Genetic and environmental interactions contribute to immune variation in rewilded mice.

The relative and synergistic contributions of genetics and environment to interindividual immune response variation remain unclear, despite implications in evolutionary biology and medicine. Here we quantify interactive effects of genotype and environment on immune traits by investigating C57BL/6, 129S1 and PWK/PhJ inbred mice, rewilded in an outdoor enclosure and infected with the parasite Trichuris muris. Whereas cellular composition was shaped by interactions between genotype and environment, cytokine response heterogeneity including IFNγ concentrations was primarily driven by genotype with consequence on worm burden. In addition, we show that other traits, such as expression of CD44, were explained mostly by genetics on T cells, whereas expression of CD44 on B cells was explained more by environment across all strains. Notably, genetic differences under laboratory conditions were decreased following rewilding. These results indicate that nonheritable influences interact with genetic factors to shape immune variation and parasite burden.

serosim: An R package for simulating serological data arising from vaccination, epidemiological and antibody kinetics processes.

serosim is an open-source R package designed to aid inference from serological studies, by simulating data arising from user-specified vaccine and antibody kinetics processes using a random effects model. Serological data are used to assess population immunity by directly measuring individuals' antibody titers. They uncover locations and/or populations which are susceptible and provide evidence of past infection or vaccination to help inform public health measures and surveillance. Both serological data and new analytical techniques used to interpret them are increasingly widespread. This creates a need for tools to simulate serological studies and the processes underlying observed titer values, as this will enable researchers to identify best practices for serological study design, and provide a standardized framework to evaluate the performance of different inference methods. serosim allows users to specify and adjust model inputs representing underlying processes responsible for generating the observed titer values like time-varying patterns of infection and vaccination, population demography, immunity and antibody kinetics, and serological sampling design in order to best represent the population and disease system(s) of interest. This package will be useful for planning sampling design of future serological studies, understanding determinants of observed serological data, and validating the accuracy and power of new statistical methods.

Leveraging serology to titrate immunisation programme functionality for diphtheria in Madagascar.

Diphtheria is a potentially devastating disease whose epidemiology remains poorly described in many settings, including Madagascar. Diphtheria vaccination is delivered in combination with pertussis and tetanus antigens and coverage of this vaccine is often used as a core measure of health system functioning. However, coverage is challenging to estimate due to the difficulty in translating numbers of doses delivered into numbers of children effectively immunised. Serology provides an alternative lens onto immunisation, but is complicated by challenges in discriminating between natural and vaccine-derived seropositivity. Here, we leverage known features of the serological profile of diphtheria to bound expectations for vaccine coverage for diphtheria, and further refine these using serology for pertussis. We measured diphtheria antibody titres in 185 children aged 6-11 months and 362 children aged 8-15 years and analysed them with pertussis antibody titres previously measured for each individual. Levels of diphtheria seronegativity varied among age groups (18.9% of children aged 6-11 months old and 11.3% of children aged 8-15 years old were seronegative) and also among the districts. We also find surprisingly elevated levels of individuals seropositive to diphtheria but not pertussis in the 6-11 month old age group suggesting that vaccination coverage or efficacy of the pertussis component of the DTP vaccine remains low or that natural infection of diphtheria may be playing a significant role in seropositivity in Madagascar.

Host heterogeneity mitigates virulence evolution.

Parasites often infect genetically diverse host populations, and the evolutionary trajectories of parasite populations may be shaped by levels of host heterogeneity. Mixed genotype host populations, compared to homogeneous host populations, can reduce parasite prevalence and potentially reduce rates of parasite adaptation due to trade-offs associated with adapting to specific host genotypes. Here, we used experimental evolution to select for increased virulence in populations of the bacterial parasite Serratia marcescens exposed to either heterogeneous or homogeneous populations of Caenorhabditis elegans. We found that parasites exposed to heterogeneous host populations evolved significantly less virulence than parasites exposed to homogeneous host populations over several hundred bacterial generations. Thus, host heterogeneity impeded parasite adaptation to host populations. While we detected trade-offs in virulence evolution, parasite adaptation to two specific host genotypes also resulted in modestly increased virulence against the reciprocal host genotypes. These results suggest that parasite adaptation to heterogeneous host populations may be impeded by both trade-offs and a reduction in the efficacy of selection as different host genotypes exert different selective pressures on a parasite population.

