Microparticles from patients with metabolic syndrome induce vascular hypo-reactivity via Fas/Fas-ligand pathway in mice

Peer reviewedPublisher PD

Interleukin-1 regulates multiple atherogenic mechanisms in response to fat feeding

Background: Atherosclerosis is an inflammatory process that develops in individuals with known risk factors that include hypertension and hyperlipidaemia, influenced by diet. However, the interplay between diet, inflammatory mechanisms and vascular risk factors requires further research. We hypothesised that interleukin-1 (IL-1) signaling in the vessel wall would raise arterial blood pressure and promote atheroma. Methodology/Principal Findings: Apoe(-/-) and Apoe(-/-)/IL-1R1(-/-) mice were fed high fat diets for 8 weeks, and their blood pressure and atherosclerosis development measured. Apoe(-/-)/IL-R1(-/-) mice had a reduced blood pressure and significantly less atheroma than Apoe(-/-) mice. Selective loss of IL-1 signaling in the vessel wall by bone marrow transplantation also reduced plaque burden (p<0.05). This was associated with an IL-1 mediated loss of endothelium-dependent relaxation and an increase in vessel wall Nox 4. Inhibition of IL-1 restored endothelium-dependent vasodilatation and reduced levels of arterial oxidative stress. Conclusions/Significance: The IL-1 cytokine system links atherogenic environmental stimuli with arterial inflammation, oxidative stress, increased blood pressure and atherosclerosis. This is the first demonstration that inhibition of a single cytokine can block the rise in blood pressure in response to an environmental stimulus. IL-1 inhibition may have profound beneficial effects on atherogenesis in man

The prognosis for pain, disability, activities of daily living and quality of life after an acute osteoporotic vertebral body fracture: its relation to fracture level, type of fracture and grade of fracture deformation

The level of the acute osteoporotic vertebral fracture, fracture type and grade of fracture deformation were determined in 107 consecutive patients and related to pain, disability, activities of daily living (ADL) and quality of life (QoL) after 3 weeks, 3, 6 and 12 months. Two-thirds of the fractured patients were women and with a similar average age, around 75 years, as the men. Fifty-eight of the acute fractures were located in the thoracic spine and 49 in the lumbar spine and predominantly at the Th12 and L1 levels. Sixty-nine percent of the fractures were wedge, 19% concave and 12% crush fractures. There were 22 mildly, 50 moderately and 35 severely deformed vertebrae. The grade of fracture deformation was not related to gender, age or fracture location. Severely deformed vertebrae predominantly (92%) occurred among the crush fracture type. One year after the fracture, irrespective of fracture level, fracture type or grade of fracture deformation, 4/5 still had pronounced pain and deteriorated QoL. Initial severe fracture deformation by far was the worst prognostic factor for severe lasting pain and disability, and deterioration of ADL and QoL. Factors like fracture level, lumbar fractures tended to improve steadily while thoracic deteriorated, type of fracture, the wedge and concave resulting in less pain and better QoL than the crush fracture type and gender influenced to a lesser extent the outcomes during the year after the acute fracture

The pigmented life of a redhead.

As a redhead I have had a personal interest in red hair, freckles and sunburns since childhood. An observation of a formaldehyde-induced fluorescence in human epidermal melanocytes initiated my scientific interest in these cells. Prota and Nicolaus demonstrated that oxidation products of cysteinyldopas are the main components of pheomelanin. Our identification of 5-S-cysteinyldopa as the source of formaldehyde-induced fluorescence of normal and pathological melanocytes started a series of investigations into this amino acid, enzymatic and non-enzymatic oxidation of catecholic compounds and the metabolism of thiols. All melanocytes with functioning tyrosinase produce cysteinyldopas and the levels of 5-S-cysteinyldopa in serum and urine are related to the size and pigment forming activity of the melanocyte population. The determination of 5-S-cysteinyldopa in serum or urine is a sensitive diagnostic method in the detection of melanoma metastasis. Some non-specific formation of cysteinyldopa is present in the body, as demonstrated by 5-S-cysteinyldopa in individuals with tyrosinase-negative albinism

