RxPG News : Immunology

Faulty immune memory can trigger cold sores

Thu, 12 Nov 2009 12:35:46 PST

( from http://www.rxpgnews.com ) A faulty immune memory can trigger infections that may lead to cold sores and even cancer in some people, say researchers.

The memory circuit, identified by the research team, involves a gene and protein called DOCK8, which helps white blood cells form synapses, tiny points of cell contact, that are responsible for memory in the brain.

An increased understanding of immune memory would not only lead to enhanced vaccines but also improve the treatment of cancer, transplant rejection, auto-immunity and allergies.

'Vaccines that provoke long-lasting immunity are among the greatest advances delivered by health research, but the circuits that determine whether they work or not have been among the most difficult to decipher,' said Chris Goodnow from the John Curtin School of Medical Research in Australia and co-leader of the research team.

Lapses of immunological memory also explain the reactivation of infections responsible for cold sores, shingles, yeast infections, and possibly some forms of cancer.

Katrina Randall, clinical immunologist and co-research team leader said: 'Immunity normally lasts for years after we are immunised or infected because our immune system remembers the shape and 'fingerprints' of an infecting microbe...'

'When immunological memory wanes we become susceptible to infection again. For some vaccines like the tetanus vaccine this occurs after several years, and for many experimental vaccines their memory has so far proved just too short to be useful.'

The findings were published in the latest issue of Nature Immunology.

New Mount Sinai research finds 9/11 responders twice as likely to have asthma

Tue, 03 Nov 2009 04:59:36 PST

( from http://www.rxpgnews.com ) First responders who were exposed to caustic dust and toxic pollutants following the 2001 World Trade Center (WTC) terrorist attacks suffer from asthma at more than twice the rate of the general U.S. population, according to data presented today by Mount Sinai School of Medicine researchers at CHEST 2009, the 75th annual international scientific assembly of the American College of Chest Physicians (ACCP), in San Diego.

As many as eight percent of the workers and volunteers who engaged in rescue and recovery, essential service restoration, and clean-up efforts in the wake of 9/11 reported experiencing post-9/11 asthma attacks or episodes. Asthma is typically seen in only four percent of the population.

Although previous WTC studies have shown significant respiratory problems, this is the first study to directly quantify the magnitude of asthma among WTC responders, said Hyun Kim, ScD, Instructor of Preventive Medicine at Mount Sinai School of Medicine (MSSM) and lead author of the analysis. Eight years after 9/11 the WTC Program is still observing responders affected by asthma episodes and attacks at rates more than twice that of people not exposed to WTC dust.

Researchers examined the medical records of 20,843 WTC responders who received medical screenings from July 2002 to December 2007 as part of the Mount Sinai School of Medicine-coordinated WTC Program. Results were compared with the U.S. National Health Survey Interviews adult sample data for the years 2000 and 2002 to 2007.

In the general population, the prevalence of asthma episodes and/or attacks in the previous 12 months remained relatively constant at slightly less than four percent from 2000 to 2007. In contrast, among WTC responders, while fewer than one percent reported asthma episodes occurring during the year 2000, eight percent reported asthma episodes in the years 2005 to 2007. In an age-adjusted ratio, WTC responders were 2.3 times more likely to report asthma episodes/attacks that had occurred during the previous 12 months when compared to the general population of the United States.

Of the study's rescue and recovery workers, 86 percent were men and the average duration of work at WTC sites was 80 days. The study followed uniformed and other law enforcement and protective service workers (42 percent of subjects), as well as construction workers and other responders who had engaged in paid and volunteer WTC-related rescue and recovery, essential service restoration and/or debris removal and clean-up efforts.

It is important to note that this report focused on findings from baseline or initial visit examinations, said Philip J. Landrigan, MD, Ethel H. Wise Professor and Chair of MSSM's Department of Preventive Medicine and Principal Investigator of the WTC Program Data and Coordination Center. The data show an increasing percentage of responders reporting asthmatic episodes, rising to double that seen in the general population. It is clearly vital that we continue to track responders' health and look further into the medical outcomes of this population.

Asthma and other chronic lung conditions remain a significant burden for rescue and recovery workers responding to the attacks on the World Trade Center, said Kalpalatha Guntupalli, MD, FCCP President of the American College of Chest Physicians. The significant chronic health problems associated with the WTC attacks only reinforces the need for stronger disaster preparedness plans as well as long-term medical follow-up for 9/11 responders and individuals who respond to disaster-related events.

Progress made on group B streptococcus vaccine

Fri, 30 Oct 2009 03:59:36 PST

( from http://www.rxpgnews.com ) WHAT: Scientists supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, have completed a Phase II clinical study that indicates a vaccine to prevent Group B Streptococcus (GBS) infection is possible. GBS is the most common cause of sepsis and meningitis in newborns in the United States, according to the Centers for Disease Control and Prevention (CDC). It can also cause severe illness in pregnant women, the elderly and adults with chronic illnesses. Colonization of the genital or gastrointestinal tract is a critical risk factor for infections due to GBS.

The researchers, led by Sharon L. Hillier, Ph.D., from the Magee-Womens Research Institute at the University of the Pittsburgh, found that the vaccine used in the study can cause a modest but sustained reduction in genital and gastrointestinal GBS bacterial colonization.

The GBS bacterium, which is commonly found in the gut and genital tracts, can infect the fetus during gestation and birth or after delivery. Pregnancy-related infections can lead to serious consequences for women including stillbirth. Currently, one-third of pregnant women in the United States test positive for asymptomatic GBS and receive antibiotics during labor to prevent infection of the newborn. Although this antibiotic strategy is highly effective, the broad use of antibiotics in pregnant women is of concern to public health officials. Many women are allergic to penicillin and penicillin-type antibiotics that are the preferred treatment, and GBS is increasingly resistant to other common antibiotics.

Dr. Hillier and her colleagues conducted a double-blind, randomized trial of the GBS vaccine that included a total of 650 sexually active, non-pregnant women ages 18 to 40 who were GBS-negative in the vagina and rectum at the beginning of the study. Approximately one-half of the women were in the control group and received a licensed tetanus and diphtheria toxoids (Td) vaccine instead of the GBS vaccine. The women were followed for 18 months after they were vaccinated and checked for GBS bacteria at regular intervals. The goal of the study was to see whether vaccination could prevent or decrease colonization by one of the most common subtypes of GBS bacteria: Type III.

Although the vaccine had a modest effect on bacterial colonization (36 percent in the vagina and 43 percent in the rectum), it provided some protection over the entire period of the study. The GBS vaccine also was found to be safe and well-tolerated, and elicited a strong immune response. The next step to prevent GBS disease would be to develop vaccines that provide protection against a broader range of GBS types and test them in clinical trials.

WHEN: Dr. Hillier will present these findings on Friday Oct. 30, 2009, at 10:00 a.m. at the 47th Annual Meeting of the Infectious Diseases Society of America in Philadelphia.

WHO: Fran A. Rubin, Ph.D., Program Officer for Group A streptococci, Group B streptococci, Maternal Immunization Respiratory Diseases Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases

UC Davis leads attack on deadly new diseases

Fri, 23 Oct 2009 03:59:36 PST

( from http://www.rxpgnews.com ) In hopes of preventing the next global pandemic and a possible deathtoll into the millions, UC Davis today launches an unprecedentedinternational effort to find and control diseases that move betweenwildlife and people.

The global early warning system, named PREDICT, will be developedwith funding of up to $75 million over five years and is one of fivenew initiatives of the U.S. Agency for International Development(USAID) known in combination as the Emerging Pandemic ThreatsProgram. Building on its long-standing programs in diseasesurveillance and response, USAID is developing these initiatives tohelp prepare the world for infectious diseases like H1N1 flu, avianflu, SARS and Ebola.

UC Davis' primary PREDICT partners, which have formed a globalconsortium to implement PREDICT around the world, are: WildlifeConservation Society, Wildlife Trust, Global Viral Forecasting Inc.,and Smithsonian Institution.