The Cardiovascular Effects of Marijuana: Are the Potential Adverse Effects Worth the High?

Marijuana is the most commonly abused illicit drug in the United States (US) and much of the Westernized World with a steadily increasing prevalence in usage and abuse over the past decade, especially among adolescents. Much of the available data on 9-tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana, relates to its neurological effects and anti-emetic properties, with very little on the cardiovascular (CV) effects of THC. Available literature shows that THC has three major effects on the CV and the peripheral vasculature in the form of "cannabis arteritis," cannabis-induced vasospasms, and platelet aggregation, with an unknown verdict on the relationship between marijuana use and atherosclerosis progression. This manuscript reviews these effects and possible mechanisms of action. Moreover, limitations on current views of marijuana and indirect causes of CV toxicity will be investigated, such as concurrent drug use, lifestyle, and mental health. The effects of marijuana on the CV system are extremely worrisome and likely need more attention due to the growing legalization of cannabis for medicinal and recreational use across the US. As a result, awareness among health care professionals about potential side effects and toxicities associated with acute and chronic exposure of cannabis will increase in importance.

The Microvascular and Macrovascular Benefits of Fibrates in Diabetes and the Metabolic Syndrome: A review.

BACKGROUND: The purpose of this article is to discuss the evidence regarding potential macrovascular and microvascular benefits of fibrate therapy in general and fenofibrate specifically. METHODS: We performed a literature review summarizing the results of studies testing fibrates on relevant. RESULTS: Although statins are the first line therapy with an unparalleled amount of evidence for reducing the risk of cardiovascular disease (CVD) in patients with dyslipidemia and the metabolic syndrome (MetS), there are several landmark studies that have focused on the potential benefits of fibrate therapy for reducing CVD risk. Fibrates confer benefits mostly for patients with diabetes mellitus (DM), MetS, and atherogenic dyslipidemia. Recently, many studies have shown that fibrates confer benefits on the vascular system as well as the liver and kidneys. Fibrates also have demonstrable benefits in cohorts of patients with DM and renal disease. CONCLUSIONS: Fibrates appear to provide significant microvascular and macrovascular benefits particularly in patients with DM, MetS, or renal disease.

Vitamin D and atherosclerosis.

PURPOSE OF REVIEW: To provide an overview of the association between vitamin D deficiency and atherosclerosis. RECENT FINDINGS: Vitamin D exerts protective effects on atherosclerosis through multiple mechanisms. It has been shown to protect against endothelial dysfunction, vascular smooth muscle cell proliferation and migration, and modulation of the immune system, as well as the inflammatory response. In addition, vitamin D has been shown to have systemic effects on insulin resistance, dyslipidemia, and hypertension. SUMMARY: Vitamin D deficiency is widely prevalent in the United States and worldwide. Although deficiency of this fat-soluble vitamin is usually associated with musculoskeletal disorder, it is associated with a wide range of disease processes that include multiple organ systems. Recently, there has been mounting evidence linking vitamin D deficiency to cardiovascular disease and atherosclerosis.

Cardiometabolic risk factors and atrial fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia worldwide; it is a significant risk factor for stroke and embolization, and has an impact on cardiac function. Despite its impact on morbidity and mortality, our understanding of the etiology and pathophysiology of this disease process is still incomplete. Over the past several decades, there has been evidence to suggest that AF has a significant correlation with metabolic syndrome (MetS). Furthermore, AF appears to be more closely related to specific components of MetS compared with others. This article provides an overview of the various components of MetS and their impact on AF.

