Association of Resistance Exercise, Independent of and Combined With Aerobic Exercise, With the Incidence of Metabolic Syndrome.

OBJECTIVE: To determine the association of resistance exercise, independent of and combined with aerobic exercise, with the risk of development of metabolic syndrome (MetS). PATIENTS AND METHODS: The study cohort included adults (mean ± SD age, 46±9.5 years) who received comprehensive medical examinations at the Cooper Clinic in Dallas, Texas, between January 1, 1987, and December, 31, 2006. Exercise was assessed by self-reported frequency and minutes per week of resistance and aerobic exercise and meeting the US Physical Activity Guidelines (resistance exercise ≥2 d/wk; aerobic exercise ≥500 metabolic equivalent min/wk) at baseline. The incidence of MetS was based on the National Cholesterol Education Program Adult Treatment Panel III criteria. We used Cox regression to generate hazard ratios (HRs) and 95% CIs. RESULTS: Among 7418 participants, 1147 (15%) had development of MetS during a median follow-up of 4 years (maximum, 19 years; minimum, 0.1 year). Meeting the resistance exercise guidelines was associated with a 17% lower risk of MetS (HR, 0.83; 95% CI, 0.73-0.96; P=.009) after adjusting for potential confounders and aerobic exercise. Further, less than 1 hour of weekly resistance exercise was associated with 29% lower risk of development of MetS (HR, 0.71; 95% CI, 0.56-0.89; P=.003) compared with no resistance exercise. However, larger amounts of resistance exercise did not provide further benefits. Individuals meeting both recommended resistance and aerobic exercise guidelines had a 25% lower risk of development of MetS (HR, 0.75; 95% CI, 0.63-0.89; P<.001) compared with meeting neither guideline. CONCLUSION: Participating in resistance exercise, even less than 1 hour per week, was associated with a lower risk of development of MetS, independent of aerobic exercise. Health professionals should recommend that patients perform resistance exercise along with aerobic exercise to reduce MetS

Impact of COVID-19 lockdown on physical activity and sedentary behaviour in Dutch cardiovascular disease patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) lockdown restrictions may impact lifestyle and therefore also physical (in)activity patterns in patients with cardiovascular disease (CVD). This study aimed to evaluate the effect of lockdown on physical activity and sedentary behaviour. METHODS: A total of 1565 Dutch CVD patients participated in this prospective cohort study, in which we compared physical activity and sedentary behaviour before and during the COVID-19 lockdown period. Baseline measures were assessed in 2018 and data on follow-up measures were collected between 17 and 24 April 2020 (5 weeks after the introduction of COVID-19 lockdown restrictions). Validated questionnaires were used to assess physical activity and sedentary behaviour. RESULTS: Moderate-to-vigorous physical activities increased from 1.6 (0.9, 2.8) to 2.0 (1.0, 3.5) h/day [median (interquartile range)] (p < 0.001) during the COVID-19 lockdown, mainly due to an increase in time spent walking and doing odd jobs. In contrast, time spent exercising significantly declined [1.0 (0.0, 2.3) to 0.0 (0.0, 0.6) h/week], whereas sedentary time increased from 7.8 (6.1, 10.4) to 8.9 (6.8, 11.4) h/day (p < 0.001). The absolute increase in physical activity was 13 (-36, 81) min/day, whereas sedentary behaviour increased by 55 (-72, 186) min/day. CONCLUSION: Despite a small increase in physical activities, the larger increase in sedentary time induced a net reduction in habitual physical activity levels in Dutch CVD patients during the first-wave COVID-19 lockdown. Since a more inactive lifestyle is strongly associated with disease progression and mortality, we encourage CVD patients and their caregivers to explore novel solutions to increase physical activity levels and reduce sedentary time during (and beyond) the COVID-19 pandemic

Exercise-Induced Cardiac Troponin I Increase and Incident Mortality and Cardiovascular Events.

