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Sepsis

Description
Sepsis is a condition in which your body is fighting a severe infection. It is a severe illness caused by overwhelming infection of the bloodstream by toxin-producing bacteria. If you become "septic," you will likely be in a state of low blood pressure termed "shock." Major organs and systems, including the kidneys, liver, lungs, and central nervous system, stop functioning normally. This condition can develop either as a result of your body's own defense system or from toxic substances made by the infecting agent (such as a bacteria, virus, or fungus). Sepsis can originate anywhere bacteria can gain entry to the body; common sites include the genitourinary tract, the liver and its bile ducts, the gastrointestinal tract, and the lungs. Sepsis is often life-threatening, especially in people with a weakened immune system or other medical illnesses.

Who is at Risk?
People whose immune systems are not functioning well because of an illness, such as cancer or AIDS, are more prone to have sepsis. Because their immune systems are not completely developed, very young babies may get sepsis if they become infected and are not treated in a timely manner. The elderly population, especially those with other medical illnesses, such as diabetes, may be at increased risk as well.

Source: eMedicine.com, Inc., A.D.A.M., Inc., The Thomson Corporation

TSRI Scientists Show that Rare Genetic Mutations Increase Susceptibility to Sepsis
A group of researchers from TSRI have discovered rare genetic mutations in a subset of people who have come down with a particular kind of severe sepsis, an acute and often deadly disease. These rare mutations in a human gene called TLR4 lend susceptibility to meningococcal sepsis, which strikes over 2,500 people a year in the United States. About half of those who contract meningococcal sepsis are younger than the age of two, and the disease has an overall case fatality rate of 12 percent. Professor Bruce Beutler, M.D., led the research. The study suggested that it may be possible to protect people who are at risk. While not practical at the moment, eventually patients with mutations to their TLR4 genes might be given prophylactic treatment, for instance, before they undergo surgery or travel somewhere they are likely to be exposed to meningococcal bacteria.

This is the first time that a comparison of the collective mutations at a given genetic locus has been made in any infectious disease. Beutler and his team had to write special software to make the comparison of the thousand different sequences possible and find the individual mutations therein. Significantly, the technique of measuring the genetic variation "load" of the entire gene locus could be applied to other sorts of diseases as well - particularly diseases in which both genes and environment play a role.

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Sepsis Vaccine Proves Protective in Preliminary Studies
A group of researchers from TSRI, led by Kim Janda, Ph.D., Ely R. Callaway Chair in Chemistry, have designed a vaccine that might be useful to protect against the pernicious consequences of severe sepsis, an acute and often deadly disease that is estimated to strike 700,000 Americans a year and millions more worldwide. Though the new vaccine has not yet been applied to clinical trials in humans, it has worked well in preclinical studies. Sepsis, also known as septic shock and systemic inflammatory response syndrome, is characterized by shock to one's organs following poisoning with endotoxins - chemical components of certain bacteria. The prognosis for sepsis is dire. It can affect many parts of the body, from the bones to the brain, and death due to septic shock can occur in a matter of hours. Sepsis is one of the ten leading causes of both infant and adult mortality in the United States, and, in 1999, directly caused more than 30,000 deaths.

The best current treatment is to administer broad-spectrum antibiotics to try to quell the infection after the fact, but this is often too little too late and scientists have sought a better approach for years. Since many patients who fall victim to sepsis acquire bacterial infections in the hospital, after undergoing major surgeries for instance, one approach would be to try to "prophylactically" protect a patient before he/she undergoes surgery. The TSRI team sought to use active immunization to protect patients against sepsis. Active immunization involves exposing patients to a substance that resembles the pathogen that one is immunizing against. Post-vaccination, the team observed a nearly 95 percent reduction in the inflammatory chemical TNF-a, which indicated that the vaccine successfully controlled the body"s response to infection. The researchers are now looking to formulate their synthetic glycoconjugate into a slow-release form that can be administered well in advance of major surgery, for instance, in the hope of someday providing outstanding protection of hospital patients.

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A Potential New Approach to Preventing Stroke Damage
A compound already used to treat severe sepsis could open up a whole new approach for treating stroke, the leading cause of long-term disability in the nation. The research shows that a compound known as activated protein C or APC directly protects brain cells that normally die as a result of stroke by curbing the cells' auto-destruct program. The research, led by Professor Berislav Zlokovic of the University of Rochester and Professor John H. Griffin, Ph.D. of TSRI opens up a new vista in a field where effective treatments are scant. The new work is surprising because it points to an unsuspected ability of APC to directly prevent programmed cell death, which has quietly emerged over the past several years as the key to reducing the effects of stroke.

