The outbreak of carp disease caused by CyHV-3 as a model for new emerging viral diseases in aquaculture: a review

Aquacultured koi and common carp (Cyprinus carpio) are intensively bred for ornamental purposes and for human consumption worldwide. The carp and koi farming industries have suffered enormous economic losses over the past decade due to an epizootic disease caused by Cyprinus herpesvirus-3 (CyHV-3) also known as koi herpesvirus and carp interstitial nephritis gill necrosis virus. CyHV-3 is a large dsDNA virus, morphologically similar to herpesviruses, yet contains genetic elements similar to those of pox, irido- and herpesviruses. Considering the phylogenic distance between CyHV-3 and higher vertebrate herpesviruses, CyHV-3 represents the prototype of viruses assigned to the novel family Alloherpesviridae. Although emergence of a new virus rarely initiates a pandemic so severe that it reduces the life expectancy of a population, CyHV-3 is exceptional because of its enormous impact on the world carp population. High population density is the major contributing factor to the epizootic disease caused by CyHV-3.     

Using a newly introduced framework to measure ecological stressor interactions

Understanding how stressors combine to affect population abundances and trajectories is a fundamental ecological problem with increasingly important implications worldwide. Generalisations about interactions among stressors are challenging due to different categorisation methods and how stressors vary across species and systems. Here, we propose using a newly introduced framework to analyse data from the last 25 years on ecological stressor interactions, for example combined effects of temperature, salinity and nutrients on population survival and growth. We contrast our results with the most commonly used existing method – analysis of variance (ANOVA) – and show that ANOVA assumptions are often violated and have inherent limitations for detecting interactions. Moreover, we argue that rescaling – examining relative rather than absolute responses – is critical for ensuring that any interaction measure is independent of the strength of single‐stressor effects. In contrast, non‐rescaled measures – like ANOVA – find fewer interactions when single‐stressor effects are weak. After re‐examining 840 two‐stressor combinations, we conclude that antagonism and additivity are the most frequent interaction types, in strong contrast to previous reports that synergy dominates yet supportive of more recent studies that find more antagonism. Consequently, measuring and re‐assessing the frequency of stressor interaction types is imperative for a better understanding of how stressors affect populations.     

Absence of fatty acid transporter CD36 protects against Western-type diet-related cardiac dysfunction following pressure overload in mice

Cardiac patients often are obese and have hypertension, but in most studies these conditions are investigated separately. Here, we aimed at 1) elucidating the interaction of metabolic and mechanophysical stress in the development of cardiac dysfunction in mice and 2) preventing this interaction by ablation of the fatty acid transporter CD36. Male wild-type (WT) C57Bl/6 mice and CD36(-/-) mice received chow or Western-type diet (WTD) for 10 wk and then underwent a sham surgery or transverse aortic constriction (TAC) under anesthesia. After a 6-wk continuation of the diet, cardiac function, morphology, lipid profiles, and molecular parameters were assessed. WTD administration affected body and organ weights of WT and CD36(-/-) mice, but it affected only plasma glucose and insulin concentrations in WT mice. Cardiac lipid concentrations increased in WT mice receiving WTD, decreased in CD36(-/-) on chow, and remained unchanged in CD36(-/-) receiving WTD. TAC induced cardiac hypertrophy in WT mice on chow but did not affect cardiac function and cardiac lipid concentrations. WTD or CD36 ablation worsened the outcome of TAC. Ablation of CD36 protected against the WTD-related aggravation of cardiac functional and structural changes induced by TAC. In conclusion, cardiac dysfunction and remodeling worsen when the heart is exposed to two stresses, metabolic and mechanophysical, at the same time. CD36 ablation prevents the metabolic stress resulting from a WTD. Thus, metabolic conditions are a critical factor for the compromised heart and provide new targets for metabolic manipulation in cardioprotection.     

Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing

Background

Hypertension is one of the leading causes of cardiovascular disease (CVD). A range of antihypertensive drugs exists, and their prices vary widely mainly due to patent rights. The objective of this study was to explore the cost-effectiveness of different generic antihypertensive drugs as first, second and third choice for primary prevention of cardiovascular disease.

Methods

We used the Norwegian Cardiovascular Disease model (NorCaD) to simulate the cardiovascular life of patients from hypertension without symptoms until they were all dead or 100 years old. The risk of CVD events and costs were based on recent Norwegian sources.

Results

In single-drug treatment, all antihypertensives are cost-effective compared to no drug treatment. In the base-case analysis, the first, second and third choice of antihypertensive were calcium channel blocker, thiazide and angiotensin-converting enzyme inhibitor. However the sensitivity and scenario analyses indicated considerable uncertainty in that angiotensin receptor blockers as well as, angiotensin-converting enzyme inhibitors, beta blockers and thiazides could be the most cost-effective antihypertensive drugs.

