C-reactive protein as a risk factor versus risk marker

PURPOSE OF REVIEW: C-reactive protein (CRP) is consistently associated with cardiovascular disease in prospective and cross-sectional clinical and epidemiological studies. Inflammation is an important mechanism in cardiovascular disease, and the plasma level of CRP is considered to reflect the inflammatory condition of the patient and/or the vessel wall. In addition, there are also a number of indications for a causal role of CRP in cardiovascular disease. RECENT FINDINGS: A number of new publications show potential causal effects of CRP on cardiovascular disease, and evidence from human-CRP transgenic animals also indicates a causal contribution of CRP to cardiovascular disease. On the other hand, a new large prospective study and an updated meta-analysis indicate that the contribution of CRP to cardiovascular disease is less impressive than reported earlier (odds ratio, 1.58; 95% confidence interval, 1.48-1.68). SUMMARY: We review here the most recent evidence on mechanisms by which CRP is involved as a causal factor in the precipitation of cardiovascular disease. Evidence for such a role is accumulating.     

Neutron versus Á-ray risk estimates

While it is recognized that neutrons contributed to the excess cancer incidence and mortality among the atomic bomb survivors in Hiroshima, there is no possibility to deduce the magnitude of this contribution from the data. This remains true even if the neutron doses in the dosimetry system DS86 are corrected upwards in line with recent neutron activation measurements. In spite of this fact, important information can be obtained in the form of an inverse relation of the risk coefficients for γ-rays and neutrons. Such an interrelation must apply because the observed excess incidence or mortality is made up of a γ-ray and a neutron component; increased attribution to neutrons decreases the attribution to photons. Computations with the uncorrected and the corrected DS86 are performed for the mortality and the incidence of solid tumors combined. They refer to doses up to 2 Gy and employ the constant relative risk model and a linear-quadratic dose dependence with variable ratio – the neutron relative biological effectiveness (RBE) at low doses – of the linear component for neutrons and γ-rays. In line with past analyses, no quadratic component is obtained with the uncorrected DS86, but it is seen, even in these calculations, that the assumption of increased neutron RBEs does not translate into proportional increases of the risk coefficients of neutrons, because it leads to substantially reduced risk estimates for γ-rays. Calculations with the corrected dosimetry bring out this reciprocity even more clearly. High values of the neutron RBE reduce – in line with recent suggestions by Rossi and Zaider – the risk estimates for γ-rays substantially. Even a purely quadratic dose relation for γ-rays is consistent with the data; it requires no major increase of the nominal risk coefficients for neutrons over the currently assumed values. The cancer data from Hiroshima can still provide `prudent' risk estimates for photons, but with the corrected DS86, they do not prove that there is a linear component in the dose dependence for photons. Received: 20 January 1997 / Accepted in revised form: 14 March 1997     

High Risk versus Proportional Benefit: Modelling Equitable Strategies in Cardiovascular Prevention

Objective

To examine the performances of an alternative strategy to decide initiating BP-lowering drugs called Proportional Benefit (PB). It selects candidates addressing the inequity induced by the high-risk approach since it distributes the gains proportionally to the burden of disease by genders and ages.

Study Design and Setting

Mild hypertensives from a Realistic Virtual Population by genders and 10-year age classes (range 35–64 years) received simulated treatment over 10 years according to the PB strategy or the 2007 ESH/ESC guidelines (ESH/ESC). Primary outcomes were the relative life-year gain (life-years gained-to-years of potential life lost ratio) and the number needed to treat to gain a life-year. A sensitivity analysis was performed to assess the impact of changes introduced by the ESH/ESC guidelines appeared in 2013 on these outcomes.

Results

The 2007 ESH/ESC relative life-year gains by ages were 2%; 10%; 14% in men, and 0%; 2%; 11% in women, this gradient being abolished by the PB (relative gain in all categories = 10%), while preserving the same overall gain in life-years. The redistribution of benefits improved the profile of residual events in younger individuals compared to the 2007 ESH/ESC guidelines. The PB strategy was more efficient (NNT = 131) than the 2013 ESH/ESC guidelines, whatever the level of evidence of the scenario adopted (NNT = 139 and NNT = 179 with the evidence-based scenario and the opinion-based scenario, respectively), although the 2007 ESH/ESC guidelines remained the most efficient strategy (NNT = 114).