Predicting where new diseases may emerge from wild animals, anddetecting viruses and other pathogens before they spread amongpeople, give us the best chance to prevent new pandemics, said JonnaMazet, the UC Davis scientist leading PREDICT. Mazet directs the UCDavis Wildlife Health Center within the new One Health Institute atthe School of Veterinary Medicine.

The concept of 'One Health' -- that human, animal and environmentalhealth are inextricably linked and should be considered holistically-- is a core principle of the PREDICT team.

To establish and maintain global pathogen surveillance, we will workdirectly with local governments and conservation organizations tobuild or expand programs in wildlife and human health. Together wewant to stop the next HIV, Mazet said. This collaborative approachis key to PREDICT's success.

The PREDICT team will be active in global hotspots where importantwildlife host species have significant interaction with domesticanimals and high-density human populations. They may include SouthAmerica's Amazon Basin, Africa's Congo Basin and neighboring RiftValley, South Asia's Gangetic Plain, and Southeast Asia. Asactivities in targeted regions come on-line, the team will focus ondetecting disease-causing organisms in wildlife before they spillover into people.

While no one can predict with certainty where the next pandemicdisease will emerge, being ready for early detection and rapidresponse will minimize its potential impact on our social andeconomic well-being, said Murray Trostle, deputy director of theAvian and Pandemic Influenza Preparedness and Response Unit of USAID.

UC Davis will bring on emerging-disease authority Stephen S. Morse ofColumbia University Mailman School of Public Health as director ofPREDICT. Morse said that, historically, pandemics -- epidemics thatspread around the world -- occurred perhaps every 30 to 40 years.But in our modern world, the chances of novel diseases or even a newpandemic emerging are higher than ever, because of how we live andthe extent to which we travel, Morse said. Our human settlements androadways push deeper into forests and wild areas where we now raiselivestock and poultry; and we transport ourselves, our animals andour food farther and faster around the globe.

Those conditions enable the spread of microbes, especially virusesand bacteria, from animals to humans. Among the 1,461 pathogensrecognized to cause diseases in humans, at least 60 percent are ofanimal origin.

Notable outbreaks of these animal-to-human diseases, or zoonoses(pronounced ZO-oh-NO-sees), include:

New therapy for vasculitis will help patients avoid infertility and cancer

Sat, 17 Oct 2009 03:59:36 PST

( from http://www.rxpgnews.com ) Researchers have identified that Rituxan, a drug previously approved for the treatment of non-Hodgkin's B cell lymphoma and rheumatoid arthritis, can treat severe ANCA-associated vasculitis as effectively as cyclophosphamide, the current standard therapy. The news will be presented October 18 at the annual meeting of the American College of Rheumatology in Philadelphia.

The reason this is a big deal is that this is a disease where people would come in and be told 'listen, we are probably going to be able to get on top of your life-threatening disease by using cyclophosphamide, there is the potential for major side effects down the road from this drug,' said Robert Spiera, M.D., an associate attending rheumatologist at Hospital for Special Surgery in New York. This study provides strong evidence that Rituxan works as well as cyclophosphamide, at least in terms of getting patients into remission, and over that acute hump of being very ill. And, we can treat patients without the likelihood of causing infertility or causing secondary cancers, which have been a concern with the use of cyclophosphamide.

Hospital for Special Surgery was one of nine centers involved in the Phase III trial, which was led by Ulrich Specks, M.D., a professor of medicine in the Department of Pulmonary and Critical Care Medicine at the Mayo Clinic, and John Stone, M.D., MPH, director, Clinical Rheumatology, Massachusetts General Hospital.

Vasculitis, an inflammation of the blood vessels, can damage tissues and organs and, in severe cases, lead to death. Specifically, the study examined something known as ANCA-associated vasculitis that includes Wegener's granulomatosis and microscopic polyangiitis. The reason this is such a significant study is that this is an uncommon but devastating group of diseases, said Dr. Spiera. Prior to the use of cyclophosphamide treatment, 70 percent of patients who were diagnosed with severe forms of ANCA-associated vasculitis could be expected to be dead within three years. In the 1970s, doctors discovered that cyclophosphamide was extremely effective at combating the disease and could put people into remission. In the ensuing decades, however, doctors recognized that these drugs came with a price.

If you followed patients long enough, you found they had a higher risk of leukemias, lymphomas and solid tumors, said Dr. Spiera, who is also an Associate Professor at Weill Cornell Medical College. People would sometimes develop terrible infections. Women, almost reliably, would become infertile, as did many men. So, although it was a dramatically effective drug at reducing remissions in these patients, it came at a price.

In the current study, nine centers enrolled a total of 197 patients with severe Wegener's granulomatosis or microscopic polyangiitis, two of the more common types of ANCA-associated vasculitis. Patients were given steroids and randomized to receive either the standard treatment with cyclophosphamide or Rituxan given at a dose of 375 mg/m2 weekly for four weeks. Investigators used the standard tools to assess disease status and remission. The study was rigorously designed and was double-blinded, meaning that neither patient nor doctor knew which drug individuals were getting.

At the time of the data analysis, 84 of the 99 (85%) patients in the Rituxan arm and 81 of the 98 patients (83%) in the cyclophosphamide arm had completed six months of follow-up. Investigators found that the treatments were equally effective in putting patients into remission and that, in fact, the treatment outcomes looked slightly better in patients receiving Rituxan (64% vs. 55%). This difference, however, was not considered statistically significant (P=0.21).

These results show that the Rituxan worked at least as well as cyclophosphamide, Dr. Spiera said. If anything, there was almost a hint of it maybe looking a little better, and even in the short term, it looked safer in some respects. This study shows that there is strong evidence that Rituxan may be an alternative to cyclophosphamide in this disease. It might help manage flares in patients who have gone into remission, and it could be a consideration as first-line therapy, especially in women of child bearing potential who have a good chance of losing their fertility if treated with cyclophosphamide.

Until this study, there was only anecdotal evidence that Rituxan would be beneficial in patients with vasculitis. ANCA-associated vasculitis is one of the few rheumatic diseases that is equally represented in men and women. It can occur in people of all ages. Rituxan, manufactured by Genentech, is currently approved in the U.S. to treat non-Hodgkin's lymphoma and rheumatoid arthritis.

NIH prepares to launch 2009 H1N1 influenza vaccine trial in people with asthma

Fri, 09 Oct 2009 03:59:36 PST

( from http://www.rxpgnews.com ) The National Institutes of Health is preparing to launch the first government-sponsored clinical trial to determine what dose of the 2009 H1N1 influenza vaccine is needed to induce a protective immune response in people with asthma, especially those with severe disease. The study is cosponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Heart, Lung, and Blood Institute (NHLBI), both part of NIH.

People with severe asthma often take high doses of glucocorticoids that can suppress their immune system, placing them at greater risk for infection and possibly serious disease caused by 2009 H1N1 influenza virus, says NIAID Director Anthony S. Fauci, M.D. We need to determine the optimal dose of 2009 H1N1 influenza vaccine that can be safely administered to this at-risk population and whether one or two doses are needed to produce an immune response that is predictive of protection.

The study plan has been submitted to the Food and Drug Administration for review. With FDA allowing it to proceed, the clinical trial will be conducted at seven sites across the United States that participate in NHLBI's Severe Asthma Research Program.

This program already has a well-characterized group of participants with mild, moderate or severe asthma who may be eligible for this new study. These groups are largely distinguished by the amount and frequency of glucocorticoids needed to control asthma symptoms. People with mild disease may not need glucocorticoids, or may require low doses of inhaled glucocorticoids; those with moderate asthma need low to moderate doses of inhaled glucocorticoids; and those with severe asthma need high doses of inhaled glucocorticoids and frequently use oral glucocorticoids as well.

Individuals who already have been infected with 2009 H1N1 influenza or have received a 2009 H1N1 influenza vaccination will not be eligible for the study.

