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

Evaluation of the cardiac amyloidosis clinical pathway implementation: A real-world experience

AIMS: The aim of this study is to evaluate the implementation of the cardiac amyloidosis (CA) clinical pathway on awareness among referring cardiologists, diagnostic delay, and severity of CA at diagnosis. METHODS AND RESULTS: Patients with CA were retrospectively included in this study and divided into two periods: pre-implementation of the CA clinical pathway (2007–18; T1) and post-implementation (2019–20; T2). Patients’ and disease characteristics were extracted from electronic health records and compared. In total, 113 patients (mean age 67.8 ± 8.5 years, 26% female) were diagnosed with CA [T1 (2007–18): 56; T2 (2019–20): 57]. The number of CA diagnoses per year has increased over time. Reasons for referral changed over time, with increased awareness of right ventricular hypertrophy (9% in T1 vs. 36% in T2) and unexplained heart failure with preserved ejection fraction (22% in T1 vs. 38% in T2). Comparing T1 with T2, the diagnostic delay also improved (14 vs. 8 months, P < 0.01), New York Heart Association Class III (45% vs. 23%, P = 0.03), and advanced CA stage (MAYO/Gillmore Stage III/IV; 61% vs. 33%, P ≤ 0.01) at time of diagnosis decreased. CONCLUSION: After implementation of the CA clinical pathway, the awareness among referring cardiologists improved, diagnostic delay was decreased, and patients had less severe CA at diagnosis. Further studies are warranted to assess the prognostic impact of CA clinical pathway implementation

Increased frequency of circulating IL-21 producing Th-cells in patients with granulomatosis with polyangiitis (GPA).

INTRODUCTION: The present study aimed to explore a possible role for IL-21 producing Th-cells in the immunopathogenesis of granulomatosis with polyangiitis (GPA). METHODS: Peripheral blood from 42 GPA patients in remission and 29 age-matched healthy controls (HCs) were stimulated in vitro, and the frequencies of IL-21 producing Th-cells were determined by flow cytometry. Since Th17-cells produce a low level of IL-21, IL-17 was also included in the analysis. Given that IL-21 is a hallmark cytokine for T follicular helper cells (T(FH)), we next evaluated the expression of their key transcription factor BCL-6 by RT-PCR and flow cytometry. To investigate the effect of IL-21 on autoantibody-production, PBMCs from GPA patients were stimulated in vitro with BAFF/IL-21 and total IgG and ANCA levels were measured in supernatants. In addition, the expression of IL-21-receptor on B-cells was analyzed. RESULTS: Percentages of IL-21 producing Th-cells were significantly elevated in GPA-patients compared to HCs, and were restricted to ANCA-positive patients. The expression of BCL-6 was significantly higher in ANCA-positive GPA-patients, as compared with ANCA-negative patients and HCs. IL-21 enhanced the production of IgG and ANCA in vitro in stimulated PBMCs from GPA patients. No difference was found in the expression of the IL-21-receptor on B-cells between ANCA-negative patients, ANCA-positive patients, and HCs. CONCLUSION: The increased frequency of circulating IL-21 producing Th-cells in ANCA-positive GPA patients and the stimulating capacity of IL-21 on ANCA-production suggest a role for these cells in the immunopathogenesis of GPA. Blockade of IL-21 could constitute a new therapeutic strategy for GPA

Cohort profile: the Utrecht Cardiovascular Cohort-Second Manifestations of Arterial Disease (UCC-SMART) Study-an ongoing prospective cohort study of patients at high cardiovascular risk in the Netherlands

PURPOSE: The Utrecht Cardiovascular Cohort-Second Manifestations of Arterial Disease (UCC-SMART) Study is an ongoing prospective single-centre cohort study with the aim to assess important determinants and the prognosis of cardiovascular disease progression. This article provides an update of the rationale, design, included patients, measurements and findings from the start in 1996 to date. PARTICIPANTS: The UCC-SMART Study includes patients aged 18-90 years referred to the University Medical Center Utrecht, the Netherlands, for management of cardiovascular disease (CVD) or severe cardiovascular risk factors. Since September 1996, a total of 14 830 patients have been included. Upon inclusion, patients undergo a standardised screening programme, including questionnaires, vital signs, laboratory measurements, an ECG, vascular ultrasound of carotid arteries and aorta, ankle-brachial index and ultrasound measurements of adipose tissue, kidney size and intima-media thickness. Outcomes of interest are collected through annual questionnaires and adjudicated by an endpoint committee. FINDINGS TO DATE: By May 2022, the included patients contributed to a total follow-up time of over 134 000 person-years. During follow-up, 2259 patients suffered a vascular endpoint (including non-fatal myocardial infarction, non-fatal stroke and vascular death) and 2794 all-cause deaths, 943 incident cases of diabetes and 2139 incident cases of cancer were observed up until January 2020. The UCC-SMART cohort contributed to over 350 articles published in peer-reviewed journals, including prediction models recommended by the 2021 European Society of Cardiology CVD prevention guidelines. FUTURE PLANS: The UCC-SMART Study guarantees an infrastructure for research in patients at high cardiovascular risk. The cohort will continue to include about 600 patients yearly and follow-up will be ongoing to ensure an up-to-date cohort in accordance with current healthcare and scientific knowledge. In the near future, UCC-SMART will be enriched by echocardiography, and a food frequency questionnaire at baseline enabling the assessment of associations between nutrition and CVD and diabetes

Perceived need for mental health care and barriers to care in the Netherlands and Australia