Genetic and Environmental interactions contribute to immune variation in rewilded mice.

The relative and synergistic contributions of genetics and environment to inter-individual immune response variation remain unclear, despite its implications for understanding both evolutionary biology and medicine. Here, we quantify interactive effects of genotype and environment on immune traits by investigating three inbred mouse strains rewilded in an outdoor enclosure and infected with the parasite, Trichuris muris. Whereas cytokine response heterogeneity was primarily driven by genotype, cellular composition heterogeneity was shaped by interactions between genotype and environment. Notably, genetic differences under laboratory conditions can be decreased following rewilding, and variation in T cell markers are more driven by genetics, whereas B cell markers are driven more by environment. Importantly, variation in worm burden is associated with measures of immune variation, as well as genetics and environment. These results indicate that nonheritable influences interact with genetic factors to shape immune variation, with synergistic impacts on the deployment and evolution of defense mechanisms.

Spatiotemporal-social association predicts immunological similarity in rewilded mice.

Environmental influences on immune phenotypes are well-documented, but our understanding of which elements of the environment affect immune systems, and how, remains vague. Behaviors, including socializing with others, are central to an individual's interaction with its environment. We therefore tracked behavior of rewilded laboratory mice of three inbred strains in outdoor enclosures and examined contributions of behavior, including associations measured from spatiotemporal co-occurrences, to immune phenotypes. We found extensive variation in individual and social behavior among and within mouse strains upon rewilding. In addition, we found that the more associated two individuals were, the more similar their immune phenotypes were. Spatiotemporal association was particularly predictive of similar memory T and B cell profiles and was more influential than sibling relationships or shared infection status. These results highlight the importance of shared spatiotemporal activity patterns and/or social networks for immune phenotype and suggest potential immunological correlates of social life.

Anticoagulation strategies in atrial fibrillation.

Atrial fibrillation (AF) is a major risk factor for stroke and systemic embolization, particularly in the elderly. Approximately 2.3 million adults in the United States have AF, and it is projected that this number will increase to approximately 5.6 million individuals by the year 2050, with over 50% aged 80 years or older. Vitamin K antagonists are currently the most widely accepted means of stroke prevention in patients with AF; unfortunately, this method of treatment is not a feasible option for many patients for numerous reasons. This article examines and compares the various newer therapeutic agents that have either been approved by the US Food and Drug Administration or are still in various stages of clinical testing, and provides an overview of established antithrombotic therapies. We also discuss the role of anticoagulation in the setting of cardioversion in patients with AF.

Proteomic analysis of Trypanosoma cruzi spliceosome complex.

The unicellular protists of the group Kinetoplastida include the genera Leishmania and Trypanosoma, which are pathogens of invertebrate and vertebrate animals. Despite their medical and economical importance, critical aspects of their biology such as specific molecular characteristics of gene expression regulation are just beginning to be deciphered. Gene expression regulation also depends on post-transcriptional processing steps, such as the trans-splicing process. Despite being widely used in trypanosomes, trans-splicing is a rare event in other eukaryotes. We sought to describe the protein composition of spliceosomes in epimastigotes of T. cruzi, the etiological agent of Chagas disease. We used two TAP-tagged proteins to affinity purify spliceosomes and analyzed their composition by mass spectrometry. Among the 115 identified proteins we detected conserved spliceosome components, as Sm and LSm proteins, RNA helicases, U2- and U5-snRNP specific proteins. Importantly, by comparing our data with proteomic data of human and T. brucei spliceosome complexes, we observed a core group of proteins common to all spliceosomes. By using amino acid sequence comparisons, we identified RNA-associated proteins that might be involved with splicing regulation in T. cruzi, namely the orthologous of WDR33, PABPCL1 and three different HNRNPs. Data are available via ProteomeXchange with identifier PXD018776.