The results of this study will have immediate implications for individuals with severe asthma as well as those who have milder asthma, says NHLBI Director Elizabeth G. Nabel, M.D.

Early results from other clinical trials of 2009 H1N1 influenza vaccines in healthy adults have shown that a single 15-microgram dose of 2009 H1N1 influenza vaccine without adjuvant is well tolerated and induces a strong immune response in most participants. The same vaccine also generates an immune response that is expected to be protective in healthy children ages 10 to 17 years. Ongoing trials are comparing the immune response to one and two doses of 15- or 30-micrograms of vaccine given three weeks apart in various populations.

The Centers for Disease Control and Prevention has recommended that certain at-risk populations receive the new H1N1 vaccine as a priority before the general population. These target populations include pregnant women, health care providers and individuals with underlying chronic medical conditions, including asthma.

People who have severe asthma may be particularly at risk for infection with the 2009 H1N1 influenza virus. A report published in 2004 suggested that some people who took high doses of glucocorticoids to treat their asthma may receive less protection from influenza vaccines against some strains of influenza. Early in the 2009 H1N1 flu outbreak a CDC review of hospital records found that people with asthma have a four-fold increased risk of being hospitalized with infection compared to the general population.

The study will enroll approximately 350 people with mild, moderate and severe asthma. Participants will be organized into two groups: those with mild or moderate asthma and those with severe asthma. Half of the participants in each group will receive a 15-microgram dose of vaccine, and the other half a 30-microgram dose. Three weeks later, each participant will receive a second dose of the same amount. The strength of the immune response induced by the vaccine will be determined in blood samples by measuring the level of antibodies against 2009 H1N1 flu virus.

Safety data will be collected and examined throughout the course of the study by trial investigators and by an independent safety monitoring committee. Participants will be monitored for any side effects they may experience because of the vaccine, as well as asthma attacks that occur during the study period.

The vaccine to be used in the trial, manufactured by Novartis, contains inactivated 2009 H1N1 influenza virus and therefore cannot cause anyone to become infected with the virus.

The trial will be conducted at the following locations:

NIH launches 2009 H1N1 influenza vaccine trials in HIV-infected pregnant women

Fri, 09 Oct 2009 03:59:36 PST

( from http://www.rxpgnews.com ) The first clinical trials to test whether the 2009 H1N1 influenza vaccine can safely elicit a protective immune response in pregnant women launched yesterday, and a trial to conduct the same test in HIV-infected children and youth will begin next week. The International Maternal Pediatric Adolescent AIDS Clinical Trials Group is conducting the studies, which are sponsored and funded by the National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), both part of the National Institutes of Health.

These studies are important because HIV infection and pregnancy both increase the risk for a poor immune response to the normal 15-microgram dose of seasonal influenza vaccine given to the general population, says NIAID Director Anthony S. Fauci, M.D. Moreover, children, young people and pregnant women are at higher risk for more severe illness from the 2009 H1N1 influenza virus than other groups, and HIV-infected individuals in these populations may be particularly vulnerable.

Because of the increased vulnerability of these populations, these trials are testing whether doses of licensed 2009 H1N1 influenza vaccine that are higher than doses being tested in other groups can safely elicit protective immune responses in HIV-infected children, youth and pregnant women, adds Lynne Mofenson, M.D., chief of the Pediatric, Adolescent and Maternal AIDS Branch in NICHD.

One trial will enroll 130 HIV-infected pregnant women ages 18 to 39 years who are in their second or third trimester (14 to 34 weeks) of pregnancy. The other trial will enroll 140 children and youth aged 4 to 24 years who were infected with HIV at birth.

Thirty-five sites and eight sub-sites across the United States and Puerto Rico are eligible to conduct the trials. Each volunteer will receive two 30-microgram doses of 2009 H1N1 influenza vaccine 21 days apart. (In contrast, the NIAID studies of 2009 H1N1 influenza vaccine in HIV-uninfected children, youth and pregnant women are testing doses of 15 and 30 micrograms.)

Safety data will be collected and monitored closely by the study investigators and an independent safety monitoring committee. The strength and longevity of the immune response elicited by the vaccine will be gauged in several ways.

The study team will take blood samples from the pregnant women after each dose and three and six months after delivery to measure the concentration of antibodies the women produce against 2009 H1N1 influenza virus and how strong that antibody response remains over time. After the women give birth, study staff will sample umbilical cord blood to measure the concentration of maternal antibodies against the H1N1 virus that were transferred to the infants through the placenta. The study team also will collect small blood samples from the infants at 3 and 6 months of age to measure their level of maternally derived antibody protection from the virus over time. The infants will not receive vaccine.

Similarly, in children and young people, the strength and longevity of the immune response will be gauged by testing blood samples taken 21 days after the first dose, 10 days after the second dose, and six months after entering the study.

The vaccine, manufactured by Novartis Vaccines and Diagnostics, contains inactivated 2009 H1N1 influenza virus, so it is impossible to become infected with the virus by receiving the vaccine. The vaccine does not contain adjuvant, a substance added to some vaccines to improve the body's response to vaccine.

Research on seasonal influenza vaccine and vaccines for other diseases in HIV-infected and other populations suggest that higher doses of vaccine tend to elicit stronger immune responses. These stronger responses, in turn, increase the concentration of protective antibodies in the bloodstream, which likely is beneficial to both the vaccinated individual and, if pregnant, to her fetus. This is the rationale for testing whether higher doses of licensed 2009 H1N1 influenza vaccine elicit a protective immune response in HIV-infected individuals and whether that protection is transferred to the fetuses of vaccinated pregnant women.

NIAID announces vaccine adjuvant discovery contracts

Thu, 08 Oct 2009 03:59:36 PST

( from http://www.rxpgnews.com ) The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has awarded six new research contracts to discover and characterize novel adjuvants, substances that can be added to vaccines to enhance the protective immune response they induce.

The goal of these awards is to find safe new adjuvants that will boost the effectiveness of vaccines, says NIAID Director Anthony S. Fauci, M.D. Adjuvants can be used not only to enhance the immune response to a vaccine and thereby offer better protection but also to extend the vaccine supply if needed, enabling more people to be vaccinated with fewer doses.

Currently, the only vaccine adjuvant approved for use in the United States is an aluminum mixture known as alum.

NIAID has awarded a total of approximately $60 million over five years for these contracts. The awardees will identify novel compounds with the potential to be vaccine adjuvants. All compounds will be tested in animal models and human cells to determine how well they stimulate the immune response. The investigators also will examine and describe the cellular reactions the compounds induce.

The goal of these awards is not only to identify new adjuvant candidates but also to describe how these candidates work, says Helen Quill, Ph.D., chief of NIAID's basic immunology research branch. We would hope that these adjuvant candidates will become part of a robust pipeline leading to the development of many different vaccines.

The awardees of the adjuvant contracts will work to identify and characterize novel adjuvants that trigger receptors of the inborn, or innate, immune system. These receptors recognize and bind small molecules that are unique to harmful microorganisms. Binding stimulates an immediate innate immune response, a broadly protective reaction. The innate immune response also is required for the development of the highly specific antibody and T-cell responses that characterize long-term immunity.

The investigators also will seek to identify the cellular receptor for each of the novel adjuvant candidates, determine how it triggers the innate immune response, and then make changes to the adjuvant to improve its ability to induce the innate immune response. Although a number of innate immune receptors already have been described, many more likely exist and are expected to be uncovered in the course of these projects.

The award of these contracts is an integral part of NIAID's long-range plan to expand the adjuvant pipeline, says Daniel Rotrosen, M.D., director of NIAID's Division of Allergy, Immunology, and Transplantation, which oversees these awards. A first round of NIAID contracts, awarded in 2003, limited the discovery of novel adjuvants to those that stimulated the only group of innate immune receptors known at the time. With this second round of awards, we intend to increase the number of adjuvant candidates by expanding the research scope to include all known innate immune receptors.

