Modulation of interferon-[alpha] secretion by activated platelets in systemic lupus erythematosus.

Type I interferons play a key role in systemic lupus erythematosus (SLE) pathogenesis as an "IFN signature" is found in the majority of patients with active SLE. Immune complexes are internalized by plasmacytoid dendritic cells (DC) via Fc-[gamma] ReceptorIIA, reach the endosomal compartment and activate IFN-[alpha] secretion through TLR7/9-dependent pathways. Naturally occurring differences in expression of the TLR7/9 gene as well as factors that modulate TLR7/9 expression, including CD154 could therefore contribute to SLE pathogenesis. Although its origin is not elucidated CD154 is hyperexpressed in SLE patients, and is important for the differentiation of autoantibody-secreting cells. We hypothesized that platelets which are an abundant source of CD154, and which can mediate proinflammatory effects could be an actor involved in SLE pathogenesis. Platelets from SLE patients are activated _in vivo_ by circulating immune complexes which are abundant in SLE sera, via a CD32-dependent mechanism. Activated platelets formed aggregates with antigen-presenting cells in SLE patients and enhanced interferon-[alpha] secretion induced by immune-complexes stimulated plasmacytoid DCs. Finally, _in vivo_ depletion of platelets and megakaryocytes in NZBxNZW(F1) lupus prone mice improved all parameters assessing disease activity, whereas transfusion of activated platelets worsened the disease course. Altogether, these data identify platelets as a mediator of SLE pathogenesis and a new therapeutical target

Forty Years of Erratic Insecticide Resistance Evolution in the Mosquito Culex pipiens

One view of adaptation is that it proceeds by the slow and steady accumulation of beneficial mutations with small effects. It is difficult to test this model, since in most cases the genetic basis of adaptation can only be studied a posteriori with traits that have evolved for a long period of time through an unknown sequence of steps. In this paper, we show how ace-1, a gene involved in resistance to organophosphorous insecticide in the mosquito Culex pipiens, has evolved during 40 years of an insecticide control program. Initially, a major resistance allele with strong deleterious side effects spread through the population. Later, a duplication combining a susceptible and a resistance ace-1 allele began to spread but did not replace the original resistance allele, as it is sublethal when homozygous. Last, a second duplication, (also sublethal when homozygous) began to spread because heterozygotes for the two duplications do not exhibit deleterious pleiotropic effects. Double overdominance now maintains these four alleles across treated and nontreated areas. Thus, ace-1 evolution does not proceed via the steady accumulation of beneficial mutations. Instead, resistance evolution has been an erratic combination of mutation, positive selection, and the rearrangement of existing variation leading to complex genetic architecture

Prescription Medicines and the Risk of Road Traffic Crashes: A French Registry-Based Study

Using three nationwide databases in France, Ludivine Orriols, Emmanuel Lagarde, and colleagues provide evidence that prescribed medicines contribute to the risk of experiencing a road traffic crash

Asian financial integration: Global or regional? Evidence from money and bond markets

This paper investigates the degree of global versus regional financial integration in Southeast Asia during the period 2004–2012. We examine integration in the money and bond markets in Asia by employing a covered-interest-parity-based measure of financial integration. The impact of the 2008 financial crisis as well as the recent regional bond initiatives on the integration process of Asian money and bond markets respectively are specifically investigated. Empirically, we adopt the Phillips and Sul (2007) convergence methodology that has not been previously employed to examine the integration process in Asian money and bond markets. We find evidence of both global and regional integration in the money market pre 2008 but once the crisis hit, the process of global integration comes to an abrupt halt. However, regional integration, albeit at a slower pace, is still clearly evident in the post-crisis period. As for the Asian bond market, evidence of both global and regional integration is found but, in comparison, the latter is more convergent post 2008. Regional integration is stronger when interest rates with longer maturity are considered. In addition, we identify some convergent subgroups of countries and this suggests that a multi-tiered style of convergence is present