There is currently only one effective treatment for stroke which reaches only a small percentage of patients, so the researchers are hopeful that this finding will spur further research that could help people who will otherwise have lifelong disability due to a brain attack. The scientists showed that, in mice that had strokes, more than 65 percent of the brain cells that normally would die after a stroke survive because of APC. The compound reduced the neurological impact of the stroke by 91 percent. Stroke, a huge problem, is the third leading cause of death in the nation. The study's results are very exciting.

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Mysteries of a Therapy Unveiled
Several years ago, a blood protein called activated protein C was found to lower the mortality in patients who acquire severe sepsis. Activated protein C has been approved in recombinant form by the Food and Drug Administration for use in severe sepsis after the protein proved effective in lowering mortality. Today the drug is sold under the brand name Xigris and is manufactured by Eli Lilly. Despite its demonstrated efficacy, and despite the fact that scientists had pondered its beneficial therapeutic effect for a decade, exactly how activated protein C improved the prognosis for sepsis had remained a mystery. Now a group of researchers at TSRI, led by Associate Professor Wolfram Ruf, M.D., have described how activated protein C works. The group has elucidated the signaling pathway through which activated protein C works - the receptors on the surface of cells it binds to and activates. Activated protein C fights inflammation without compromising the body's ability to fight the bacteria and lowers the mortality due to sepsis. But nobody knew how activated protein C was mediating anti-inflammatory reactions.

The Ruf laboratory, drawing on several years of work on related areas of research, figured out the pathway through which activated protein C works. In sepsis, the physiological balance between the enzyme thrombin and activated protein C is lost, because inflammatory cytokines cause a loss of thrombomodulin from endothelial cells. Thrombin can no longer activate protein C, and without activated protein C, the endothelial cells cannot be protected. Clinical trials had established that endothelial cells can be protected by activated protein C during sepsis, but nobody knew how. Ruf and his colleagues demonstrated that activated protein C protected these endothelial cells through the thrombin receptor PAR1 signaling by asking whether the genes that the activated protein C induced could be accounted for by the activation of the PAR1 receptor. Thus, the mystery was solved. Thrombin binds to thrombomodulin on the surface of endothelial cells and activates the nearby protein C bound to the endothelial cell protein C receptor. And activated protein C will then activate the PAR1 receptor.

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A New Therapeutic Target for the Treatment of Sepsis
In patients with sepsis, the levels of inflammatory cytokines like Interleukin-6 (which makes a person feverish), stay high. The release of these inflammatory molecules that fight infection can become too widespread and lead to complications, such as multi-organ failure. Another problem with sepsis is the activation of the coagulation within the vasculature. Widespread coagulation in the blood vessels of vital organs leads to blockade of the microcirculation and organ shut down. Frequently, the vital function of kidneys and lungs are affected. Treatment to reduce inflammation proved to make patients worse off because the therapies compromised their immune system to the bacteria. For many years, the best treatment has been to administer broad antibiotics to try to quell the infection.

A new form of treatment for sepsis arrived in 2001 when the United States Food and Drug Administration approved the recombinant form of the anti-coagulant activated protein C for use in severe sepsis. Now TSRI Associate Professor Nigel Mackman, Ph.D., is looking at the effect of other anti-coagulants, such as antibodies against tissue factor. He is interested in the mechanism by which these anti-coagulants reduce inflammation as well as coagulation, and whether they might also be used to protect against sepsis in humans. Studies in the Mackman laboratory have shown that protease activated receptors (PARs) mediate cross talk between coagulation and inflammation during endotoxemia. Thus, PARS represent a new therapeutic target for the treatment of sepsis.

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International Team Finds Structure of Protein Important for Bacterial Virulence
A team of scientists at The Scripps Research Institute, Stanford Synchrotron Radiation Lightsource, the University of Tokyo, and other institutions has solved the structure of a protein that helps bacteria cause disease. The research provides new clues for understanding the mechanisms behind bacterial infections and for working toward the development of novel treatments to combat conditions including pneumonia, sepsis, and meningitis. The study illuminates a novel structural arrangement in a protein called CvfB, found in a variety of virulent bacteria. Scripps Research Professor Ian Wilson, Ph.D., served as senior author of the study and principal investigator of the Joint Center for Structural Genomics, a multi-institutional consortium. This structure provides insights into an important piece of the puzzle to better understand how bacteria cause infection.

In the research, the scientists examined CvfB from the organisms Staphylococcus aureus (a common cause of potentially life-threatening staph infections, especially in hospital settings) and Streptococcus pneumoniae (a frequent cause of pneumonia, ear infections, sinus infections, and meningitis). The study's results provide new insight into the structure and function of a key bacterial protein, which consists of an unusual combination of nucleic acid binding modules.

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