This study of Australian and Dutch people with anxiety or depressive disorder aims to examine people's perceived needs and barriers to care, and to identify possible similarities and differences. Data from the Australian National Survey of Mental Health and Well-Being and the Netherlands Study of Depression and Anxiety were combined into one data set. The Perceived Need for Care Questionnaire was taken in both studies. Logistic regression analyses were performed to check if similarities or differences between Australia and the Netherlands could be observed. In both countries, a large proportion had unfulfilled needs and self-reliance was the most frequently named barrier to receive care. People from the Australian sample (N = 372) were more likely to perceive a need for medication (OR 1.8; 95% CI 1.3-2.5), counselling (OR 1.4; 95% CI 1.0-2.0) and practical support (OR 1.8; 95% CI 1.2-2.7), and people's overall needs in Australia were more often fully met compared with those of the Dutch sample (N = 610). Australians were more often pessimistic about the helpfulness of medication (OR 3.8; 95% CI 1.4-10.7) and skills training (OR 3.0; 95% CI 1.1-8.2) and reported more often financial barriers for not having received (enough) information (OR 2.4; 95% CI 1.1-5.5) or counselling (OR 5.9; 95% CI 2.9-11.9). In both countries, the vast majority of mental health care needs are not fulfilled. Solutions could be found in improving professionals' skills or better collaboration. Possible explanations for the found differences in perceived need and barriers to care are discussed; these illustrate the value of examining perceived need across nations and suggest substantial commonalities of experience across the two countries

Subduction controls the distribution and fragmentation of Earth’s tectonic plates

International audienceThe theory of plate tectonics describes how the surface of the Earth is split into an organized jigsaw of seven large plates 1 of similar sizes and a population of smaller plates, whose areas follow a fractal distribution 2,3. The reconstruction of global tectonics during the past 200 My 4 suggests that this layout is probably a long-term feature of our planet, but the forces governing it are unknown. Previous studies 3,5,6 , primarily based on statistical properties of plate distributions, were unable to resolve how the size of plates is determined by lithosphere properties and/or underlying mantle convection. Here, we demonstrate that the plate layout of the Earth is produced by a dynamic feedback between mantle convection and the strength of the lithosphere. Using 3D spherical models of mantle convection with plate-like behaviour that match the plate size-frequency distribution observed for Earth, we show that subduction geometry drives the tectonic fragmentation that generates plates. The spacing between slabs controls the layout of large plates, and the stresses caused by the bending of trenches, break plates into smaller fragments. Our results explain why the fast evolution in small back-arc plates 7,8 reflects the dramatic changes in plate motions during times of major reorganizations. Our study opens the way to use convection simulations with plate-like behaviour to unravel how global tectonics and mantle convection are dynamically connected

Circulating Lipoproteins Are a Crucial Component of Host Defense against Invasive Salmonella typhimurium Infection

Contains fulltext : 79883.pdf (Publisher’s version ) (Open Access)BACKGROUND: Circulating lipoproteins improve the outcome of severe Gram-negative infections through neutralizing lipopolysaccharides (LPS), thus inhibiting the release of proinflammatory cytokines. METHODS/PRINCIPAL FINDINGS: Low density lipoprotein receptor deficient (LDLR-/-) mice, with a 7-fold increase in LDL, are resistant against infection with Salmonella typhimurium (survival 100% vs 5%, p<0.001), and 100 to 1000-fold lower bacterial burden in the organs, compared with LDLR+/+ mice. Protection was not due to differences in cytokine production, phagocytosis, and killing of Salmonella organisms. The differences were caused by the excess of lipoproteins, as hyperlipoproteinemic ApoE-/- mice were also highly resistant to Salmonella infection. Lipoproteins protect against infection by interfering with the binding of Salmonella to host cells, and preventing organ invasion. This leads to an altered biodistribution of the microorganisms during the first hours of infection: after intravenous injection of Salmonella into LDLR+/+ mice, the bacteria invaded the liver and spleen within 30 minutes of infection. In contrast, in LDLR-/- mice, Salmonella remained constrained to the circulation from where they were efficiently cleared, with decreased organ invasion. CONCLUSIONS: plasma lipoproteins are a potent host defense mechanism against invasive Salmonella infection, by blocking adhesion of Salmonella to the host cells and subsequent tissue invasion

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

The effects of exercise and weight loss in overweight patients with hip osteoarthritis: design of a prospective cohort study

BACKGROUND: Hip osteoarthritis (OA) is recognised as a substantial source of disability, with pain and loss of function as principal symptoms. An aging society and a growing number of overweight people, which is considered a risk factor for OA, contribute to the growing number of cases of hip OA. In knee OA patients, exercise as a single treatment is proven to be very effective towards counteracting pain and physical functionality, but the combination of weight loss and exercise is demonstrated to be even more effective. Exercise as a treatment for hip OA patients is also effective, however evidence is lacking for the combination of weight loss and exercise. Consequently, the aim of this study is to get a first impression of the potential effectiveness of exercise and weight loss in overweight patients suffering from hip OA. METHODS/DESIGN: This is a prospective cohort study. Patients aged 25 or older, overweight (BMI > 25) or obese (BMI > 30), with clinical and radiographic evidence of OA of the hip and able to attend exercise sessions will be included. The intervention is an 8-month exercise and weight-loss lifestyle program. Main goal is to increase aerobic capacity, lose weight and stimulate a low-calorie and active lifestyle. Primary outcome is self-reported physical functioning. Secondary outcomes include pain, stiffness, health-related quality of life and habitual activity level. Weight loss in kilograms and percentage of fat-free mass will also be measured. DISCUSSION: The results of this study will give a first impression of potential effectiveness of exercise and weight loss as a combination program for patients with OA of the hip. Once this program is proven to be effective it may lead to postponing the moment of total hip replacement. TRIAL REGISTRATION NUMBER: NTR1053