BACKGROUND: Blood concentrations of cardiac troponin above the 99th percentile are a key criterion for the diagnosis of acute myocardial injury and infarction. Troponin concentrations, even below the 99th percentile, predict adverse outcomes in patients and the general population. Elevated troponin concentrations are commonly observed after endurance exercise, but the clinical significance of this increase is unknown. We examined the association between postexercise troponin I concentrations and clinical outcomes in longdistance walkers. METHODS: We measured cardiac troponin I concentrations in 725 participants (61 [54–69] yrs) before and immediately after 30 to 55 km of walking. We tested for an association between postexercise troponin I concentrations above the 99th percentile (>0.040 µg/L) and a composite end point of all-cause mortality and major adverse cardiovascular events (myocardial infarction, stroke, heart failure, revascularization, or sudden cardiac arrest). Continuous variables were reported as mean ± standard deviation when normally distributed or median [interquartile range] when not normally distributed. RESULTS: Participants walked 8.3 [7.3–9.3] hours at 68±10% of their maximum heart rate. Baseline troponin I concentrations were >0.040 µg/L in 9 participants (1%). Troponin I concentrations increased after walking (P0.040 µg/L. During 43 [23–77] months of follow-up, 62 participants (9%) experienced an end point; 29 died and 33 had major adverse cardiovascular events. Compared with 7% with postexercise troponin I ≤0.040 µg/L (log-rank P0.040 µg/L experienced an end point. The hazard ratio was 2.48 (95% CI, 1.29–4.78) after adjusting for age, sex, cardiovascular risk factors (hypertension, hypercholesterolemia or diabetes mellitus), cardiovascular diseases (myocardial infarction, stroke, or heart failure), and baseline troponin I concentrations. CONCLUSIONS: Exercise-induced troponin I elevations above the 99th percentile after 30 to 55 km of walking independently predicted higher mortality and cardiovascular events in a cohort of older long-distance walkers. Exercise-induced increases in troponin may not be a benign physiological response to exercise, but an early marker of future mortality and AQ3 cardiovascular events

Balancing Selection at the Tomato RCR3 Guardee Gene Family Maintains Variation in Strength of Pathogen Defense

Coevolution between hosts and pathogens is thought to occur between interacting molecules of both species. This results in the maintenance of genetic diversity at pathogen antigens (or so-called effectors) and host resistance genes such as the major histocompatibility complex (MHC) in mammals or resistance (R) genes in plants. In plant-pathogen interactions, the current paradigm posits that a specific defense response is activated upon recognition of pathogen effectors via interaction with their corresponding R proteins. According to the''Guard-Hypothesis,'' R proteins (the ``guards'') can sense modification of target molecules in the host (the ``guardees'') by pathogen effectors and subsequently trigger the defense response. Multiple studies have reported high genetic diversity at R genes maintained by balancing selection. In contrast, little is known about the evolutionary mechanisms shaping the guardee, which may be subject to contrasting evolutionary forces. Here we show that the evolution of the guardee RCR3 is characterized by gene duplication, frequent gene conversion, and balancing selection in the wild tomato species Solanum peruvianum. Investigating the functional characteristics of 54 natural variants through in vitro and in planta assays, we detected differences in recognition of the pathogen effector through interaction with the guardee, as well as substantial variation in the strength of the defense response. This variation is maintained by balancing selection at each copy of the RCR3 gene. Our analyses pinpoint three amino acid polymorphisms with key functional consequences for the coevolution between the guardee (RCR3) and its guard (Cf-2). We conclude that, in addition to coevolution at the ``guardee-effector'' interface for pathogen recognition, natural selection acts on the ``guard-guardee'' interface. Guardee evolution may be governed by a counterbalance between improved activation in the presence and prevention of auto-immune responses in the absence of the corresponding pathogen

[Patients on the move: validated methods to quantify physical activity].