Conclusions

Generic antihypertensives are cost-effective in a wide range of risk groups. There is considerable uncertainty, however, regarding which drug is the most cost-effective.     

Myocardial insulin action and the contribution of insulin resistance to the pathogenesis of diabetic cardiomyopathy

Heart disease is the leading cause of death in patients with insulin resistance and type 2 diabetes (DM2). Even in the absence of coronary artery disease and hypertension, functional and structural abnormalities exist in patients with well-controlled and uncomplicated DM2. These derangements are collectively designated by the term diabetic cardiomyopathy (DCM). Changes in myocardial energy metabolism, due to altered substrate supply and utilization, largely underlie the development of DCM. Insulin is an important regulator of myocardial substrate metabolism, but also exerts regulatory effects on intracellular Ca2+ handling and cell survival. The current paper reviews the multiple functional and molecular effects of insulin on the heart, all of which ultimately seem to be cardioprotective both under normal conditions and under ischemia. In particular, the dismal consequences of myocardial insulin resistance contributing to the development of DCM will be discussed.     

Fusidic acid, an immunosuppressive drug with functions similar to cyclosporin A

Fusidic acid, a tetracyclic triterpenoic acid, is used for local and systemic treatment of bacterial infections. Its in vitro effects on the human immune response were tested. Activated blood mononuclear cells released lower levels of interleukin (IL) 1 in the presence of nontoxic and clinically attainable levels of fuscidic acid (15 to 50 micrograms/mL). In contrast, the drug failed to affect the production of two other monocyte-derived cytokines, tumor necrosis factor (TNF)-alpha and IL 6. The production of the T-cell-derived cytokines, IL 2 and interferon-gamma (IFN-gamma), were also suppressed (IC50: 5 to 15 micrograms/mL). The early costimulatory effects of IL 1 and IL 6 on mouse thymocytes and human T cells were suppressed by similar levels of the drug, as was the hybridoma growth-promoting function of IL 6. T-cell proliferation induced by phytohemagglutinin or allogeneic cells was reversibly inhibited (IC50: 15 micrograms/mL). These functions of fusidic acid were strikingly similar to those of cyclosporin A. Because of the low toxicity of the former, it may have a role as a clinically useful suppressor of immunoinflammatory processes.     

Phosphorylation of PRAS40 on Thr246 by PKB/AKT facilitates efficient phosphorylation of Ser183 by mTORC1

Type 2 diabetes is associated with alterations in protein kinase B (PKB/Akt) and mammalian target of rapamycin complex 1 (mTORC1) signalling. The proline-rich Akt substrate of 40-kDa (PRAS40) is a component of mTORC1, which has a regulatory function at the intersection of the PKB/Akt and mTORC1 signalling pathway. Phosphorylation of PRAS40-Thr246 by PKB/Akt, and PRAS40-Ser183 and PRAS40-Ser221 by mTORC1 results in dissociation from mTORC1, and its binding to 14-3-3 proteins. Although all phosphorylation sites within PRAS40 have been implicated in 14-3-3 binding, substitution of Thr246 by Ala alone is sufficient to abolish 14-3-3 binding under conditions of intact mTORC1 signalling. This suggests that phosphorylation of PRAS40-Thr246 may facilitate efficient phosphorylation of PRAS40 on its mTORC1-dependent sites. In the present study, we investigated the mechanism of PRAS40-Ser183 phosphorylation in response to insulin. Insulin promoted PRAS40-Ser183 phosphorylation after a euglycaemic–hyperinsulinaemic clamp in human skeletal muscle. The insulin-induced PRAS40-Ser183 phosphorylation was further evidenced in vivo in rat skeletal and cardiac muscle, and in vitro in A14 fibroblasts, 3T3L1 adipocytes and L6 myotubes. Inhibition of mTORC1 by rapamycin or amino acid deprivation partially abrogated insulin-mediated PRAS40-Ser183 phosphorylation in cultured cell lines. However, lowering insulin-induced PRAS40-Thr246 phosphorylation using wortmannin or palmitate in cell lines, or by feeding rats a high-fat diet, completely abolished insulin-mediated PRAS40-Ser183 phosphorylation. In addition, replacement of Thr246 by Ala reduced insulin-mediated PRAS40-Ser183 phosphorylation. We conclude that PRAS40-Ser183 is a component of insulin action, and that efficient phosphorylation of PRAS40-Ser183 by mTORC1 requires the phosphorylation of PRAS40-Thr246 by PKB/Akt.