Production of Superoxide Anions by Keratinocytes Initiates P. acnes-Induced Inflammation of the Skin

Acne vulgaris is a chronic inflammatory disorder of the sebaceous follicles. Propionibacterium acnes (P. acnes), a gram-positive anareobic bacterium, plays a critical role in the development of these inflammatory lesions. This study aimed at determining whether reactive oxygen species (ROS) are produced by keratinocytes upon P. acnes infection, dissecting the mechanism of this production, and investigating how this phenomenon integrates in the general inflammatory response induced by P. acnes. In our hands, ROS, and especially superoxide anions (O2•−), were rapidly produced by keratinocytes upon stimulation by P. acnes surface proteins. In P. acnes-stimulated keratinocytes, O2•− was produced by NAD(P)H oxidase through activation of the scavenger receptor CD36. O2•− was dismuted by superoxide dismutase to form hydrogen peroxide which was further detoxified into water by the GSH/GPx system. In addition, P. acnes-induced O2•− abrogated P. acnes growth and was involved in keratinocyte lysis through the combination of O2•− with nitric oxide to form peroxynitrites. Finally, retinoic acid derivates, the most efficient anti-acneic drugs, prevent O2•− production, IL-8 release and keratinocyte apoptosis, suggesting the relevance of this pathway in humans

Mangafodipir Protects against Hepatic Ischemia-Reperfusion Injury in Mice

Mangafodipir is a contrast agent used in magnetic resonance imaging that concentrates in the liver and displays pleiotropic antioxidant properties. Since reactive oxygen species are involved in ischemia-reperfusion damages, we hypothesized that the use of mangafodipir could prevent liver lesions in a mouse model of hepatic ischemia reperfusion injury. Mangafodipir (MnDPDP) was compared to ischemic preconditioning and intermittent inflow occlusion for the prevention of hepatic ischemia-reperfusion injury in the mouse.Mice were subjected to 70% hepatic ischemia (continuous ischemia) for 90 min. Thirty minutes before the ischemic period, either mangafodipir (10 mg/kg) or saline was injected intraperitoneally. Those experimental groups were compared with one group of mice preconditioned by 10 minutes' ischemia followed by 15 minutes' reperfusion, and one group with intermittent inflow occlusion. Hepatic ischemia-reperfusion injury was evaluated by measurement of serum levels of aspartate aminotransferase (ASAT) activity, histologic analysis of the livers, and determination of hepatocyte apoptosis (cytochrome c release, caspase 3 activity). The effect of mangafodipir on the survival rate of mice was studied in a model of total hepatic ischemia.<0.01), and by higher rates of survival in treated than in untreated animals (P<0.001). The level of protection by mangafodipir was similar to that observed following intermittent inflow occlusion and higher than after ischemic preconditioning.Mangafodipir is a potential new preventive treatment for hepatic ischemia-reperfusion injury

Mediterranean Jellyfish Venoms: A Review on Scyphomedusae

The production of natural toxins is an interesting aspect, which characterizes the physiology and the ecology of a number of marine species that use them for defence/offence purposes. Cnidarians are of particular concern from this point of view; their venoms are contained in specialized structures–the nematocysts–which, after mechanical or chemical stimulation, inject the venom in the prey or in the attacker. Cnidarian stinging is a serious health problem for humans in the zones where extremely venomous jellyfish or anemones are common, such as in temperate and tropical oceanic waters and particularly along several Pacific coasts, and severe cases of envenomation, including also lethal cases mainly induced by cubomedusae, were reported. On the contrary, in the Mediterranean region the problem of jellyfish stings is quite modest, even though they can have anyhow an impact on public health and be of importance from the ecological and economic point of view owing to the implications on ecosystems and on some human activities such as tourism, bathing and fishing. This paper reviews the knowledge about the various aspects related to the occurrence and the stinging of the Mediterranean scyphozoan jellyfish as well as the activity of their venoms