The Impact of Central and Peripheral Cyclooxygenase Enzyme Inhibition on Exercise-induced Core Body Temperature Elevations.

PURPOSE: Exercise increases core body temperature (TC) due to metabolic heat production. However, the exercise-induced release of inflammatory cytokines including interleukin-6 may also contribute to the rise in TC by increasing the hypothalamic temperature setpoint. We aimed to investigate whether the exercise-induced increase in TC is partly caused by an altered hypothalamic temperature setpoint. METHODS: 15 healthy, active male subjects aged 36±14 years were recruited. Subjects performed submaximal treadmill exercise in 3 randomized test conditions: (1) ibuprofen 400mg and acetaminophen 1000mg (IBU/APAP), (2) acetaminophen 1000mg (APAP) and (3) a control condition (CTRL). Acetaminophen and ibuprofen were used to block the effect of interleukin-6 at a central and peripheral level, respectively. TC, skin temperature and heart rate were measured continuously during the submaximal exercise tests. RESULTS: Baseline values of TC, skin temperature and heart rate did not differ across conditions. Serum interleukin-6 concentrations increased in all three conditions. A significantly lower peak TC was observed in IBU/APAP (38.8±0.4°C) versus CTRL (39.2±0.5°C, p=0.02), but not in APAP (38.9±0.4°C) versus CTRL. Similarly, a lower ΔTC was observed in IBU/APAP (1.7±0.3°C) versus CTRL (2.0±0.5°C, p<0.02), but not in APAP (1.7±0.5°C) versus CTRL. No differences were observed in skin temperature and heart rate responses across conditions. CONCLUSIONS: The combined administration of acetaminophen and ibuprofen resulted in an attenuated increase in TC during exercise when compared to a control condition. This observation suggests that a prostaglandin E2 induced elevated hypothalamic temperature setpoint may contribute to the exercise-induced rise in TC

Aortic stiffness is associated with cardiac function and cerebral small vessel disease in patients with type 1 diabetes mellitus: assessment by magnetic resonance imaging

To evaluate, with the use of magnetic resonance imaging (MRI), whether aortic pulse wave velocity (PWV) is associated with cardiac left ventricular (LV) function and mass as well as with cerebral small vessel disease in patients with type 1 diabetes mellitus (DM). We included 86 consecutive type 1 DM patients (49 male, mean age 46.9 +/- 11.7 years) in a prospective, cross-sectional study. Exclusion criteria included aortic/heart disease and general MRI contra-indications. MRI of the aorta, heart and brain was performed for assessment of aortic PWV, as a marker of aortic stiffness, systolic LV function and mass, as well as for the presence of cerebral white matter hyperintensities (WMHs), microbleeds and lacunar infarcts. Multivariate linear or logistic regression was performed to analyse the association between aortic PWV and outcome parameters, with covariates defined as age, gender, mean arterial pressure, heart rate, BMI, smoking, DM duration and hypertension. Mean aortic PWV was 7.1 +/- 2.5 m/s. Aortic PWV was independently associated with LV ejection fraction ( = -0.406, P = 0.006), LV stroke volume ( = -0.407, P = 0.001), LV cardiac output ( = -0.458, P = 0.001), and with cerebral WMHs (P < 0.05). There were no independent associations between aortic stiffness and LV mass, cerebral microbleeds or lacunar infarcts. Aortic stiffness is independently associated with systolic LV function and cerebral WMHs in patients with type 1 DM.Neuro Imaging Researc

The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution

Recurrent submicroscopic deletions in genes affecting key cellular pathways are a hallmark of pediatric acute lymphoblastic leukemia (ALL). To gain more insight into the mechanism underlying these deletions, we have studied the occurrence and nature of abnormalities in one of these genes, the B-cell translocation gene 1 (BTG1), in a large cohort of pediatric ALL cases. BTG1 was found to be exclusively affected by genomic deletions, which were detected in 65 out of 722 B-cell precursor ALL (BCP-ALL) patient samples (9%), but not in 109 T-ALL cases. Eight different deletion sizes were identified, which all clustered at the telomeric site in a hotspot region within the second (and last) exon of the BTG1 gene, resulting in the expression of truncated BTG1 read-through transcripts. The presence of V(D)J recombination signal sequences at both sites of virtually all deletions strongly suggests illegitimate RAG1/RAG2-mediated recombination as the responsible mechanism. Moreover, high levels of histone H3 lysine 4 trimethylation (H3K4me3), which is known to tether the RAG enzyme complex to DNA, were found within the BTG1 gene body in BCP-ALL cells, but not T-ALL cells. BTG1 deletions were rarely found in hyperdiploid BCP-ALLs, but were predominant in other cytogenetic subgroups, including the ETV6-RUNX1 and BCR-ABL1 positive BCP-ALL subgroups. Through sensitive PCR-based screening, we identified multiple additional BTG1 deletions at the subclonal level in BCP-ALL, with equal cytogenetic distribution which, in some cases, grew out into the major clone at relapse. Taken together, our results indicate that BTG1 deletions may act as “drivers” of leukemogenesis in specific BCP-ALL subgroups, in which they can arise independently in multiple subclones at sites that are prone to aberrant RAG1/RAG2-mediated recombination events. These findings provide further evidence for a complex and multiclonal evolution of ALL

