele, which concerns approximately 25% of all patients with STGD1, suggesting that STGD1 should be considered a polygenic or multifactorial disease rather than a disease caused by ABCA4 gene mutations alone. The findings suggest that sex should be considered as a potential disease-modifying variable in both basic research and clinical trials on STGD1