Physical activity is an important component in the maintenance and improvement of general health; physical inactivity is, however, an increasing problem in the Netherlands. Requests for advice on physical activity are increasing within the healthcare. Assessment of an individual's physical activity pattern is required to provide tailored advice. There are a number of methods for measuring physical activity; these are divided into subjective and objective methods. Subjective measures include physical activity questionnaires and diaries. Objective measures include indirect calorimetry, measurement with doubly labelled water, heart-rate monitoring and the use of an accelerometer or pedometer. The choice of method depends predominantly on the aim of the measurement, and the availability of personnel, time and financial resources. In clinical practice a validated questionnaire is usually the preferred method, but when measuring effects this should be combined with an objective measurement instrument

Multimodal Treatment Eliminates Cancer Stem Cells and Leads to Long-Term Survival in Primary Human Pancreatic Cancer Tissue Xenografts.

Copyright: 2013 Hermann et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.PURPOSE: In spite of intense research efforts, pancreatic ductal adenocarcinoma remains one of the most deadly malignancies in the world. We and others have previously identified a subpopulation of pancreatic cancer stem cells within the tumor as a critical therapeutic target and additionally shown that the tumor stroma represents not only a restrictive barrier for successful drug delivery, but also serves as a paracrine niche for cancer stem cells. Therefore, we embarked on a large-scale investigation on the effects of combining chemotherapy, hedgehog pathway inhibition, and mTOR inhibition in a preclinical mouse model of pancreatic cancer. EXPERIMENTAL DESIGN: Prospective and randomized testing in a set of almost 200 subcutaneous and orthotopic implanted whole-tissue primary human tumor xenografts. RESULTS: The combined targeting of highly chemoresistant cancer stem cells as well as their more differentiated progenies, together with abrogation of the tumor microenvironment by targeting the stroma and enhancing tissue penetration of the chemotherapeutic agent translated into significantly prolonged survival in preclinical models of human pancreatic cancer. Most pronounced therapeutic effects were observed in gemcitabine-resistant patient-derived tumors. Intriguingly, the proposed triple therapy approach could be further enhanced by using a PEGylated formulation of gemcitabine, which significantly increased its bioavailability and tissue penetration, resulting in a further improved overall outcome. CONCLUSIONS: This multimodal therapeutic strategy should be further explored in the clinical setting as its success may eventually improve the poor prognosis of patients with pancreatic ductal adenocarcinoma

On the solution of differential-algebraic equations through gradient flow embedding

In this paper Gradient Flow methods are used to solve systems of differential-algebraic equations via a novel reformulation strategy, focusing on the solution of index-1 differential-algebraic equation systems. A reformulation is first effected on semi-explicit index-1 differential-algebraic equation systems, which casts them as pure ordinary differential equation systems subject to an embedded pointwise least-squares problem. This is then formulated as a gradient flow optimization problem. Rigorous proofs for this novel scheme are provided for asymptotic and epsilon convergence. The computational results validate the predictions of the effectiveness of the proposed approach, with efficient and accurate solutions obtained for the case studies considered. Beyond the theoretical and practical value for the solution of DAE systems as pure ODE ones, the methodology is expected to have an impact in similar cases where an ODE system is subjected to algebraic constraints, such as the Hamiltonian necessary conditions of optimality in optimal control problems.Author E. A. del Rio-Chanona would like to acknowledge CONACyT scholarship No. 522530 for funding this project

Absence of Fitness Improvement Is Associated with Outcomes in Heart Failure Patients.