Conclusion

The Proportional Benefit strategy provides the first response ever proposed against the inequity of resource use when treating highest risk people. It occupies an intermediate position with regards to the efficiency expected from the application of historical and current ESH/ESC hypertension guidelines. Our approach allows adapting recommendations to the risk and resources of a particular country.     

Dispersal: risk spreading versus local adaptation

I investigate how risk spreading in stochastic environments and adaptation to permanent properties of local habitats interplay in the simultaneous evolution of dispersal and habitat specialization. In a simple two-patch model, I find many types of locally evolutionarily stable attractors of dispersal and of a trait involved in habitat specialization, including a single habitat specialist and a coalition of two specialists with low dispersal, a generalist with high dispersal, and several types of dispersal polymorphisms. In general, only one attractor is a global evolutionarily stable strategy (ESS). In addition to the ESS analysis, I also present some examples of the dynamics of evolution that exhibit adaptive diversification by evolutionary branching.     

Behavioural versus physiological mediation of life history under predation risk

Predator-generated variation in prey energy intake remains the dominant explanation of adaptive response to predation risk in prey life history, morphology and physiology across a wide range of taxa. This "behavioural hypothesis" suggest that chemical or visual signals of predation risk reduce prey energy intake leading to a life history characterized by a small size and late age at maturity. However, size-selective predation can induce either smaller size-early age or large size-late age life history. The alternative "physiological hypothesis" suggests that size-selective cues decouple the relationship between energy and life history, acting instead directly on development. Here we use a series of experiments in a fish-daphnid predator-prey system to ask whether size-selective predator cues induce a physiological mediation of development, overshadowing behaviourally based changes in food intake. We found fish chemical cues reduce the net energy intake in Daphnia magna, suggesting a behaviourally mediated reduction in energy. Experimental manipulation of food levels show further that reductions in food lead to later but smaller size at maturity. However, in line with the physiological hypothesis, we show that D. magna matures earlier and at a smaller size when exposed to fish predation cues. Furthermore, our data shows that they do this by increasing their development rate (earlier maturity) for a given growth rate, resulting in a smaller size at maturity. Our data, from a classic size-selective predation system, indicate that predator-induced changes in this system are driven by physiological mediation of development rather than behavioural mediation of energy intake.     

Lack of Functional Benefit with Glutamine versus Placebo in Duchenne Muscular Dystrophy: A Randomized Crossover Trial

Background

Oral glutamine decreases whole body protein breakdown in Duchenne muscular dystrophy (DMD). We evaluated the functional benefit of 4 months oral glutamine in DMD.

Methodology/Principal Findings

30 ambulant DMD boys were included in this double-blind, randomized crossover trial with 2 intervention periods: glutamine (0.5 g/kg/d) and placebo, 4 months each, separated by a 1-month wash-out, at 3 outpatient clinical investigation centers in France. Functional benefit was tested by comparing glutamine versus placebo on change in walking speed at 4 months. Secondary outcome measures were: 2-minute walk test, work, power, muscle mass (urinary creatinine), markers of myofibrillar protein breakdown (urinary 3-methyl-histidine/creatinine), serum creatine phospho-kinase, body composition (fat free mass, fat mass percentage), safety and oral nutrient intake. There was no improvement in the primary end point (walking speed) or in secondary measures of muscle function (2-minute walk test, work, power) in the glutamine group compared with placebo. However, subjects receiving glutamine or placebo showed no deterioration in functional measures over the course of the 9-month trial. No differences in muscle mass, markers of protein breakdown or serum creatine phosho-kinase were observed, except for a blunted increase in fat free mass in the glutamine group which led to a greater increase in fat mass percentage. Glutamine was safe and well-tolerated.

