Causality and the Interpretation of Epidemiologic Evidence

There is an ongoing debate regarding how and when an agent’s or determinant’s impact can be interpreted as causation with respect to some target disease. The so-called criteria of causation, originating from the seminal work of Sir Austin Bradford Hill and Mervyn Susser, are often schematically applied disregarding the fact that they were meant neither as criteria nor as a checklist for attributing to a hazard the potential of disease causation. Furthermore, there is a tendency to misinterpret the lack of evidence for causation as evidence for lack of a causal relation. There are no criteria in the strict sense for the assessment of evidence concerning an agent’s or determinant’s propensity to cause a disease, nor are there criteria to dismiss the notion of causation. Rather, there is a discursive process of conjecture and refutation. In this commentary, I propose a dialogue approach for the assessment of an agent or determinant. Starting from epidemiologic evidence, four issues need to be addressed: temporal relation, association, environmental equivalence, and population equivalence. If there are no valid counterarguments, a factor is attributed the potential of disease causation. More often than not, there will be insufficient evidence from epidemiologic studies. In these cases, other evidence can be used instead that increases or decreases confidence in a factor being causally related to a disease. Even though every verdict of causation is provisional, action must not be postponed until better evidence is available if our present knowledge appears to demand immediate measures for health protection

Regulation of vascular smooth muscle cell bioenergetic function by protein glutathiolation

AbstractProtein thiolation by glutathione is a reversible and regulated post-translational modification that is increased in response to oxidants and nitric oxide. Because many mitochondrial enzymes contain critical thiol residues, it has been hypothesized that thiolation reactions regulate cell metabolism and survival. However, it has been difficult to differentiate the biological effects due to protein thiolation from other oxidative protein modifications. In this study, we used diamide to titrate protein glutathiolation and examined its impact on glycolysis, mitochondrial function, and cell death in rat aortic smooth muscle cells. Treatment of cells with diamide increased protein glutathiolation in a concentration-dependent manner and had comparably little effect on protein–protein disulfide formation. Diamide increased mitochondrial proton leak and decreased ATP-linked mitochondrial oxygen consumption and cellular bioenergetic reserve capacity. Concentrations of diamide above 200 μM promoted acute bioenergetic failure and caused cell death, whereas lower concentrations of diamide led to a prolonged increase in glycolytic flux and were not associated with loss of cell viability. Depletion of glutathione using buthionine sulfoximine had no effect on basal protein thiolation or cellular bioenergetics but decreased diamide-induced protein glutathiolation and sensitized the cells to bioenergetic dysfunction and death. The effects of diamide on cell metabolism and viability were fully reversible upon addition of dithiothreitol. These data suggest that protein thiolation modulates key metabolic processes in both the mitochondria and cytosol

Metabolic Mechanisms of Exercise-Induced Cardiac Remodeling

Exercise has a myriad of physiological benefits that derive in part from its ability to improve cardiometabolic health. The periodic metabolic stress imposed by regular exercise appears fundamental in driving cardiovascular tissue adaptation. However, different types, intensities, or durations of exercise elicit different levels of metabolic stress and may promote distinct types of tissue remodeling. In this review, we discuss how exercise affects cardiac structure and function and how exercise-induced changes in metabolism regulate cardiac adaptation. Current evidence suggests that exercise typically elicits an adaptive, beneficial form of cardiac remodeling that involves cardiomyocyte growth and proliferation; however, chronic levels of extreme exercise may increase the risk for pathological cardiac remodeling or sudden cardiac death. An emerging theme underpinning acute as well as chronic cardiac adaptations to exercise is metabolic periodicity, which appears important for regulating mitochondrial quality and function, for stimulating metabolism-mediated exercise gene programs and hypertrophic kinase activity, and for coordinating biosynthetic pathway activity. In addition, circulating metabolites liberated during exercise trigger physiological cardiac growth. Further understanding of how exercise-mediated changes in metabolism orchestrate cell signaling and gene expression could facilitate therapeutic strategies to maximize the benefits of exercise and improve cardiac health

Childhood body weight in relation to morbidity from cardiovascular disease and cancer in older adulthood: 67-year follow-up of participants in the 1947 Scottish Mental Survey.