PURPOSE: To examine the clinical impact of cardiorespiratory fitness (CRF) and improvements in CRF after cardiac rehabilitation (CR) in heart failure (HF) patients for their risk of all-cause mortality and unplanned hospitalization. Secondly, to investigate possible factors associated with the absence of improvement in CRF after rehabilitation. METHODS: We included 155 HF patients receiving CR between October 2009 and January 2015. Patients performed an incremental bicycle test to assess CRF through peak oxygen uptake (VO2-peak) before and after CR-based supervised exercise training. Patients were classified as responders or non-responders based on pre-to-post CR changes in VO2-peak (≥6% and <6%, respectively). Cox proportional hazards models evaluated all-cause mortality and unplanned hospitalization during 5 years of follow-up. Patient characteristics, HF features and co-morbidities were used to predict changes in VO2-peak using logistic regression analysis. RESULTS: Seventy HF patients (45%) were classified as responder. Non-responders had a significantly higher risk of all-cause mortality or hospitalization (HR = 2.15, 95% CI = 1.17-3.94) compared to responders. This was even higher in non-responders with low CRF at baseline (HR = 4.88, 95% CI = 1.71-13.93). Factors associated with non-response to CR were age (OR = 1.07/year, 95% CI = 1.03-1.11), baseline VO2-peak (OR = 1.16/ml/min/kg, 95% CI = 1.06-1.26) and adherence to CR (OR = 0.98/percentage, 95% CI = 0.96-0.998). CONCLUSION: Independent from baseline CRF, the inability to improve VO2-peak by CR doubled the risk of death or unplanned hospitalization. The combination of lower baseline CRF and non-response was associated with even poorer clinical outcomes. Especially older HF patients with higher baseline VO2-peak and lower adherence have a higher probability of becoming a non-responder

Dynamic Modelling under Uncertainty: The Case of Trypanosoma brucei Energy Metabolism

Kinetic models of metabolism require detailed knowledge of kinetic parameters. However, due to measurement errors or lack of data this knowledge is often uncertain. The model of glycolysis in the parasitic protozoan Trypanosoma brucei is a particularly well analysed example of a quantitative metabolic model, but so far it has been studied with a fixed set of parameters only. Here we evaluate the effect of parameter uncertainty. In order to define probability distributions for each parameter, information about the experimental sources and confidence intervals for all parameters were collected. We created a wiki-based website dedicated to the detailed documentation of this information: the SilicoTryp wiki (http://silicotryp.ibls.gla.ac.uk/wiki/Glycolysis). Using information collected in the wiki, we then assigned probability distributions to all parameters of the model. This allowed us to sample sets of alternative models, accurately representing our degree of uncertainty. Some properties of the model, such as the repartition of the glycolytic flux between the glycerol and pyruvate producing branches, are robust to these uncertainties. However, our analysis also allowed us to identify fragilities of the model leading to the accumulation of 3-phosphoglycerate and/or pyruvate. The analysis of the control coefficients revealed the importance of taking into account the uncertainties about the parameters, as the ranking of the reactions can be greatly affected. This work will now form the basis for a comprehensive Bayesian analysis and extension of the model considering alternative topologies

Association between sedentary time and cognitive function: A focus on different domains of sedentary behavior.

Studies which examined the association between sedentary behavior (SB) and cognitive function have presented equivocal findings. Mentally active/inactive sedentary domains may relate differently to cognitive function. We examined associations between SB and cognitive function, specifically focusing on different domains. Participants were recruited from the Nijmegen Exercise Study 2018 in the Netherlands. SB (hours/day) was measured with the Sedentary Behavior Questionnaire. Cognitive function was assessed with a validated computer self-test (COST-A), and a z-score calculated for global cognitive function. Multivariate linear regression assessed associations between tertiles of sedentary time and cognitive function. Cognition tests were available from 2821 participants, complete data from 2237 participants (43% female), with a median age of 61 [IQR 52-67] and a mean sedentary time of 8.3 ± 3.2 h/day. In fully adjusted models, cognitive function was significantly better in participants with the highest total sedentary time (0.07 [95% CI 0.02-0.12], P = 0.01), work-related sedentary time (0.13 [95% CI 0.07-0.19], P  0.05). We found a strong, independent positive association between total SB and cognitive function in a heterogenous population. This relation was not consistent across different domains, with especially work- and computer-related SB being positively associated with cognitive function. This highlights the importance of assessing the various sedentary domains in understanding the relation between sedentary time and cognitive function