The institutions receiving contracts for 2009 are

Lessons learned from H1N1 virus pandemic

Thu, 08 Oct 2009 03:59:36 PST

( from http://www.rxpgnews.com ) A comprehensive study has revealed, for the first time, the impact of swine flu on the health of the general public in Australia and New Zealand.

The lessons learned in Intensive Care Units (ICUs) across the two countries on the impact of the H1N1 (swine flu) virus are being shared with countries in the Northern Hemisphere to help them prepare for their upcoming flu season.

The three-month study, conducted at the height of the pandemic between June and August, reveals that 722 patients were admitted to ICUs and that at the peak of the epidemic up to 20 per cent of ICU beds were occupied by patients with swine flu infection.

The study was co-coordinated by the Monash University-based Australian and New Zealand IntensiveCare Research Centre (ANZIC-RC). The study involved all ICUs in Australia and New Zealand with the affected patients being treated in 109 of these units. The study was conducted utilising the resources of the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG).

Dr Ian Seppelt, a specialist in Intensive Care Medicine and based at Sydney's Nepean Hospital, saidthe impact of the virus on ICUs across Australia and New Zealand was dramatic.

Intensive Care Units specialise in the management of patients with life-threatening illness and thesurge of patients with H1N1 placed substantial strain on staff and resources. The most severely affected patients had pneumonia affecting both lungs that was caused by the virus. The number of patients admitted to ICUs with this complication represented a 600 per cent increase compared toprevious years, Dr Seppelt said.

Clinical Associate Professor Steve Webb, from the Intensive Care Unit at Royal Perth Hospital, wasanother key researcher on the project and said the information, which surfaced from the study willbenefit other countries about to head into their winter flu season.

Unlike previous 'seasonal' influenza strains, which impact heavily on elderly people and people withsevere coexisting medical conditions, the H1N1 virus affected a different profile. Critical illness due toswine flu was most common in infants and middle aged people; with pregnant patients, the overweight,and indigenous patients particularly affected. Overall, about one-third of patients admitted to anICU because of swine flu had no underlying health problems. Associate Professor Webb said.

Professor Rinaldo Bellomo, Foundation Chair of the ANZICS CTG and Director of Intensive CareResearch at Austin Health, Melbourne said the results of the study would be shared with health authorities in other countries to assist them better prepare for their flu season.

We have come through our flu season and our assessment of the impact of the H1N1 strain will assist them prepare for any outbreak. The H1N1 virus has taken hold in many countries already, but many countries in the Northern Hemisphere will benefit from the lessons we have learned, Professor Rinaldo Bellomo said.

Fortunately a vaccine is now available to prevent the complications of swine flu and it is important thatall members of the community and especially those with risk factors, consider being vaccinated, hesaid.

Research ensures 50 million vaccinated against deadly brain infection

Tue, 06 Oct 2009 03:59:36 PST

( from http://www.rxpgnews.com ) Research at the University of Liverpool has supported the vaccination of more than 50 million people against a zoonotic brain infection that affects thousands of children across Asia every year.

The infection, called Japanese encephalitis (JE), is found in pigs and wading birds and transmitted by mosquitoes in areas of Southeast Asia and the Western Pacific. The World Health Organisation (WHO) estimates that JE affects approximately 50,000 people a year and kills around 15,000. Those that survive the infection can be left brain damaged.

Scientists at Liverpool, in collaboration with Asian governments, the WHO and the Program for Appropriate Technology in Health (PATH), are improving understanding of the disease and developing immunisation programmes to control it, with the support of funds from the Bill and Melinda Gates Foundation.

Children in poor rural communities are particularly vulnerable to the infection, but as a result of improved diagnostics and clinical management, vaccinations against the disease have now reached more than 50 million children and the programme continues across Asia.

Professor Tom Solomon, Head of the University's Brain Infection Group, said: Japanese encephalitis invades the central nervous system and can cause seizures, paralysis and in severe cases, death. Approximately 50 per cent of people who survive the infection are left with physical and mental illness, which could include personality changes. It affects children between the ages of one to 15, but adults, including tourists to the region, can contract the disease also.

Although we knew this disease was important, five years ago it was virtually unrecognised due to the difficulty in diagnosing cases. It causes disability more often than it causes death, but with no standard method of quantifying the disability, it was difficult for governments to make decisions on introducing vaccines. We have been developing ways of diagnosing JE and measuring the outcome of the infection, and these methods are now being used in many countries across Asia.

Previously scientists used highly specialised laboratories to grow cultures of the virus, but these facilities were not widely available across Asia. The Liverpool team, and partner institutions, have developed simple blood tests that allow medics to detect antibodies of the disease, a procedure that can be performed in hospitals and regional labs to provide accurate diagnosis.

Scientists have been working to enhance disease detection by developing surveillance guidelines, which helps medics build a database of all patients that enter hospitals with symptoms of the infection. The system allows authorities to monitor the number of people infected so that appropriate measures can be taken to protect against the disease. The team have also developed a standard method of quantifying the disabilities caused by JE. This gives a profile of the disease and shows how to characterise the disabilities children may have after the infection has left the body.

As a result of these new measures many governments across Asia are beginning to effectively control JE through vaccination.

Vitamin D's role in preventing asthma studied in pregnant women

Thu, 01 Oct 2009 03:59:36 PST

( from http://www.rxpgnews.com ) A group of pregnant women who have asthma or allergies will get extra vitamin D as part of a study to determine if the vitamin can prevent their children from developing asthma.

Washington University School of Medicine in St. Louis is part of the multi-center trial in collaboration with Boston University and Brigham and Women's Hospital in Boston and Kaiser Permanente Medical Center in San Diego.

Children born to one or both parents with asthma or allergies have a higher risk of developing asthma than children whose parents don't have asthma or allergies. Recent studies have shown that vitamin D plays a role late in pregnancy in developing lungs and that higher levels of maternal vitamin D may be associated with lower rates of asthma in their children. However, researchers don't know if increasing or correcting those vitamin D levels prior to or during pregnancy can prevent the disease.

We want to find a definitive answer to that question, says Robert C. Strunk, M.D., a Washington University pediatric asthma and allergy specialist at St. Louis Children's Hospital. If we could simply supplement women during pregnancy and decrease asthma prevalence in children, that would be a huge impact on child health.

Strunk, lead investigator of the trial, said asthma has doubled in U.S. children over the last two decades. About 6.7 million American children suffer from asthma, according to the Centers for Disease Control and Prevention, making it the most common chronic childhood illness. About 90 percent of all cases are diagnosed before age 6.

Vitamin D deficiency is also prevalent in the United States, occurring in healthy children and adults despite fortification of foods and intake of multivitamins. Pregnant and lactating women and their children are at high risk for vitamin D deficiency, although most pregnant women take prenatal vitamins. Researchers say the shift from outdoor activities and less time spent in the sun is one factor.

The Vitamin D Antenatal Asthma Reduction Trial (VDAART), a five-year research study funded by the National Institutes of Health, will enroll women between 10-18 weeks of pregnancy and randomly divide them into two groups. One group will receive a typical prenatal vitamin with 400 units of vitamin D and a 4,000-unit vitamin D supplement. The other group will receive the same prenatal vitamin plus a placebo.

The trial seeks to enroll 870 women nationwide. Washington University School of Medicine seeks to enroll 290 women from its obstetrics and gynecology clinics and one outside clinic.

During the course of the study, patients will attend regular visits with their obstetrician, provide blood and urine samples and answer questionnaires about diet, pregnancy, sunlight exposure, physical activity, health and medications. Their children born during the study will be evaluated for asthma and recurrent wheezing at ages 1, 2 and 3.

What's very attractive about this study is how simple it is, said George A. Macones, M.D., the Mitchell and Elaine Yanow Professor and head of Obstetrics and Gynecology at the School of Medicine and a co-investigator on the study. We hope that supplementing mothers with extra Vitamin D during pregnancy will help to reduce risks of asthma in children and will improve children's health over the long term.