The influence of the accessory genome on bacterial pathogen evolution

Bacterial pathogens exhibit significant variation in their genomic content of virulence factors. This reflects the abundance of strategies pathogens evolved to infect host organisms by suppressing host immunity. Molecular arms-races have been a strong driving force for the evolution of pathogenicity, with pathogens often encoding overlapping or redundant functions, such as type III protein secretion effectors and hosts encoding ever more sophisticated immune systems. The pathogens’ frequent exposure to other microbes, either in their host or in the environment, provides opportunities for the acquisition or interchange of mobile genetic elements. These DNA elements accessorise the core genome and can play major roles in shaping genome structure and altering the complement of virulence factors. Here, we review the different mobile genetic elements focusing on the more recent discoveries and highlighting their role in shaping bacterial pathogen evolution

Sex differences in cardiovascular complications and mortality in hospital patients with covid-19: registry based observational study

Objective To assess whether the risk of cardiovascular complications of covid-19 differ between the sexes and to determine whether any sex differences in risk are reduced in individuals with pre-existing cardiovascular disease. Design Registry based observational study. Setting 74 hospitals across 13 countries (eight European) participating in CAPACITY-COVID (Cardiac complicAtions in Patients With SARS Corona vIrus 2 regisTrY), from March 2020 to May 2021 Participants All adults (aged ≥18 years), predominantly European, admitted to hospital with highly suspected covid-19 disease or covid-19 disease confirmed by positive laboratory test results (n=11 167 patients). Main outcome measures Any cardiovascular complication during admission to hospital. Secondary outcomes were in-hospital mortality and individual cardiovascular complications with ≥20 events for each sex. Logistic regression was used to examine sex differences in the risk of cardiovascular outcomes, overall and grouped by pre-existing cardiovascular disease. Results Of 11 167 adults (median age 68 years, 40% female participants) included, 3423 (36% of whom were female participants) had pre-existing cardiovascular disease. In both sexes, the most common cardiovascular complications were supraventricular tachycardias (4% of female participants, 6% of male participants), pulmonary embolism (3% and 5%), and heart failure (decompensated or de novo) (2% in both sexes). After adjusting for age, ethnic group, pre-existing cardiovascular disease, and risk factors for cardiovascular disease, female individuals were less likely than male individuals to have a cardiovascular complication (odds ratio 0.72, 95% confidence interval 0.64 to 0.80) or die (0.65, 0.59 to 0.72). Differences between the sexes were not modified by pre-existing cardiovascular disease; for the primary outcome, the female-to-male ratio of the odds ratio in those without, compared with those with, pre-existing cardiovascular disease was 0.84 (0.67 to 1.07). Conclusions In patients admitted to hospital for covid-19, female participants were less likely than male participants to have a cardiovascular complication. The differences between the sexes could not be attributed to the lower prevalence of pre-existing cardiovascular disease in female individuals. The reasons for this advantage in female individuals requires further research

MiRNA-Mediated Control of HLA-G Expression and Function

HLA-G is a non-classical HLA class-Ib molecule expressed mainly by the extravillous cytotrophoblasts (EVT) of the placenta. The expression of HLA-G on these fetal cells protects the EVT cells from immune rejection and is therefore important for a healthy pregnancy. The mechanisms controlling HLA-G expression are largely unknown. Here we demonstrate that miR-148a and miR-152 down-regulate HLA-G expression by binding its 3′UTR and that this down-regulation of HLA-G affects LILRB1 recognition and consequently, abolishes the LILRB1-mediated inhibition of NK cell killing. We further demonstrate that the C/G polymorphism at position +3142 of HLA-G 3′UTR has no effect on the miRNA targeting of HLA-G. We show that in the placenta both miR-148a and miR-152 miRNAs are expressed at relatively low levels, compared to other healthy tissues, and that the mRNA levels of HLA-G are particularly high and we therefore suggest that this might enable the tissue specific expression of HLA-G

Chemotaxis of Cell Populations through Confined Spaces at Single-Cell Resolution

Cell migration is crucial for both physiological and pathological processes. Current in vitro cell motility assays suffer from various drawbacks, including insufficient temporal and/or optical resolution, or the failure to include a controlled chemotactic stimulus. Here, we address these limitations with a migration chamber that utilizes a self-sustaining chemotactic gradient to induce locomotion through confined environments that emulate physiological settings. Dynamic real-time analysis of both population-scale and single-cell movement are achieved at high resolution. Interior surfaces can be functionalized through adsorption of extracellular matrix components, and pharmacological agents can be administered to cells directly, or indirectly through the chemotactic reservoir. Direct comparison of multiple cell types can be achieved in a single enclosed system to compare inherent migratory potentials. Our novel microfluidic design is therefore a powerful tool for the study of cellular chemotaxis, and is suitable for a wide range of biological and biomedical applications

The Rotterdam Study: 2010 objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in close to a 1,000 research articles and reports (see www.epib.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods

Pupillary Stroop effects

We recorded the pupil diameters of participants performing the words’ color-naming Stroop task (i.e., naming the color of a word that names a color). Non-color words were used as baseline to firmly establish the effects of semantic relatedness induced by color word distractors. We replicated the classic Stroop effects of color congruency and color incongruency with pupillary diameter recordings: relative to non-color words, pupil diameters increased for color distractors that differed from color responses, while they reduced for color distractors that were identical to color responses. Analyses of the time courses of pupil responses revealed further differences between color-congruent and color-incongruent distractors, with the latter inducing a steep increase of pupil size and the former a relatively lower increase. Consistent with previous findings that have demonstrated that pupil size increases as task demands rise, the present results indicate that pupillometry is a robust measure of Stroop interference, and it represents a valuable addition to the cognitive scientist’s toolbox