Cardiac rehabilitation fitness changes and subsequent survival.

Aims: Assessments of cardiac rehabilitation (CR) in coronary heart disease (CHD) cohorts usually examine mortality in aggregate. This study examines the prognosis and characteristics of patients who enrolled and completed CR, stratified by their level of improvement in cardiorespiratory fitness (CRF) by examining the characteristics, outcomes and predictors of non-response in CRF (NonRes) compared with low-responders (LowRes) and high-responders (HighRes) after CR. Methods and results: A total of 1171 CHD patients were referred for a phase II CR programme after therapy for an acute coronary syndrome, coronary artery bypass graft procedure or a percutaneous coronary intervention between 1 January 2000 and 30 June 2013 underwent cardiopulmonary exercise testing before and after CR. This cohort was divided according to absolute improvements in CRF (i.e. change in peak oxygen consumption expressed in mL⋅kg-1⋅min-1). Mortality was analysed after 0.5-13.4 years of follow-up (mean 6.4 years). A total of 266 (23%) subjects were NonRes. After adjustment for body mass index, age, gender, left ventricular ejection fraction and baseline CRF, NonRes, and LowRes had a statistically significant three-fold and two-fold higher mortality, respectively, when compared with HighRes (HighRes 8% vs. LowRes 17% vs. NonRes 22%; P < 0.001). Age, female gender, baseline CRF, hostility, and presence of diabetes were significant predictors of NonRes and LowRes. In addition, higher waist circumference was a predictor of NonRes. Conclusion: Significant proportions of subjects referred to CR have no/low improvement in CRF and higher associated mortality risks. Greater attention is required to increase improvements in CRF following CR and avoid NonRes.

Impact of Cardiac Rehabilitation and Exercise Training on Psychological Risk Factors and Subsequent Prognosis in Patients With Cardiovascular Disease.

The role of psychological risk factors has been under-recognized in most subspecialties of medicine, as well as in general medicine practices. However, considerable evidence indicates that psychosocial factors are involved in the pathogenesis and progression of cardiovascular disease (CVD). Emerging data from cardiac rehabilitation (CR) settings and CR exercise training (CRET) programs have demonstrated the value of comprehensive CRET to improve psychological functioning and reduce all-cause mortality. Recent evidence also supports the role of CRET and the added value of stress management training in the secondary prevention of CVD.

Significance of Comorbid Psychological Stress and Depression on Outcomes After Cardiac Rehabilitation.

BACKGROUND: Depression is associated with increased mortality in stable coronary heart disease. Cardiac rehabilitation and exercise training has been shown to decrease depression, psychological stress, and mortality after a coronary heart disease event. The presence of depression at completion of cardiac rehabilitation and exercise training is associated with increased mortality. However, it is unknown if depression with comorbid psychological risk factors such as anxiety or hostility confers an additional mortality disadvantage. We evaluated the mortality effect of anxiety and hostility on depression after cardiac rehabilitation and exercise training. PATIENTS AND METHODS: We studied 1150 patients with coronary heart disease following major coronary heart disease events who had completed formal cardiac rehabilitation and exercise training. Using Kellner questionnaires, stress levels were measured in 1 of 3 domains: anxiety, hostility, and depression (with an aggregated overall psychological stress score) and divided into 3 groups: nondepressed (n = 1072), depression alone (n = 18), and depression with anxiety or hostility (n = 60). Subjects were analyzed for all-cause mortality over 161 months of follow-up (mean 6.4 years) by National Death Index. RESULTS: Depression after cardiac rehabilitation was not common (6.8%; mortality 20.8%) but when present, frequently associated with either anxiety or hostility (77% of depressed patients; mortality 22.0%). After adjustment for age, sex, ejection fraction, and baseline peak oxygen consumption, depression alone (hazard ratio [HR] 1.73, P = .04), as well as depression with comorbid psychological stress, was associated with higher mortality (HR 1.98, P = .03). Furthermore, our data showed an increased mortality when both anxiety and hostility were present in addition to depression after cardiac rehabilitation (HR 2.41, P = .04). CONCLUSIONS: After cardiac rehabilitation, depression, when present, is usually associated with other forms of psychological stress, which confers additional mortality. More measures are needed to address psychological stress after cardiac rehabilitation.