HIV vaccine regimen demonstrates modest preventive effect in Thailand clinical study

Thu, 24 Sep 2009 03:59:36 PST

( from http://www.rxpgnews.com ) In an encouraging development, an investigational vaccine regimen has been shown to be well-tolerated and to have a modest effect in preventing HIV infection in a clinical trial involving more than 16,000 adult participants in Thailand. Following a final analysis of the trial data, the Surgeon General of the U.S. Army, the trial sponsor, announced today that the prime-boost investigational vaccine regimen was safe and 31 percent effective in preventing HIV infection.

These new findings represent an important step forward in HIV vaccine research, says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, which provided major funding and other support for the study. For the first time, an investigational HIV vaccine has demonstrated some ability to prevent HIV infection among vaccinated individuals. Additional research is needed to better understand how this vaccine regimen reduced the risk of HIV infection, but certainly this is an encouraging advance for the HIV vaccine field.

We thank the trial staff in Thailand and the United States for their years of effort in successfully conducting this study and the study participants and the people of Thailand for their long-standing support of HIV vaccine research, Dr. Fauci adds.

The Thai Phase III HIV vaccine study, also known as RV144, opened in October 2003. The placebo-controlled trial tested the safety and effectiveness of a prime-boost regimen of two vaccines: ALVAC-HIV vaccine (the primer dose), a modified canarypox vaccine developed by Sanofi Pasteur, based in Lyon, France, and AIDSVAX B/E vaccine (the booster dose), a glycoprotein 120 vaccine developed by Vaxgen Inc., and now licensed to Global Solutions for Infectious Diseases (GSID), based in South San Francisco, Calif. The vaccines are based on the subtype B and E HIV strains that commonly circulate in Thailand. The subtype B HIV strain is the one most commonly found in the United States.

Led by principal investigator Supachai Rerks-Ngarm, M.D., of the Thai Ministry of Public Health's Department of Disease Control, the study was sponsored by the U.S. Army in collaboration with NIAID, Sanofi Pasteur and GSID. The trial, conducted in the Rayong and Chon Buri provinces of Thailand, enrolled 16,402 men and women ages 18 to 30 years old at various levels of risk for HIV infection. Study participants received the ALVAC HIV vaccine or placebo at enrollment and again after 1 month, 3 months, and 6 months. The AIDSVAX B/E vaccine or placebo was given to participants at 3 and 6 months. Participants were tested for HIV infection every 6 months for 3 years. During each clinic visit, they were counseled on how to avoid becoming infected with HIV.

In the final analysis, 74 of 8,198 placebo recipients became infected with HIV compared with 51 of 8,197 participants who received the vaccine regimen. This level of effectiveness in preventing HIV infection was found to be statistically significant. The vaccine regimen had no effect, however, on the amount of virus in the blood of volunteers who acquired HIV infection during the study.

The Thai study demonstrates why the HIV vaccine field must take a balanced approach to conducting both the basic research needed to discover and design new HIV vaccines and, when appropriate, testing candidate vaccines in people, says Margaret I. Johnston, Ph.D., director of NIAID's Vaccine Research Program within the Division of AIDS. Both avenues provide critical information that will continue to help us better understand what is needed to develop a fully protective HIV vaccine.

NIAID and the collaborating partners are working with other scientific experts to determine next steps, including additional research of the RV144 vaccine regimen and the need to consider the impact of these new findings on other HIV vaccine candidates.

Individuals who acquired HIV infection while participating in the Thai trial have been provided access to HIV care and treatment, including highly active antiretroviral therapy based on the guidelines of the Thai Ministry of Public Health.

ART therapy for babies, mothers safely reduces HIV transmission

Wed, 22 Jul 2009 03:59:36 PST

( from http://www.rxpgnews.com ) Giving daily antiretroviral syrup to breastfeeding infants or treating their HIV-infected mothers with highly active antiretroviral drugs is safe and effective in preventing mother-to-child HIV transmission through breast milk, a study led by University of North Carolina at Chapel Hill investigators has found.

This is an exciting development, said Charles van der Horst, M.D., a professor in the UNC School of Medicine and the study's lead investigator. We may be able to spare mothers in the developing world a horrible choice by offering them an effective method for preventing transmission of HIV during breastfeeding.

These findings, from investigators at UNC-Chapel Hill, UNC Project-Malawi in Lilongwe, Malawi and the U.S. Centers for Disease Control and Prevention (CDC), were presented July 22 at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Cape Town, South Africa (Abstract .WELBC1 - Late Breaker C 16:30 - 17:30 Session Room 2).

Approximately 420,000 infants are infected with HIV annually, half through breast milk. HIV-infected women in resource-constrained areas face a terrible dilemma: provide the many health and nutritional benefits of breast milk but face a 20 percent chance of transmitting the virus to their baby or choose costly formula, which relies on an unsafe water supply and carries a higher risk of morbidity and mortality, and avoid transmitting HIV.

The Breastfeeding, Antiretrovirals and Nutrition (BAN) study is the only large-scale, randomized trial comparing infant prophylaxis or maternal treatment to an enhanced standard-of-care arm in the prevention of HIV transmission through breast milk. The study was conducted in Lilongwe, Malawi at a single site. Investigators randomly assigned at total of 2,367 mother-infant pairs to one of three treatment arms. For both the interventions, the probability of HIV-infection was significantly lower than in the enhanced control arm.

Of the randomized infants, 4.9 percent were found to be HIV positive at birth. Among infants who were HIV-free at one week old, 6.4 percent on the enhanced control arm were infected by 28 weeks, compared to 3.0 percent of the infants on the maternal treatment arm and 1.8 percent of the infants who received daily nevirapine syrup. Upon examining the probability of HIV infection or death by 28 weeks postpartum, 7.6 percent of the infants on the enhanced control arm were HIV-infected or died compared to 4.7 percent of the infants on the maternal treatment arm, and 2.9 percent of the infants on the infant prophylaxis arm.

The BAN study results give global and national policy makers the choice of which intervention (maternal or infant antiretroviral intervention) to implement based on the conditions and resources in their particular setting. We hope to see these results translated quickly into program and policy.

Falling birth rates shift rotavirus epidemics

Thu, 16 Jul 2009 03:59:36 PST

( from http://www.rxpgnews.com ) Fewer births in states such as California may be delaying the annual onset of a common intestinal virus in the southwest, according to epidemiologists. The timing of infectious outbreaks in other locations such as the northeast remains more or less unchanged.

Rotavirus is a leading cause of diarrhea among children, both in the developed and developing world. In the United States, the virus causes about 60,000 hospitalizations each year and kills about 40 children below the age of five.

It is an imperfectly immunizing infection, said Virginia Pitzer, postdoctoral researcher in the Center for Infectious Disease Dynamics and the department of biology, Penn State. So you can get infected multiple times throughout your life.

Up until the late 1990s, annual rotavirus epidemics in the U.S. followed a predictable pattern. Infections appeared in the southwest and peaked in December or January, then spread to the northeast, where they peaked in March. In recent years epidemics in the southwest have begun later than usual.

Pitzer and her colleagues initially looked at environmental factors such as solar radiation, precipitation and temperature but these could not explain the shifts in outbreaks of new infections. Unlike other viruses that die out and are replenished each year with new strains from outside the United States, rotavirus infections tend to linger in the summer months.

In general, the pattern of spread of rotavirus outbreaks from the southwest to the northeast is not consistent with any climatic factors, explained Pitzer, whose findings appear today (July 17) in Science. For instance, temperature tends to be high in the southwest but it also tends to be high in places like Florida, where epidemics occur much later.

Instead, Pitzer and her colleagues looked at human birth rates and the potential link to the timing of rotavirus epidemics. While birth rates are typically high in the southwest and low in the northeast, census data indicates a recent decline in the southwest, particularly in California.

Statistical analysis suggested a negative correlation between birth rates and the timing of the epidemics between 1991 and 2006.

Each time there was a decline in birth rate, whether from state to state or year to year, infections tended to happen later, explained Pitzer.

