Exercise facilitates weight control, partly through effects on appetite regulation. Single bouts of exercise induce a short-term energy deficit without stimulating compensatory effects on appetite, ...whilst limited evidence suggests that exercise training may modify subjective and homeostatic mediators of appetite in directions associated with enhanced meal-induced satiety. However, a large variability in responses exists between individuals. This article reviews the evidence relating to how adiposity, sex, and habitual physical activity modulate exercise-induced appetite, energy intake, and appetite-related hormone responses. The balance of evidence suggests that adiposity and sex do not modify appetite or energy intake responses to acute or chronic exercise interventions, but individuals with higher habitual physical activity levels may better adjust energy intake in response to energy balance perturbations. The effect of these individual characteristics and behaviours on appetite-related hormone responses to exercise remains equivocal. These findings support the continued promotion of exercise as a strategy for inducing short-term energy deficits irrespective of adiposity and sex, as well as the ability of exercise to positively influence energy balance over the longer term. Future well-controlled studies are required to further ascertain the potential mediators of appetite responses to exercise.
Antibodies play major roles in immunity to malaria; however, a limited understanding of mechanisms mediating protection is a major barrier to vaccine development. We have demonstrated that acquired ...human anti-malarial antibodies promote complement deposition on the merozoite to mediate inhibition of erythrocyte invasion through C1q fixation and activation of the classical complement pathway. Antibody-mediated complement-dependent (Ab-C′) inhibition was the predominant invasion-inhibitory activity of human antibodies; most antibodies were non-inhibitory without complement. Inhibitory activity was mediated predominately via C1q fixation, and merozoite surface proteins 1 and 2 were identified as major targets. Complement fixation by antibodies was very strongly associated with protection from both clinical malaria and high-density parasitemia in a prospective longitudinal study of children. Ab-C′ inhibitory activity could be induced by human immunization with a candidate merozoite surface-protein vaccine. Our findings demonstrate that human anti-malarial antibodies have evolved to function by fixing complement for potent invasion-inhibitory activity and protective immunity.
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•Antibodies function with complement to inhibit P. falciparum replication•Antibodies fix C1q to block invasion and lyse merozoites•Complement-fixing antibodies are strongly associated with immunity in children•Antibody-complement inhibition can be induced by human vaccination
Antibodies are important in immunity to malaria, but their protective function has been unclear. Boyle and colleagues report that acquired and vaccine-induced human antibodies recruit complement to block infection of erythrocytes and blood-stage replication of Plasmodium falciparum.
Objectives Multiple mechanisms may be involved in postoperative atrial fibrillation. Therefore, our objective was to determine the risk factors for postoperative atrial fibrillation as a function of ...time after coronary artery bypass grafting or valve surgeries to determine which risk factors might predominate at different times. Methods Parametric hazard functions were determined for 1583 patients and then in subgroups (coronary artery bypass grafting alone, mitral valve procedure, and aortic valve replacement +/− coronary artery bypass grafting). Multivariable risk factor analyses were performed, and the risk for postoperative atrial fibrillation was estimated. Results The risk for postoperative atrial fibrillation for all patients was highest immediately postoperatively and at 48 hours. The initial peak risk declined to approximately zero within 18 hours postoperatively. A second peak occurred at 48 hours, followed by a slow decline over the following 4 to 7 days. The time intervals encompassing these peaks were termed phase I and phase II. Predominant risk factors in phase I were older age (relative risk RR, 1.6; P = .006), longer crossclamp time (RR, 1.3; P = .001), and mitral valve procedure (RR, 2.5; P = .0001). In phase II, these were older age (RR, 3.0; P < .0001), greater weight (RR, 1.6; P < .0001), and Caucasian race (RR, 2.5; P = .006). For patients receiving a mitral valve procedure, the risk for postoperative atrial fibrillation in phase II was higher and remained elevated for as long as 9 days postoperatively in comparison with isolated coronary artery bypass grafting, for which the risk returned to near baseline by postoperative day 6. Conclusions Phase I and phase II periods are associated with distinct risk factors; therefore, it is likely that the mechanisms of postoperative atrial fibrillation change over time.
Chaste - Cancer, Heart And Soft Tissue Environment - is an open source C++ library for the computational simulation of mathematical models developed for physiology and biology. Code development has ...been driven by two initial applications: cardiac electrophysiology and cancer development. A large number of cardiac electrophysiology studies have been enabled and performed, including high-performance computational investigations of defibrillation on realistic human cardiac geometries. New models for the initiation and growth of tumours have been developed. In particular, cell-based simulations have provided novel insight into the role of stem cells in the colorectal crypt. Chaste is constantly evolving and is now being applied to a far wider range of problems. The code provides modules for handling common scientific computing components, such as meshes and solvers for ordinary and partial differential equations (ODEs/PDEs). Re-use of these components avoids the need for researchers to 're-invent the wheel' with each new project, accelerating the rate of progress in new applications. Chaste is developed using industrially-derived techniques, in particular test-driven development, to ensure code quality, re-use and reliability. In this article we provide examples that illustrate the types of problems Chaste can be used to solve, which can be run on a desktop computer. We highlight some scientific studies that have used or are using Chaste, and the insights they have provided. The source code, both for specific releases and the development version, is available to download under an open source Berkeley Software Distribution (BSD) licence at http://www.cs.ox.ac.uk/chaste, together with details of a mailing list and links to documentation and tutorials.