Although it has been well documented that elevated body weight in middle- and older-aged populations is associated with multiple morbidities, the influence of childhood body weight on health endpoints other than coronary heart disease is not well understood. Accordingly, using a subsample of 4,620 participants (2,288 women) from the Scottish Mental Survey of 1947, we examined the association between body mass index measured at 11 years of age and future risk of 9 independent health endpoints as ascertained from national hospital admissions and cancer registers until 2014 (up to age 77 years). Although there was some evidence of a relationship between elevated childhood body mass index and higher rates of peripheral vascular disease (per each 1-standard deviation increase in body mass index, hazard ratio = 1.21, 95% confidence interval: 1.07, 1.37) and smoking-related cancers (per each 1-standard deviation increase in body mass index, hazard ratio = 1.09, 95% confidence interval: 1.01, 1.17), there was no apparent association with coronary heart disease, stroke (including ischemic stroke), heart failure, or carcinomas of the colorectum, stomach, lung, prostate, or breast. In conclusion, a relationship between childhood body weight and later morbidity was largely lacking in the present study

Aluminium and fluoride in drinking water in relation to later dementia risk

BACKGROUND: Environmental risk factors for dementia are poorly understood. Aluminium and fluorine in drinking water have been linked with dementia but uncertainties remain about this relationship. AIMS: In the largest longitudinal study in this context, we set out to explore the individual effect of aluminium and fluoride in drinking water on dementia risk and, as fluorine can increase absorption of aluminium, we also examine any synergistic influence on dementia. METHOD: We used Cox models to investigate the association between mean aluminium and fluoride levels in drinking water at their residential location (collected 2005–2012 by the Drinking Water Quality Regulator for Scotland) with dementia in members of the Scottish Mental Survey 1932 cohort who were alive in 2005. RESULTS: A total of 1972 out of 6990 individuals developed dementia by the linkage date in 2012. Dementia risk was raised with increasing mean aluminium levels in women (hazard ratio per s.d. increase 1.09, 95% CI 1.03–1.15, P < 0.001) and men (1.12, 95% CI 1.03–1.21, P = 0.004). A dose-response pattern of association was observed between mean fluoride levels and dementia in women (1.34, 95% CI 1.28–1.41, P < 0.001) and men (1.30, 95% CI 1.22–1.39, P < 0.001), with dementia risk more than doubled in the highest quartile compared with the lowest. There was no statistical interaction between aluminium and fluoride levels in relation with dementia. CONCLUSIONS: Higher levels of aluminium and fluoride were related to dementia risk in a population of men and women who consumed relatively low drinking-water levels of both. DECLARATION OF INTEREST: NONE

Metabolic remodeling of white adipose tissue in obesity

Adipose tissue metabolism is a critical regulator of adiposity and whole body energy expenditure; however, metabolic changes that occur in white adipose tissue (WAT) with obesity remain unclear. The purpose of this study was to understand the metabolic and bioenergetic changes occurring in WAT with obesity. Wild-type (C57BL/6J) mice fed a high-fat diet (HFD) showed significant increases in whole body adiposity, had significantly lower V̇o2, V̇co2, and respiratory exchange ratios, and demonstrated worsened glucose and insulin tolerance compared with low-fat-fed mice. Metabolomic analysis of WAT showed marked changes in lipid, amino acid, carbohydrate, nucleotide, and energy metabolism. Tissue levels of succinate and malate were elevated, and metabolites that could enter the Krebs cycle via anaplerosis were mostly diminished in high-fat-fed mice, suggesting altered mitochondrial metabolism. Despite no change in basal oxygen consumption or mitochondrial DNA abundance, citrate synthase activity was decreased by more than 50%, and responses to FCCP were increased in WAT from mice fed a high-fat diet. Moreover, Pgc1a was downregulated and Cox7a1 upregulated after 6 wk of HFD. After 12 wk of high-fat diet, the abundance of several proteins in the mitochondrial respiratory chain or matrix was diminished. These changes were accompanied by increased Parkin and Pink1, decreased p62 and LC3-I, and ultrastructural changes suggestive of autophagy and mitochondrial remodeling. These studies demonstrate coordinated restructuring of metabolism and autophagy that could contribute to the hypertrophy and whitening of adipose tissue in obesity

Quantifying the age structure of free-ranging delphinid populations : testing the accuracy of Unoccupied Aerial System photogrammetry