Towards plant-odor-related olfactory neuroethology in Drosophila

Drosophila melanogaster is today one of the three foremost models in olfactory research, paralleled only by the mouse and the nematode. In the last years, immense progress has been achieved by combining neurogenetic tools with neurophysiology, anatomy, chemistry, and behavioral assays. One of the most important tasks for a fruit fly is to find a substrate for eating and laying eggs. To perform this task the fly is dependent on olfactory cues emitted by suitable substrates as e.g. decaying fruit. In addition, in this area, considerable progress has been made during the last years, and more and more natural and behaviorally active ligands have been identified. The future challenge is to tie the progress in different fields together to give us a better understanding of how a fly really behaves. Not in a test tube, but in nature. Here, we review our present state of knowledge regarding Drosophila plant-odor-related olfactory neuroethology to provide a basis for new progress

Dose optimisation in paediatric radiography - using regression models to investigate the relative impact of acquisition factors on image quality and radiation dose

Objective: To investigate the optimum pelvis X-ray acquisition factors for a 10-year-old child. Secondly, to evaluate the impact of each acquisition factor on image quality (IQ) and radiation dose. Method: Images were acquired using a pelvis phantom and a range of acquisition parameters; e.g. tube potential, additional filtration and source-to-image distance (SID). Automatic exposure control (AEC) was used with two orientations (head towards/away from two outer chambers) and three different chamber selections. Visual IQ was evaluated using relative and absolute-VGA methods. Radiation doses were measured by placing a dosimeter on the anterior surface of the phantom. Regression analysis was used to determine optimum parameters. Results: The optimised technique (178.8 µGy), with diagnostic IQ, was with 89kVp, 130 cm SID and with 1 mm Al + 0.1 mm Cu filtration. This technique was with the head towards the two outer AEC chambers. Regression analysis showed that SID had the lowest impact on IQ (β = 0.002 95% CI −0.001 to 0.005) and dose (β = −0.96 95% CI −0.40 to −1.53). The impact of filtration on dose (β = −76.24 95% CI −86.76 to −85.72) was higher than tube potential (β = −13.44 95% CI −14.34 to −12.53). The following impact ratios were higher on IQ than radiation dose: filtration/kVp; 11.28 times, filtration/SID; 7.01 times and kVp/SID; 0.62 times. Conclusion: Optimised parameters were identified as 89 kVp, 130 cm SID and with 1 mm Al + 0.1 mm Cu additional filtration. Regression analysis demonstrated that filtration and tube potential had the greatest effect on radiation dose and IQ, respectively

Could a defective epithelial sodium channel lead to bronchiectasis

<p>Abstract</p> <p>Background</p> <p>Bronchiectasis is defined as a permanent dilation of the airways arising from chronic bronchial inflammation/infection. In 50% of cases, no etiology can be identified. Recently, the role of the epithelial sodium channel ENaC has been pointed out in the pathophysiology of cystic fibrosis, a disease due to mutations in the <it>CFTR </it>gene and causing bronchiectasis in the airways. Moreover, it was found that transgenic mice overexpressing <it>ENaCβ </it>present cystic fibrosis-like lung disease symptoms. Our aim was to evaluate if a defective ENaC protein could be involved in the development of bronchiectasis.</p> <p>Methods</p> <p>We extensively analysed <it>ENaCβ </it>and <it>γ </it>genes in 55 patients with idiopathic bronchiectasis and without two mutations in the coding regions of <it>CFTR</it>. Thirty-eight patients presented functional abnormalities suggesting impaired sodium transport (abnormal sweat chloride concentration or nasal potential difference measurement), and 17 had no such evidence.</p> <p>Results</p> <p>Sequencing of the exons and flanking introns of the <it>ENaCβ </it>and <it>γ </it>gene identified five different amino-acid changes (p.Ser82Cys, p.Pro369Thr, p.Asn288Ser in <it>ENaCβ </it>; and p.Gly183Ser, p.Glu197Lys in <it>ENaCγ</it>) in heterozygous state in 8 patients. The p.Ser82Cys amino-acid change was found in 3 unrelated patients who were also heterozygous for a <it>CFTR </it>mutation or variant (1 p.F508del, 1 IVS8-5T, and 1 IVS8-5T:1716G>A (p.E528E)). The other mutations were found in patients without <it>CFTR </it>mutation, the p.Glu197Lys mutation in 2 patients and the other variants in single patients. Among the 8 patients bearing an <it>ENaC </it>mutation, 5 had functional abnormalities suggesting impaired sodium transport.</p> <p>Conclusion</p> <p>Our results suggest that several variants in <it>ENaCβ </it>and <it>γ </it>genes might be deleterious for ENaC function and lead to bronchiectasis, especially in patients who are trans-heterozygotes for <it>ENaCβ/CFTR </it>mutations or variants.</p