Conclusions

This trial did not identify additional benefit of 4 months oral glutamine over placebo on muscle mass or function in ambulatory DMD boys. Although apparently safe, current data cannot support routine supplementation in this population as a whole, until further research proves otherwise.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00296621","term_id":"NCT00296621"}}NCT00296621     

Reward versus risk: DNA cytidine deaminases triggering immunity and disease

The enzymatic deamination of cytosine to uracil, using the free base C, its nucleosides, and nucleotides as substrates, is an essential feature of nucleotide metabolism. However, the deamination of C and, especially, 5 methyl C on DNA is typically detrimental, causing mutations leading to serious human disease. Recently, a family of enzymes has been discovered that catalyzes the conversion of C to U on DNA and RNA, generating favorable mutations that are essential for human survival. Members of the Apobec family of nucleic acid-dependent cytidine deaminases include activation-induced cytidine deaminase (AID) and Apobec3G. AID is required for B cells to undergo somatic hypermutation (SHM) and class switch recombination (CSR), two processes that are needed to produce high-affinity antibodies of all isotypes. Apobec3G is responsible for protection against HIV infection. Recent advances in the biochemical and structural analyses of nucleic acid cytidine deaminases will be discussed in relation to their programmed roles in ensuring antibody diversification and in imposing innate resistance against retroviral infection. The serious negative consequences of expressing Apobec deaminases in the wrong place at the wrong time to catalyze aberrant deamination in "at risk" sequences will be discussed in terms of causing genomic instability and disease.     

Effects of resistance versus aerobic training on coronary artery disease risk factors

Individuals exhibiting "the metabolic syndrome" have multiple coronary artery disease risk factors, including insulin resistance, hyperlipidemia, hypertension, and android obesity. We performed a randomized trial to compare the effects of aerobic and resistance training regimens on coronary risk factors. Twenty-six volunteers who exhibited android obesity and at least one other risk factor for coronary artery disease were randomized to aerobic or resistance training groups. Body mass index, waist-to-hip ratio, glucose, insulin, body composition, 24-hr urinary albumin, fibrinogen, blood pressure, and lipid profile were measured at baseline and after 10 weeks of exercise training. Both groups showed a significant reduction in waist-to-hip ratio and the resistance training group also showed a reduction in total body fat. There was no significant change in mean arterial blood pressure in either group. Fasting plasma glucose, insulin, total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides were unchanged in both groups. High-density lipoprotein (HDL) cholesterol increased (13%) with aerobic training only. Plasma fibrinogen was increased (28% and 34%, P < 0.02) in both groups and both groups showed a significant decrease (34% and 28%, P < 0.03) in microalbuminuria after their respective training regimen. In conclusion, resistance training was effective in improving body composition of middle-aged obese sedentary males. Only aerobic training was effective in raising HDL cholesterol. More studies are warranted to assess the effects of exercise on plasma fibrinogen and microalbuminuria.     

Minimal versus umbilical waist circumference measures as indicators of cardiovascular disease risk

Objective: Measures of central obesity are strongly correlated with cardiovascular disease (CVD) risk. Although waist circumference (WC) is a commonly used measure of central obesity, there is no standard measurement location. We examined two WC locations to determine which was more highly correlated with CVD risk factors and metabolic syndrome (MS). Research Methods and Procedures: WC measures were taken on 266 sedentary, overweight men and women 45 to 60 years old. Intravenous glucose tolerance tests, fasting plasma lipid analysis, and computed tomography scans were conducted. Correlational analyses followed by the Test for Equal Correlations determined whether one WC measure better correlated with the cardiovascular risk factors. Results: In women, minimal waist had higher correlation coefficients than umbilical waist for all eight variables presented. High‐density lipoprotein‐cholesterol, low‐density lipoprotein particle size, and MS score were significantly correlated with minimal waist, but not umbilical waist. For high‐density lipoprotein size and insulin sensitivity, minimal waist was a better correlate, although the difference between waist measures only approached statistical significance (p < 0.06). In men, minimal waist had a higher correlation coefficient than umbilical waist for insulin sensitivity, fasting insulin, and visceral adipose tissue. Additionally, minimal waist was significantly correlated with MS in men and umbilical waist was not. For both genders, minimal waist was more highly correlated with visceral adipose tissue than umbilical waist. Discussion: For every metabolic variable presented, minimal WC was more highly correlated with CVD risk than was umbilical WC in women. The data for women indicate that WC location is important when determining CVD risk. In men, minimal waist was better, although the data were less compelling.     