A mathematical model using information on the epidemiology of rotavirus and birth rates from states confirmed the statistical correlation and predicted that given the declining birth rate in California, rotavirus epidemics in the state would gradually shift from December to February.

Since infants often have diarrhea and can be very infectious when they get rotavirus, they are the ones who tend to drive the epidemics, said Pitzer, who is also associated with Fogarty International Center at the National Institutes of Health through the Research and Policy for Infectious Disease Dynamics program. Thus, you can get outbreaks of rotavirus happening a lot sooner when and where there are more infants being born.

Vaccines introduced in 2006 further confirm Pitzer's model. Since vaccination reduces the number of infants vulnerable to symptomatic infections, the effect is analogous to a decline in birth rate.

With the effects of vaccination factored in, the model accurately predicted a small decrease in the incidence of severe diarrhea during the 2006-2007 season, and a larger decline and delay during 2007-2008, providing validation for our model, said Pitzer.

Researchers add that high levels of vaccination could further limit the intensity of new epidemics and lead to a period of years with very few cases of severe diarrhea caused by rotavirus.

The important message here is that vaccination can have a big impact in controlling rotavirus infections, explained Pitzer. Even those not vaccinated can benefit from those vaccinated because it lowers the overall prevalence of the infection in the population.

Falling birth rates shift rotavirus epidemics

Thu, 16 Jul 2009 03:59:36 PST

Common chemotherapy drug triggers fatal allergic reactions

Mon, 08 Jun 2009 03:59:36 PST

( from http://www.rxpgnews.com ) CHICAGO -- A chemotherapy drug that is supposed to help save cancer patients' lives, instead resulted in life-threatening and sometimes fatal allergic reactions.

A new study from the Research on Adverse Drug Events and Reports (RADAR) pharmacovigilance program at Northwestern University Feinberg School of Medicine identified 287 unique cases of hypersensitivity reactions submitted to the FDA's Adverse Event Report System between 1997 and 2007 with 109 (38 percent) deaths in patients who received Cremophor-based paclitaxel, a solvent-administered taxane chemotherapy.

Adverse event reports generally only represent from 1 to 10 percent of actual incidence, so the number of hypersensitivity reactions and deaths is likely significantly higher. The severe allergic reactions are believed to be caused by Cremophor, the chemical solvent - a derivative of castor oil -- that is used to dissolve some insoluble drugs before they can be injected into the blood stream.

Two patients who died from an allergic reaction had early-stage breast cancer, which had been surgically removed, and were being treated with Cremophor-containing paclitaxel to prevent the cancer from coming back. Both of these patients had received medications before the chemotherapy to reduce the risk of hypersensitivity reactions.

The study was led by Charles Bennett, M.D., RADAR program coordinator and a professor of hematology/oncology at Northwestern's Feinberg School, and Dennis Raisch, a professor of pharmacy at the University of New Mexico.

The deaths of women with early-stage breast cancer are particularly disturbing because without the adverse reaction, they could have likely had 40 years of life ahead of them, Bennett said.

RADAR investigators also found that 22 percent of all fatalities occurred in patients despite patients having received premedication to prevent hypersensitivity reactions, while another 15 percent of such patients experienced life-threatening respiratory arrest.

The report was presented at the 45th Annual Meeting of the American Society of Clinical Oncology held recently in Orlando, Fla.

Cremophor-containing paclitaxel has been associated with hypersensitivity reactions, with responses ranging from mild skin conditions to more severe effects, including anaphylaxis and cardiac collapse. Current U.S. product labeling for Cremophor containing paclitaxel includes a black-box warning alerting physicians and patients of potential toxicity and recommending the use of corticosteroids and other medications before chemotherapy administration to reduce the risk of hypersensitivity reactions.

The results of our review suggest that physicians should be vigilant in monitoring the safety of their patients undergoing chemotherapy treatment, said Bennett, who also is the A.C. Buehler Professor in Economics and Aging at the Feinberg School and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Patients receiving Cremophor-based paclitaxel should be given medications to prevent hypersensitivity reactions, but what is sobering, as the study has shown and as the black-box warning indicates, women suffer anaphylaxis despite receiving steroid premedication, Bennett said. Physicians should be diligent in reporting adverse events to regulatory agencies to better monitor the impact of Cremophor on patient safety. Physicians may also want to consider exploring other alternative chemotherapy options that do not include Cremophor.

In addition to the two women with early-stage breast cancer who died after treatment with the Cremophor-based paclitaxel, four other women with early-stage breast cancer experienced life-threatening anaphylaxis reactions. Each of them had received prior medications to prevent the reactions.

The fatal outcomes observed in patients with early-stage breast cancer were particularly striking as this is a patient population with a good prognosis that is generally treated with curative intent, said Raisch.

For the report, Bennett and Raisch reviewed adverse event reports submitted to regulatory agencies in the U.S., Europe and Japan. The most common cancer diagnosis for these patients with allergic reactions was lung cancer followed by breast cancer and ovarian cancer.

First mouse model for auto-inflammatory diseases reveals role for innate immunity

Sun, 07 Jun 2009 04:06:07 PST

( from http://www.rxpgnews.com ) Researchers at the University of California, San Diego School of Medicine have developed the first mouse model for auto-inflammatory diseases, disorders that involve the over-activation of the body's innate, primitive immune system. Their study, published early on-line in Cell Immunity on June 4, suggests that the innate – not adaptive – immune system drives auto-inflammatory diseases. The findings could open new therapeutic directions for research into disorders such as gout or inflammatory bowel disease.

"Auto-inflammatory diseases are a relatively new classification of diseases that are different from autoimmune diseases or allergies," said Hal Hoffman, MD, associate professor of medicine at UC San Diego School of Medicine. Hoffman studies a group of rare, inherited auto-inflammatory conditions called Cryopyrin-Associated Periodic Syndromes (CAPS), which includes Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS).

Autoimmune diseases arise from an overactive response of the body's adaptive, or acquired, immune system against substances and tissues normally present in the body. Allergies are also a product of the adaptive immune system, but in response to environmental substances. Both involve the action of lymphocytes such as B cells and T cells. The older innate immune system, on the other hand, recruits immune cells to sites of infection and inflammation, but doesn't confer long-time protection. Pathogens evoke an inappropriate response that doesn't involve antibodies or lymphocytes.

With CAPS, Hoffman had earlier discovered that mutations of the NLRP3 gene caused the auto-inflammatory disease symptoms because the gene causes alterations in the protein called cryopyrin. Cryopyrin regulates the release of interleukin-1, an important mediator of fever and systemic inflammation during the body's innate immune response, and alterations in cryopyrin lead to over-production of Il-1.

Mutations in the NLRP3 gene are thought to result in inappropriate activation of a multi-protein complex called an inflammasome, leading to excessive Il-1β release and manifestation of CAPS disease symptoms. Treatment with Il-1β inhibitors reduces the inflammation and symptoms in auto-inflammatory diseases; however, NLRP3 may have other effects in addition to increased Il-1β.

"Patients treated with the Il-1β inhibitors got much better, but still exhibited some symptoms," said Hoffman.

In order to examine the role of inflammatory mediators and adaptive immune responses in CAPS, the researchers developed two NLRP3 mutant knock-in mouse models. (In "knock-in" models, genetic information is inserted into a particular part of the genome; in contrast to "knock-out" mouse models, in which genetic information is removed.) These mice had systemic inflammation and poor growth, similar to some human patients.

By mating these mice to mice with various gene mutant backgrounds, the scientists showed that CAPS requires an intact inflammasome, is only partially dependent on Il-1β and is independent of T cells. Their findings may help lead to more effective treatments for CAPS syndromes.

"The data shows that CAPS are true inflammasome-mediated diseases and that the adaptive immune system is not necessary for this disease," said Hoffman.

"In the larger picture, our findings also suggest that innate and adaptive immune systems don't necessarily always 'cross talk' or communicate with one another."

