Differential host determinants contribute to the pathogenesis of 2009 pandemic H1N1 and human H5N1 influenza A viruses in experimental mouse models.

Influenza viruses are responsible for high morbidities in humans and may, eventually, cause pandemics. Herein, we compared the pathogenesis and host innate immune responses of a seasonal H1N1, two 2009 pandemic H1N1, and a human H5N1 influenza virus in experimental BALB/c and C57BL/6J mouse models. We found that both 2009 pandemic H1N1 isolates studied (A/Hamburg/05/09 and A/Hamburg/NY1580/09) were low pathogenic in BALB/c mice [log mouse lethal dose 50 (MLD(50)) >6 plaque-forming units (PFU)] but displayed remarkable differences in virulence in C57BL/6J mice.

TNF and leptin tell essentially the same story in Alzheimer's disease.

Both tumor necrosis factor (TNF) and leptin are, independently, under investigation as the central mechanism for Alzheimer's disease. The wider literature provides every indication that both mediators are part of the same pathways thought to cause functional loss in this condition. This association, which has not been specifically addressed in the Alzheimer's disease literature, may be a useful link to expedite future study into the pathogenesis of this condition.

The roles of TNF in brain dysfunction and disease.

Certain cytokines, the prototype being the highly pleiotropic TNF, have many homeostatic physiological roles, are involved in innate immunity, and cause inflammation when in excess. These cytokines have long been accepted to have central roles in the pathogenesis of systemic or local non-cerebral disease states, whether acute or chronic, and whether or not caused by infectious agents. Over the last decade they have also been appreciated to be broadly important in brain physiology.

Using Complementary and Alternative Medicines to Target the Host Response during Severe Influenza.

It is now accepted that an overwhelming inflammatory response is the cause of human deaths from avian H5N1 influenza infection. With this in mind we sought to examine the literature for examples of complementary and alternative medicines that reduce inflammation, and to place the results of this search in the context of our own work in a mouse model of influenza disease, using a pharmaceutical agent with anti-inflammatory properties. Two Chinese herbs, Angelica sinensis (Dang Gui) and Salvia miltiorrhiza (Danshen), have been recently shown to protect mice during lethal experimental sepsis via inhibition of the novel inflammatory cytokine High Mobility Group Box 1 protein (HMGB1).

Is human malarial coma caused, or merely deepened, by sequestration?

Much research into falciparum malaria coma assumes the primary event to be vascular obstruction by parasitized red blood cells. Recent evidence that vivax malaria, caused by a parasite traditionally thought not to block blood flow, seems to alter brain function to the same degree as falciparum malaria has seriously questioned this. These data are a timely call to reassess whether vascular obstruction should still be considered the primary cause of the coma of falciparum disease.

Sickness behaviour pushed too far--the basis of the syndrome seen in severe protozoal, bacterial and viral diseases and post-trauma.

Certain distinctive components of the severe systemic inflammatory syndrome are now well-recognized to be common to malaria, sepsis, viral infections, and post-trauma illness. While their connection with cytokines has been appreciated for some time, the constellation of changes that comprise the syndrome has simply been accepted as an empirical observation, with no theory to explain why they should coexist. New data on the effects of the main pro-inflammatory cytokines on the genetic control of sickness behaviour can be extended to provide a rationale for why this syndrome contains many of its accustomed components, such as reversible encephalopathy, gene silencing, dyserythropoiesis, seizures, coagulopathy, hypoalbuminaemia and hypertriglyceridaemia.

Systemic release of high mobility group box 1 protein during severe murine influenza.

Hypercytokinemia is gaining recognition as the mechanism of fatality from influenza. No work to date has addressed the role of high mobility group box 1 protein (HMGB1) in influenza, the parallel being that in other severe proinflammatory cytokine syndromes (e.g.

Understanding the role of inflammatory cytokines in malaria and related diseases.

It is now broadly accepted for infectious disease in general that it is not the invading organism, but the body's unbridled response to it--the "cytokine storm"--that causes illness and pathology. Nevertheless, many researchers still regard the harmful effects of falciparum malaria as being governed by oligaemic hypoxia arising from parasitised erythrocytes obstructing blood flow through vulnerable organs, particularly the brain, and we summarise why these notions are no longer tenable. In our view, this harmful sequestration is readily accommodated within the cytokine storm perspective as one of its secondary effects.

Increased survival after gemfibrozil treatment of severe mouse influenza.

Gemfibrozil, an agent that inhibits production of proinflammatory cytokines in addition to its clinically useful lipid-lowering activity, increased survival in BALB/c mice that were already ill from infection by influenza virus A/Japan/305/57 (H2N2). Gemfibrozil was administered intraperitoneally once daily from days 4 to 10 after intranasal exposure to the virus. Survival increased from 26% in vehicle-treated mice (n = 50) to 52% in mice given gemfibrozil at 60 mg/kg/day (n = 46) (P = 0.

Human malarial disease: a consequence of inflammatory cytokine release.

Malaria causes an acute systemic human disease that bears many similarities, both clinically and mechanistically, to those caused by bacteria, rickettsia, and viruses. Over the past few decades, a literature has emerged that argues for most of the pathology seen in all of these infectious diseases being explained by activation of the inflammatory system, with the balance between the pro and anti-inflammatory cytokines being tipped towards the onset of systemic inflammation. Although not often expressed in energy terms, there is, when reduced to biochemical essentials, wide agreement that infection with falciparum malaria is often fatal because mitochondria are unable to generate enough ATP to maintain normal cellular function.

Pathogenesis of malaria and clinically similar conditions.

There is now wide acceptance of the concept that the similarity between many acute infectious diseases, be they viral, bacterial, or parasitic in origin, is caused by the overproduction of inflammatory cytokines initiated when the organism interacts with the innate immune system. This is also true of certain noninfectious states, such as the tissue injury syndromes. This review discusses the historical origins of these ideas, which began with tumor necrosis factor (TNF) and spread from their origins in malaria research to other fields.