Biological invasion risk assessment of Tuta absoluta: mechanistic versus correlative methods

The capacity to assess invasion risk from potential crop pests before invasion of new regions globally would be invaluable, but this requires the ability to predict accurately their potential geographic range and relative abundance in novel areas. This may be unachievable using de facto standard correlative methods as shown for the South American tomato pinworm Tuta absoluta, a serious insect pest of tomato native to South America. Its global invasive potential was not identified until after rapid invasion of Europe, followed by Africa and parts of Asia where it has become a major food security problem on solanaceous crops. Early prospective assessment of its potential range is possible using physiologically based demographic modeling that would have identified knowledge gaps in T. absoluta biology at low temperatures. Physiologically based demographic models (PBDMs) realistically capture the weather-driven biology in a mechanistic way allowing evaluation of invasive risk in novel areas and climes including climate change. PBDMs explain the biological bases for the geographic distribution, are generally applicable to species of any taxa, are not limited to terrestrial ecosystems, and hence can be extended to support ecological risk modeling in aquatic ecosystems. PBDMs address a lack of unified general methods for assessing and managing invasive species that has limited invasion biology from becoming a more predictive science.

     

Habitat preferences of a corallivorous reef fish: predation risk versus food quality

Many animals preferentially select a habitat from a range of those potentially available. However, the consequences of these preferences for distribution and abundance, and the underlying basis of habitat preferences are often unknown. The present study, conducted at Great Keppel Island, Australia, examined how distribution and abundance of an obligate corallivorous filefish, Oxymonacanthus longirostris, relates to coral architecture and diversity. The main drivers of the distribution and abundance of O. longirostris among reefs were coral species richness and availability of branching coral. Feeding territories had a higher percentage of Acropora coral than surrounding habitat. In addition, feeding territories had a higher percentage of the structurally important branching coral, Acropora nobilis, and a primary prey species, Acropora millepora. A series of pair-wise choice experiments in which both structural complexity and coral tissue quality were independently manipulated showed that habitat choice was primarily based on structural complexity and shelter characteristics. In addition, the choice for the preferred coral (A. nobilis) was stronger in the presence of a piscivorous fish. These results indicate that species-diverse coral habitats, which provide sufficient structural complexity along with nutritionally important prey, are essential for population persistence of this small, corallivorous reef fish.     

Specificity of the Toxoplasma gondii-altered behaviour to definitive versus non-definitive host predation risk

The hypothesis that the parasite Toxoplasma gondii manipulates the behaviour of its intermediate rat host in order to increase its chance of being predated specifically by its feline definitive host, rather than a non-definitive host predator species, was tested. The impact of a range of therapeutic drugs, previously demonstrated to be effective in preventing the development of T. gondii-associated behavioural and cognitive alterations in rats, on definitive-host predator specificity was also tested. Using a Y-shaped maze design, we demonstrated that T. gondii-associated behavioural changes, apparently aimed to increase predation rate, do appear to be specific to that of the feline definitive host--there were significant and consistent differences between the (untreated) infected and uninfected rats groups where T. gondii-infected rats tended to choose the definitive host feline-predator-associated maze arm and nest-box significantly more often than a maze arm or nest-box treated with non-definitive host predator (mink) odour. Drug treatment of infected rats prevented any such host-specificity from being displayed. We discuss our results in terms of their potential implications both for T. gondii epidemiology and the evolution of parasite-altered behaviour.     

Short-term versus long-term risk for coronary artery disease: implications for lipid guidelines

PURPOSE OF REVIEW: The aim of this article is to describe recent advances in our understanding of lifetime risks for cardiovascular disease and their implications for lipid guidelines. RECENT FINDINGS: Recent studies have indicated that, among younger and middle-aged adults, there is a large subset with low 10-year risk but high lifetime risk for cardiovascular disease. Individuals with high lifetime risks can be identified on the basis of single adverse risk factors or on the basis of overall risk factor burden. For example, using the ATP-III online risk estimator, a 45-year-old obese, nonsmoking, nondiabetic man with total cholesterol of 200 mg/dl, HDL-cholesterol of 40 mg/dl, and untreated systolic blood pressure of 135 mmHg has an estimated 10-year risk for hard coronary heart disease of 3%. In contrast, recent data indicate that his predicted remaining lifetime risk for cardiovascular disease is 50% and his predicted median survival is over 10 years shorter than a man at the same age with optimal risk factors. SUMMARY: Lifetime risk estimation for cardiovascular disease may be an important adjunct to short-term (10-year) risk estimation that may help identify more treatment-eligible individuals at risk for cardiovascular disease, improve risk communication, motivate changes in lifestyle and behaviors, and promote adherence to therapy.     