Research misconduct in the fields of ethics and philosophy: researchers’ perceptions in Spain

This is the Author’s Original Manuscript (AOM) (also called a “preprint”) sent to review to Science and Engineering Ethics on 11/10/2020. The final version of the article was published online at SEE on 21/01/2021. The online version is available at: https://doi.org/10.1007/s11948-021-00278-wEmpirical studies have revealed a disturbing prevalence of research misconduct in a wide variety of disciplines, although not, to date, in the areas of ethics and philosophy. This study aims to provide empirical evidence on perceptions of how serious a problem research misconduct is in these two disciplines in Spain, particularly regarding the effects that the model used to evaluate academics’ research performance may have on their ethical behaviour. The methodological triangulation applied in the study combines a questionnaire, a debate at the annual meeting of scientific association, and in-depth interviews. Of the 541 questionnaires sent out, 201 responses were obtained (37.1% of the total sample), with a significant difference in the participation of researchers in philosophy (30.5%) and in ethics (52.8%); 26 researchers took part in the debate and 14 interviews were conducted. The questionnaire results reveal that 91.5% of the respondents considered research misconduct to be on the rise; 63.2% considered at least three of the fraudulent practices referred to in the study to be commonplace, and 84.1% identified two or more such practices. The researchers perceived a high prevalence of duplicate publication (66.5%) and self-plagiarism (59.0%), use of personal influence (57.5%) and citation manipulation (44.0%), in contrast to a low perceived incidence of data falsification or fabrication (10.0%). The debate and the interviews corroborated these data. Researchers associated the spread of these misconducts with the research evaluation model applied in Spain

A Common Polymorphism in the Promoter Region of the TNFSF4 Gene Is Associated with Lower Allele-Specific Expression and Risk of Myocardial Infarction

BACKGROUND: The TNFSF4/TNFRSF4 system, along with several other receptor-ligand pairs, is involved in the recruitment and activation of T-cells and is therefore tentatively implicated in atherosclerosis and acute coronary syndromes. We have previously shown that genetic variants in TNFSF4 are associated with myocardial infarction (MI) in women. This prompted functional studies of TNFSF4 expression. METHODS AND RESULTS: Based on a screening of the TNFSF4 genomic region, a promoter polymorphism (rs45454293) and a haplotype were identified, conceivably involved in gene regulation. The rs45454293T-allele, in agreement with the linked rs3850641G-allele, proved to be associated with increased risk of MI in women. Haplotype-specific chromatin immunoprecipitation of activated polymerase II, as a measure of transcriptional activity in vivo, suggested that the haplotype including the rs45454293 and rs3850641 polymorphisms is functionally important, the rs45454293T- and rs3850641G-alleles being associated with lower transcriptional activity in cells heterozygous for both polymorphisms. The functional role of rs45454293 on transcriptional levels of TNFSF4 was clarified by luciferase reporter assays, where the rs45454293T-allele decreased gene expression when compared with the rs45454293C-allele, while the rs3850641 SNP did not have any effect on TNFSF4 promoter activity. Electromobility shift assay showed that the rs45454293 polymorphism, but not rs3850641, affects the binding of nuclear factors, thus suggesting that the lower transcriptional activity is attributed to binding of one or more transcriptional repressor(s) to the T-allele. CONCLUSIONS: Our data indicate that the TNFSF4 rs45454293T-allele is associated with lower TNFSF4 expression and increased risk of MI