Lifestyle modification in the prevention and treatment of atrial fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia worldwide and has a significant impact on morbidity and mortality. Additionally, the incidence and prevalence of AF is expected to increase in the United States and worldwide over the next few decades. While the pathophysiology concerning the development of AF is not completely understood, multiple modifiable, as well as non-modifiable risk factors, for AF development have been discovered. The goal of this paper is to provide an overview of the modifiable risk factors that contribute to the development and recurrence of AF, in addition to discussing potential lifestyle changes that may aid in the prevention and treatment of AF.

Gender, race and cardiac rehabilitation in the United States: is there a difference in care?

Coronary heart disease is the leading cause of death within the United States, involving both genders and among all races and ethnic populations. Cardiac rehabilitation (CR) has been shown to significantly improve morbidity and mortality, and these benefits extend to individuals of both genders and all ages with coronary heart disease. Despite this, referral and participation rates remain surprisingly low. Furthermore, women and minorities have even lower referral rates than do their male and white counterparts. Over the course of this article, we will review CR referral and participation among women, as well as racial and ethnic minorities in the United States. We will also examine barriers to CR participation among these subgroups.

Cardiac rehabilitation in the elderly.

Coronary heart disease (CHD) is the leading cause of death worldwide. Advanced age is associated with a higher prevalence of CHD as well as increased morbidity and mortality. One key vulnerability relates to the fact that older individuals are generally among the least fit, least active cohort and at increased risk of complications after an acute cardiac event and/or major surgery. There is ample evidence to demonstrate the beneficial effects of exercised-based cardiac rehabilitation (CR) programs on improving functional capacity and other indices of cardiovascular (CV) health. Although the predominant number of studies is in middle-aged patients, there is an escalating amount of new information that establishes the cardioprotective role of CR and, in particular, structured exercise therapy (ET) among the elderly. The present review summarizes the current data available regarding CR and ET and its salutary impact on today's growing population of older adults with CHD.

Cardiac rehabilitation in the United States.

Coronary heart disease (CHD) is a significant cause of morbidity and mortality in the United States (US). In addition to this, many of the risk factors of CHD, such as obesity, sedentary lifestyle, diabetes mellitus, and poor nutrition, are disproportionately high in the US. Despite the many known benefits of cardiac rehabilitation (CR), referral and participation rates in these programs are paradoxically low. Over the course of this review, we will discuss some of the many benefits of CR, some of the risk factors for CHD in the US, and factors that affect referral and participation in these programs.

Meditation and coronary heart disease: a review of the current clinical evidence.

BACKGROUND: Chest pain from coronary heart disease (CHD) accounts for more than 8 million emergency department visits every year in the United States, emphasizing the need for cardiovascular (CV) interventions to help reduce this high number. Meditation--a state of contemplation, concentration, and reflection--has the potential to help decrease CV disease. METHODS: This article reviews the available data regarding the effects of meditation on various aspects of CV health. RESULTS: During the past few decades, multiple studies have demonstrated the beneficial effects of meditation on various CV risk factors. In addition to decreasing CV mortality, meditation has also been shown to improve conditions such as hypertension, type 2 diabetes mellitus, dyslipidemia, and high cortisol levels. Still unclear is how current medical therapies impact overall CHD in comparison to meditation techniques. CONCLUSION: Prospective trials are needed to study the effects of meditation on CV risk factors, to provide guidelines for daily meditation practice, and to determine the efficacy of meditation compared to current pharmacologic therapies.