Mortality risk versus food quality trade-offs in ants: patch use over time

Abstract.

• 1 Foragers of the ant species Lasius pallitarsis (Provancher) and Myrmica incompleta Provancher were given access to two food patches that differed in nutritive quality. In about half of the trials, the higher quality patch also had a mortality risk for the foragers in the form of a large Formica subnuda Emery ant located along the trail. Colonies were given access to the food for 4 or 24 h, every second day.
• 2 Use of the higher quality patch by L.pallitarsis foragers was depressed by the mortality risk. In contrast to the predictions of a food stress hypothesis, foragers used the risky patch more in the longer access trials. This appears due to a decline in the activity level of the F.subnuda, which results in a significantly lower mortality risk per trip.
• 3 M.incompfeta also significantly decreased their use of the higher quality patch when a F.subnuda was present. However, the length of time a colony had access to the patches had no effect on the use of the risky patch. M.incompleta foraging behaviour seems relatively insensitive to short-term food stress or changing levels of mortality risk.
• 4 The differences between species in their exploitation of patches and reactions to F.subnuda are discussed in terms of the species’natural history.

     

Detecting genomic clustering of risk variants from sequence data: cases versus controls

As the ability to measure dense genetic markers approaches the limit of the DNA sequence itself, taking advantage of possible clustering of genetic variants in, and around, a gene would benefit genetic association analyses, and likely provide biological insights. The greatest benefit might be realized when multiple rare variants cluster in a functional region. Several statistical tests have been developed, one of which is based on the popular Kulldorff scan statistic for spatial clustering of disease. We extended another popular spatial clustering method—Tango’s statistic—to genomic sequence data. An advantage of Tango’s method is that it is rapid to compute, and when single test statistic is computed, its distribution is well approximated by a scaled χ ² distribution, making computation of p values very rapid. We compared the Type-I error rates and power of several clustering statistics, as well as the omnibus sequence kernel association test. Although our version of Tango’s statistic, which we call “Kernel Distance” statistic, took approximately half the time to compute than the Kulldorff scan statistic, it had slightly less power than the scan statistic. Our results showed that the Ionita-Laza version of Kulldorff’s scan statistic had the greatest power over a range of clustering scenarios.     

Benefit valuation predicts gratitude

Gratitude is an emotion that promotes cooperative relationships and is elicited when an act reveals that an actor values the recipient, especially when the benefit conferred is greater than the recipient expected. But, recipient expectations might vary depending on how much the benefactor is perceived to value the recipient — all else equal, the greater the benefactor is perceived to value the recipient's welfare, the greater the recipient's expectations of benefit delivery. Thus, at a given benefit level, it might be easier to exceed the threshold of expectation in a relationship for which the recipient holds low expectations (e.g., a stranger) as compared to a relationship for which the recipient holds high expectations (e.g., a sibling). This leads to the prediction that cognitive representations of welfare valuation inversely correlate with gratitude: The greater the expected welfare valuation, the more difficult it is to exceed expectations of benefit delivery and, therefore, the less felt gratitude. To test this prediction, we conducted two experiments in which subjects estimated how much they perceived a particular person in their social network to value the subject's welfare. Next, subjects estimated how grateful they would feel if this person provided them with differing levels of benefits. Contrary to our model, we found that gratitude was predicted by the magnitude of the benefit, but not by the recipient's perception of the benefactor's valuation of the recipient.     

Modelling extinction risk in multispecies data sets: phylogenetically independent contrasts versus decision trees

Many recent studies of extinction risk have attempted to determine what differences exist between threatened and non-threatened species. One potential problem in such studies is that species-level data may contain phylogenetic non-independence. However, the use of phylogenetic comparative methods (PCM) to account for non-independence remains controversial, and some recent studies of extinction have recommended other methods that do not account for phylogenetic non-independence, notably decision trees (DTs). Here we perform a systematic comparison of techniques, comparing the performance of PCM regression models with corresponding non-phylogenetic regressions and DTs over different clades and response variables. We found that predictions were broadly consistent among techniques, but that predictive precision varied across techniques with PCM regression and DTs performing best. Additionally, despite their inability to account for phylogenetic non-independence, DTs were useful in highlighting interaction terms for inclusion in the PCM regression models. We discuss the implications of these findings for future comparative studies of extinction risk.