This study was funded by NOAA-PIFSC and RCUH JIMAR (NA19NMF4720181, NA16NMF4320058), CIMAR (NA21NMF4320043), and the Office of Naval Research (N000142012624).Understanding the population health status of long-lived and slow-reproducing species is critical for their management. However, it can take decades with traditional monitoring techniques to detect population-level changes in demographic parameters. Early detection of the effects of environmental and anthropogenic stressors on vital rates would aid in forecasting changes in population dynamics and therefore inform management efforts. Changes in vital rates strongly correlate with deviations in population growth, highlighting the need for novel approaches that can provide early warning signs of population decline (e.g., changes in age structure). We tested a novel and frequentist approach, using Unoccupied Aerial System (UAS) photogrammetry, to assess the population age structure of small delphinids. First, we measured the precision and accuracy of UAS photogrammetry in estimating total body length (TL) of trained bottlenose dolphins (Tursiops truncatus). Using a log-transformed linear model, we estimated TL using the blowhole to dorsal fin distance (BHDF) for surfacing animals. To test the performance of UAS photogrammetry to age-classify individuals, we then used length measurements from a 35-year dataset from a free-ranging bottlenose dolphin community to simulate UAS estimates of BHDF and TL. We tested five age classifiers and determined where young individuals (Publisher PDFPeer reviewe

P-rex1 cooperates with PDGFRβ to drive cellular migration in 3D microenvironments

Expression of the Rac-guanine nucleotide exchange factor (RacGEF), P-Rex1 is a key determinant of progression to metastasis in a number of human cancers. In accordance with this proposed role in cancer cell invasion and metastasis, we find that ectopic expression of P-Rex1 in an immortalised human fibroblast cell line is sufficient to drive multiple migratory and invasive phenotypes. The invasive phenotype is greatly enhanced by the presence of a gradient of serum or platelet-derived growth factor, and is dependent upon the expression of functional PDGF receptor β. Consistently, the invasiveness of WM852 melanoma cells, which endogenously express P-Rex1 and PDGFRβ, is opposed by siRNA of either of these proteins. Furthermore, the current model of P-Rex1 activation is advanced through demonstration of P-Rex1 and PDGFRβ as components of the same macromolecular complex. These data suggest that P-Rex1 has an influence on physiological migratory processes, such as invasion of cancer cells, both through effects upon classical Rac1-driven motility and a novel association with RTK signalling complexes

Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation.

Fibroblast to myofibroblast differentiation is crucial for the initial healing response but excessive myofibroblast activation leads to pathological fibrosis. Therefore, it is imperative to understand the mechanisms underlying myofibroblast formation. Here we report that mitochondrial calcium (mCa2+) signaling is a regulatory mechanism in myofibroblast differentiation and fibrosis. We demonstrate that fibrotic signaling alters gating of the mitochondrial calcium uniporter (mtCU) in a MICU1-dependent fashion to reduce mCa2+ uptake and induce coordinated changes in metabolism, i.e., increased glycolysis feeding anabolic pathways and glutaminolysis yielding increased α-ketoglutarate (αKG) bioavailability. mCa2+-dependent metabolic reprogramming leads to the activation of αKG-dependent histone demethylases, enhancing chromatin accessibility in loci specific to the myofibroblast gene program, resulting in differentiation. Our results uncover an important role for the mtCU beyond metabolic regulation and cell death and demonstrate that mCa2+ signaling regulates the epigenome to influence cellular differentiation

A translational framework for public health research

&lt;p&gt;&lt;b&gt;Background&lt;/b&gt;&lt;/p&gt; &lt;p&gt;The paradigm of translational medicine that underpins frameworks such as the Cooksey report on the funding of health research does not adequately reflect the complex reality of the public health environment. We therefore outline a translational framework for public health research.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Discussion&lt;/b&gt;&lt;/p&gt; &lt;p&gt;Our framework redefines the objective of translation from that of institutionalising effective interventions to that of improving population health by influencing both individual and collective determinants of health. It incorporates epidemiological perspectives with those of the social sciences, recognising that many types of research may contribute to the shaping of policy, practice and future research. It also identifies a pivotal role for evidence synthesis and the importance of non-linear and intersectoral interfaces with the public realm.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Summary&lt;/b&gt;&lt;/p&gt; &lt;p&gt;We propose a research agenda to advance the field and argue that resources for 'applied' or 'translational' public health research should be deployed across the framework, not reserved for 'dissemination' or 'implementation'.&lt;/p&gt