According to the researchers, given the importance of IL-Β and the inflammasome to innate immunity, NLRP3 knock-in mice may be applied to the study of many diseases along the autoinflammatory-autoimmune spectrum.

Obesity does not worsen asthma, but may reduce response to medications

Wed, 03 Jun 2009 03:59:36 PST

( from http://www.rxpgnews.com ) Being overweight or obese does not make asthma worse in patients with mild and moderate forms of the disease, according to a study by National Jewish Health researchers, although it may reduce the response to medications.

With both asthma and obesity on the rise in recent years, there has been much interest in the possible link between these two conditions, said lead author E. Rand Sutherland, Associate Professor of Medicine at National Jewish Health. By studying a well characterized group of patients with asthma, we were able to determine that increased weight is not associated with more severe asthma. Although benefits can be obtained with weight loss in other diseases, these findings suggest that an improvement in asthma may not necessarily result from weight loss.

The findings also suggest that patients and physicians should be aware that obese asthma patients may not respond well to corticosteroids, the most successful controller medication for asthma, which can affect dosing decisions and choices of possible alternatives to steroids.

Previous studies have suggested that obesity predisposes people to developing asthma, to suffer more severe asthma symptoms, and to respond less to medications. However, the exact mechanism for these links has been unclear, and the studies have generally relied upon patients' reports of their diagnosis and symptoms rather than using more precise tools to characterize patients.

Dr. Sutherland and his colleagues decided to examine the issue in a well characterized group of 1,256 patients who had participated in NIH-sponsored studies. They divided them into patients with a body mass index of less than 25 (lean) and greater than or equal to 25 (overweight and obese). They found that lean asthma patients had slightly greater forced expiratory volume in one second , or FEV1 (3.05 liters vs 2.91 liters), and slightly greater ratio of FEV1 to forced vital capacity (83.5% vs. 82.4%), both common measures of lung function. They also found slightly greater use of rescue inhalers among overweight patients (1.2 puffs per day vs. 1.1 puffs per day) and slightly higher scores asthma-relate quality of life questionnaires (5.77 vs. 5.59).

These differences were small and are unlikely to be of any real clinical significance, said Dr. Sutherland.

Response to medications, however, did show an effect of increased weight. Among a subgroup of 183 people, lean patients taking inhaled corticosteroids alone showed a 55% greater reduction in exhaled nitric oxide, a measure of inflammation. Lean patients taking a combination inhaled steroid and long-acting beta agonist increased their FEV1 by 80 more milliliters. There were no differences, however, between these patients in the number of asthma exacerbations.

The data suggest overweight and obese people respond less well to controller medications for asthma than do their lean counterparts, said Dr. Sutherland. These data come from already-completed studies designed to answer other questions, however, and ongoing studies are being conducted to more definitively determine the effect of increased weight on treatment response in asthma.

Indiana U. research at the American College of Sports Medicine conference

Sat, 30 May 2009 03:59:36 PST

( from http://www.rxpgnews.com ) Note: Information about the high-speed accelerometers study presented on Saturday is embargoed until the time of the 10:30 a.m. PDT presentation. Information about the other studies is not embargoed

CAFFEINE SHOWN AS EFFECTIVE AT REDUCING EXERCISE-INDUCED ASTHMA SYMPTOMS AS AN ALBUTEROL INHALER

An Indiana University study found that the ingestion of caffeine within an hour of exercise can reduce the symptoms of exercise induced asthma (EIA).

A large dose -- 9 milligrams of caffeine per kilogram of body weight -- was as effective as the use of an albuterol inhaler, which is commonly used to treat or prevent exercise-induced asthma. Smaller amounts of caffeine -- for example, 3 and 6 milligrams of caffeine per kilogram of body weight -- also reduced the wheezing, coughing and other symptoms of EIA.

Timothy Mickleborough, an associate professor in the Department of Kinesiology and co-investigator of the study, said no additional benefit was found when caffeine was combined with an albuterol inhaler.

Mickleborough and his research colleagues have been investigating the efficacy of a number of nutritional factors, and his research to date has shown that a diet high in fish oil and antioxidants and low in salt has the potential to reduce the severity of EIA and perhaps reduce the reliance on pharmacotherapy. This is especially important since prolonged use of daily medications can result in reduced effectiveness, and there is growing concern about the potential side effects of inhaled corticosteroid use.

*Background: The caffeine study involved 10 asthmatic subjects who also had EIA, in a randomized, double-blind double-dummy crossover study. They ingested 3, 6, or 9 milligrams of caffeine per kilogram of body weight or a placebo an hour before running on a treadmill. Pulmonary function tests were conducted 15 minutes before the a eucapnic voluntary hyperpnea challenge (a surrogate for an exercise challenge) and then again 1, 5, 10, 15 and 30 minutes afterward.

For someone weighing 150 pounds, 3 to 9 milligrams of caffeine per kilogram of body weight equals around 205 to 610 milligrams of caffeine. Earlier research has found that caffeine can reduce the symptoms of EIA. This study extends this earlier work and is the first to examine any synergistic effect of caffeine use along with an albuterol inhaler.

The study, Comparative and Synergistic Effects of Caffeine and Albuterol on The Severity of Exercise-Induced Bronchoconstriction, was presented at the American College of Sports Medicine conference during the Respiratory Session on Friday morning. Co-authors include lead author Timothy A. VanHaitsma, now at the University of Utah; Martin R. Lindley, Loughborough University, United Kingdom; and David Koceja and Joel Stager, IU's Department of Kinesiology.

Mickleborough can be reached at 812-855-0753 and

New vaccine strategy might offer protection against pandemic influenza strains

Mon, 18 May 2009 03:59:36 PST

( from http://www.rxpgnews.com ) A novel vaccine strategy using virus-like particles (VLPs) could provide stronger and longer-lasting influenza vaccines with a significantly shorter development and production time than current ones, allowing public health authorities to react more quickly in the event of a potential pandemic.

Ted Ross, Ph.D., an assistant professor at the University of Pittsburgh's Center for Vaccine Research, will present his laboratory's latest data on the efficacy of VLP vaccines for potential pandemic strains, such as H5N1 and 1918 influenza, today at the 109th General Meeting of the American Society for Microbiology in Philadelphia.

Virus-like particles look just like a live virus, but they are hollow shells without a genome inside and they cannot reproduce, Ross explained. Because they look like the virus, they evoke a more robust immune response against the real thing.

Ross and his colleagues have already made VLP vaccines that have been tested in early clinical trials and appear to provide complete protection against both the H5N1 avian influenza virus and the 1918 Spanish influenza virus.

There is a debate in the influenza community about priming the human population for potential pandemic strains such as H5N1 or 1918, Ross said. Some researchers advocate adding these strains to the annual flu vaccine. They might not match the next pandemic flu strain exactly, but could provide some of protection.

Others contend that it might be premature, as well as costly, to vaccinate people against a virus that may never emerge, he said.

The current injectable vaccine for seasonal influenza is a trivalent, inactivated vaccine. It consists of three different influenza strains that are grown in eggs and then inactivated, or killed, by chemicals that break them into tiny pieces. Because they no longer look like the circulating virus, conventionally made vaccines strains do not elicit as strong an immune response as VLP vaccines. Because it is made with live, attenuated virus, the inhaled, mist-based vaccine can elicit a strong immune response but can also increase the risk of side effects.

VLPs can be quickly and easily produced in several ways, including growing them in cell cultures or in plants. Also, if the genes in the disease virus are identified, then researchers can generate particles for a vaccine without an actual sample of the agent.

The sequence for the recent H1N1 'swine flu' virus was online and available to scientists long before physical samples could be delivered, Dr. Ross noted. It would have been possible to produce VLPs in quantity in as little as 12 weeks while conventional vaccines require physical samples of the virus and production can take approximately nine months.

One VLP-based vaccine already is on the market, namely the human papilloma virus (HPV) vaccine.