Objective Lung cancer is the leading cause of cancer death in North America. Low-dose computed tomography screening can reduce lung cancer–specific mortality by 20%. Method The American Association ...for Thoracic Surgery created a multispecialty task force to create screening guidelines for groups at high risk of developing lung cancer and survivors of previous lung cancer. Results The American Association for Thoracic Surgery guidelines call for annual lung cancer screening with low-dose computed tomography screening for North Americans from age 55 to 79 years with a 30 pack-year history of smoking. Long-term lung cancer survivors should have annual low-dose computed tomography to detect second primary lung cancer until the age of 79 years. Annual low-dose computed tomography lung cancer screening should be offered starting at age 50 years with a 20 pack-year history if there is an additional cumulative risk of developing lung cancer of 5% or greater over the following 5 years. Lung cancer screening requires participation by a subspecialty-qualified team. The American Association for Thoracic Surgery will continue engagement with other specialty societies to refine future screening guidelines. Conclusions The American Association for Thoracic Surgery provides specific guidelines for lung cancer screening in North America.
We assess climate impacts of global warming using ongoing observations and paleoclimate data. We use Earth's measured energy imbalance, paleoclimate data, and simple representations of the global ...carbon cycle and temperature to define emission reductions needed to stabilize climate and avoid potentially disastrous impacts on today's young people, future generations, and nature. A cumulative industrial-era limit of ∼500 GtC fossil fuel emissions and 100 GtC storage in the biosphere and soil would keep climate close to the Holocene range to which humanity and other species are adapted. Cumulative emissions of ∼1000 GtC, sometimes associated with 2°C global warming, would spur "slow" feedbacks and eventual warming of 3-4°C with disastrous consequences. Rapid emissions reduction is required to restore Earth's energy balance and avoid ocean heat uptake that would practically guarantee irreversible effects. Continuation of high fossil fuel emissions, given current knowledge of the consequences, would be an act of extraordinary witting intergenerational injustice. Responsible policymaking requires a rising price on carbon emissions that would preclude emissions from most remaining coal and unconventional fossil fuels and phase down emissions from conventional fossil fuels.
Knowledge of species distribution is critical to ecological management and conservation biology. Effective management requires the detection of populations, which can sometimes be at low densities ...and is usually based on visual detection and counting. Recently, there has been considerable interest in the detection of short species‐specific environmental DNA (eDNA) fragments to allow aquatic species monitoring within different environments due to the potential of greater sensitivity over traditional survey methods which can be time‐consuming and costly. Environmental DNA analysis is increasingly being used in the detection of rare or invasive species and has also been applied to eDNA persistence studies and estimations of species biomass and distribution. When combined with next‐generation sequencing methods, it has been demonstrated that entire faunas can be identified. Different environments require different sampling methodologies, but there remain areas where laboratory methodologies could be standardized to allow results to be compared across studies. Synthesis and applications. We review recently published studies that use eDNA to monitor aquatic populations, discuss the methodologies used and the application of eDNA analysis as a survey tool in ecology. We include innovative ideas for how eDNA can be used for conservation and management citing test cases, for instance, the potential for on‐site analyses, including the application of eDNA analysis to carbon nanotube platforms or laser transmission spectroscopy to facilitate rapid on‐site detections. The use of eDNA monitoring is already being adopted in the UK for ecological surveys.
Ceftriaxone increases expression of the astrocytic glutamate transporter, EAAT2, which might protect from glutamate-mediated excitotoxicity. A trial using a novel three stage nonstop design, ...incorporating Phases I-III, tested ceftriaxone in ALS. Stage 1 determined the cerebrospinal fluid pharmacokinetics of ceftriaxone in subjects with ALS. Stage 2 evaluated safety and tolerability for 20-weeks. Analysis of the pharmacokinetics, tolerability, and safety was used to determine the ceftriaxone dosage for Stage 3 efficacy testing.
In Stage 1, 66 subjects at ten clinical sites were enrolled and randomized equally into three study groups receiving intravenous placebo, ceftriaxone 2 grams daily or ceftriaxone 4 grams daily divided BID. Participants provided serum and cerebrospinal fluid for pharmacokinetic analysis on study day 7. Participants continued their assigned treatment in Stage 2. The Data and Safety Monitoring Board (DSMB) reviewed the data after the last participants completed 20 weeks on study drug.
Stage 1 analysis revealed linear pharmacokinetics, and CSF trough levels for both dosage levels exceeding the pre-specified target trough level of 1 µM (0.55 µg/mL). Tolerability (Stages 1 and 2) results showed that ceftriaxone at dosages up to 4 grams/day was well tolerated at 20 weeks. Biliary adverse events were more common with ceftriaxone but not dose-dependent and improved with ursodeoxycholic (ursodiol) therapy.
The goals of Stages 1 and 2 of the ceftriaxone trial were successfully achieved. Based on the pre-specified decision rules, the DSMB recommended the use of ceftriaxone 4 g/d (divided BID) for Stage 3, which recently closed.
ClinicalTrials.gov NCT00349622.
A main determinant of prolonged Trypanosoma brucei infection and transmission and success of the parasite is the interplay between host acquired immunity and antigenic variation of the parasite ...variant surface glycoprotein (VSG) coat. About 0.1% of trypanosome divisions produce a switch to a different VSG through differential expression of an archive of hundreds of silent VSG genes and pseudogenes, but the patterns and extent of the trypanosome diversity phenotype, particularly in chronic infection, are unclear. We applied longitudinal VSG cDNA sequencing to estimate variant richness and test whether pseudogenes contribute to antigenic variation. We show that individual growth peaks can contain at least 15 distinct variants, are estimated computationally to comprise many more, and that antigenically distinct 'mosaic' VSGs arise from segmental gene conversion between donor VSG genes or pseudogenes. The potential for trypanosome antigenic variation is probably much greater than VSG archive size; mosaic VSGs are core to antigenic variation and chronic infection.
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