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

Late Lessons from Early Warnings: Toward Realism and Precaution with Endocrine-Disrupting Substances

The histories of selected public and environmental hazards, from the first scientifically based early warnings about potential harm to the subsequent precautionary and preventive measures, have been reviewed by the European Environment Agency. This article relates the “late lessons” from these early warnings to the current debates on the application of the precautionary principle to the hazards posed by endocrine-disrupting substances (EDSs). Here, I summarize some of the definitional and interpretative issues that arise. These issues include the contingent nature of knowledge; the definitions of precaution, prevention, risk, uncertainty, and ignorance; the use of differential levels of proof; and the nature and main direction of the methodological and cultural biases within the environmental health sciences. It is argued that scientific methods need to reflect better the realities of multicausality, mixtures, timing of dose, and system dynamics, which characterize the exposures and impacts of EDSs. This improved science could provide a more robust basis for the wider and wise use of the precautionary principle in the assessment and management of the threats posed by EDSs. The evaluation of such scientific evidence requires assessments that also account for multicausal reality. Two of the often used, and sometimes misused, Bradford Hill “criteria,” consistency and temporality, are critically reviewed in light of multicausality, thereby illustrating the need to review all of the criteria in light of 40 years of progress in science and policymaking

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

Abrupt transition to heightened poliomyelitis epidemicity in England and Wales, 1947–1957, associated with a pronounced increase in the geographical rate of disease propagation

The abrupt transition to heightened poliomyelitis epidemicity in England and Wales, 1947–1957, was associated with a profound change in the spatial dynamics of the disease. Drawing on the complete record of poliomyelitis notifications in England and Wales, we use a robust method of spatial epidemiological analysis (swash-backwash model) to evaluate the geographical rate of disease propagation in successive poliomyelitis seasons, 1940–1964. Comparisons with earlier and later time periods show that the period of heightened poliomyelitis epidemicity corresponded with a sudden and pronounced increase in the spatial rate of disease propagation. This change was observed for both urban and rural areas and points to an abrupt enhancement in the propensity for the geographical spread of polioviruses. Competing theories of the epidemic emergence of poliomyelitis in England and Wales should be assessed in the light of this evidence

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

A new conceptual framework for revenge firesetting

Revenge has frequently been acknowledged to account for a relatively large proportion of motives in deliberate firesetting. However, very little is actually known about the aetiology of revenge firesetting. Theoretical approaches to revenge-seeking behaviour are discussed. A brief review of how revenge is accounted for in existing theoretical explanations of deliberate firesetting and the known characteristics of revenge firesetters are provided. On this basis, the authors suggest, as a motive, revenge firesetting has to date been misconceptualised. A new conceptual framework is thus proposed, paying particular attention to the contextual, affective, cognitive, volitional and behavioural factors which may influence and generate a single episode of revenge firesetting. Treatment implications and suggestions for future research are also provided

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

<p><b>Background</b></p> <p>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.</p> <p><b>Discussion</b></p> <p>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.</p> <p><b>Summary</b></p> <p>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'.</p&gt