New procedure alleviates symptoms in people with severe asthma

Mon, 18 May 2009 03:59:36 PST

( from http://www.rxpgnews.com ) A new drug-free treatment for asthma has been shown to be effective in an international study of patients with severe, uncontrolled asthma. The results showed statistically significant improvements in quality of life and reductions in asthma attacks and emergency room visits for patients who underwent the treatment.

Conducted at 30 sites around the world, including Washington University School of Medicine in St. Louis, the trial tested a procedure designed to reduce the ability of the lung's airways to contract and interfere with breathing. The findings will be presented May 18 at the international conference of the American Thoracic Society in San Diego.

An acute asthma attack is characterized by contraction of muscle tissue in the airway walls in response to irritation, infection or inflammation. Although drugs can lessen the constriction of the breathing passages in many patients, some patients can't control their asthma symptoms even with high doses of medications. The new treatment uses a device to heat the walls of the lung's air passages to reduce the amount of muscle tissue and potentially inhibit narrowing of the airways.

One of the reasons I find this treatment exciting is that many patients with severe asthma are already taking the best drug therapy we have and are still experiencing debilitating symptoms, says the study's lead U.S. investigator, Mario Castro, M.D., a Washington University pulmonary specialist at Barnes-Jewish Hospital. This device provides a meaningful new treatment for such patients.

The device is the Alair Bronchial Thermoplasty System, developed by Asthmatx Inc., which funded the study. None of the trial's investigators has financial interest in the company.

The study, the Asthma Intervention Research 2 (AIR2) Trial, a randomized, double-blind, sham-controlled trial, follows the earlier AIR Trial, completed in 2005. AIR compared bronchial thermoplasty to standard medical care for moderate to severe asthma. That trial showed use of the device reduced asthma exacerbations and provided more symptom-free days than standard care.

But past research has shown that almost any medical procedure has the potential for a placebo effect or to cause a benefit not related to actual treatment. So the larger AIR2 trial compared patients who had bronchial thermoplasty with patients who had a sham procedure. In the sham procedure, all the instrumentation looked and sounded the same, but no heat was applied to airway tissue. In all, 297 patients participated in AIR2, two-thirds receiving the bronchial thermoplasty procedure and one-third getting the sham treatment. All patients were followed for one year.

During the post-treatment period, the treated group had an average 32 percent reduction in the rate of severe exacerbations and 84 percent fewer visits to the emergency department for respiratory symptoms compared to the sham group. Further, the treated group missed fewer days of work or school due to asthma symptoms, had more symptom-free days and needed rescue medication (fast-acting bronchodilators) less often than the sham group.

The researchers also determined how well patients responded using a standard quality of life questionnaire, which measured the physical and emotional impact of asthma. For both groups, the quality of life score rose, but the treatment group reported a greater improvement. Starting at an average score of 4.3 on a scale of one to seven (seven indicating high quality of life), the treated group experienced an average increase of 1.35, while the sham group saw an increase of 1.16. The difference in scores between the groups was statistically significant.

Although we were expecting the sham group to improve, the amount of their improvement surprised us, says Castro, professor of medicine and pediatrics in the Division of Pulmonary and Critical Care Medicine and director of the Asthma Center and Pulmonary Function Laboratory. Nevertheless, it was clear that the treatment did benefit most patients who received it.

Patients were sedated during the procedure, which involved inserting the catheter of the Aliar device deep into the main air passages of the lungs. The catheter has an expandable wire array at its tip. When deployed, the wires touch the airway walls and deliver heat. The thermoplasty treatments took place in three sessions, three weeks apart, and each session targeted a different area of the lungs.

During this treatment period, some patients in both groups experienced upper respiratory tract infections and a worsening of asthma symptoms such as wheezing, chest discomfort and cough. The treated group had somewhat more of these side effects during the treatment period but fewer during the post-treatment period compared to the sham group.

Patients considering the procedure will want to balance the possible risk of adverse events with the potential benefit, Castro says. There's no one answer for every patient. Each person feels differently about the impact of their asthma and what they might be willing to do to alleviate it. That's going to have to be a personal decision in consultation with their physicians.

The AIR2 trial is no longer recruiting participants, and before the thermoplasty procedure will be available to patients outside of the trial, the U.S. Food and Drug Administration (FDA) must approve the device for use in the treatment of asthma. Asthmatx has submitted it for FDA review, and a ruling is expected by fall of 2009.

Alzheimer's, asthma, cancer, malaria and TB focus of new Singapore grants

Tue, 28 Apr 2009 03:59:36 PST

( from http://www.rxpgnews.com ) Over 50 research grants totaling $24 million in U.S. dollars have been awarded to Singapore universities, research institutes and hospitals to fund studies related to asthma and other immune system disorders, infectious diseases, aging and cancer.

The extramural grants were awarded by the Biomedical Research Council (BMRC) of A*STAR (Agency for Science, Technology and Research), the government agency driving Singapore's transformation into an international powerhouse in the biomedical and physical sciences.

In addition to extramural research grants, A*STAR sponsors the research institutes at Singapore's Biopolis and Fusionopolis.

The common dust mite, Blomia tropicalis, which can have an immense impact on quality of life and even be life threatening when it causes allergies in patients with chronic diseases such as cancer, is the focus of three grants awarded to Chua Kaw Yan, Ph.D., of the National University of Singapore's Department of Pediatrics.

One of Dr. Chua's studies will examine the mechanisms of an oral vaccine against the predominant allergen, the Blo t 5 protein, in B. tropicalis, which is responsible for 60-70% of allergy cases in Singapore, including asthma, allergic rhinitis and eczema.

Optimizing the potency of a genetic vaccine against the dust mite will be the focus of her second grant, while the third project will be directed at creating a modified or recombinant protein to foster immunity against Blo t 5.

Immunotherapy remains the only truly disease-modifying treatment for asthma and allergic rhinitis, said Dr. Chua. Traditional forms of immunotherapy use natural sources of allergens and have numerous disadvantages, such as the presence of undefined material, huge variability in sample composition, and contamination of allergens from other sources.

We therefore hope to use the major allergen, Blo t 5, to develop a novel and effective therapeutic vaccine for immunotherapy, she added.

Grants also were awarded to support research using genomics, proteomics and bioimaging to investigate the mechanisms of infection in tuberculosis and malaria, which cause deaths as well as serious illness despite widespread efforts to prevent their transmission.

In their studies of Mycobacterium tuberculosis (MTB), which infects an estimated two billion people worldwide, National Cancer Centre of Singapore (NCCS) scientists will sift through a bank of DNA samples extracted from drug-resistant MTB strains to identify novel mutated genes conferring resistance to Isoniazid, the main drug now used to treat tuberculosis.

In Singapore, the incidence rate of tuberculosis has increased for the first time in 10 years, leading to concerns over increased transmission of the MTB bacteria.

Ann Lee, Ph.D., who heads the NCCS research team that will investigate MTB, said: The identification of additional genes associated with Isoniazid resistance is important for the development of comprehensive molecular strategies that are potentially more efficient than current susceptibility testing methods, and could aid in giving more appropriate treatment to patients and decrease the spread of resistant strains. In addition, the discovery of new genes may reveal novel targets suitable for the development of alternative therapeutic options.

At Nanyang Technological University (NTU), a research team led by Peter Preiser, Ph.D., was awarded a grant to conduct basic research on the pathology of malaria, which infects as many as 600 million people worldwide and kills over 1 million yearly.

Novel lung cancer vaccine shows promise in fighting early-stage lung cancer

Mon, 06 Apr 2009 03:59:36 PST

( from http://www.rxpgnews.com ) CHICAGO - An experimental vaccine that triggers the patient's immune system to identify and attack specific tumor cells is showing new promise for the treatment of early lung cancer. Thoracic surgeons at Rush University Medical Center are researching the vaccine called MAGE-A3 Antigen-Specific Cancer Immunotherapeutic, which is designed to kill cancer cells without harming normal cells. Rush is one of only five hospitals in Illinois offering the vaccine.

The MAGRIT (MAGE-A3 as Adjuvant Non-Small Cell LunG Cancer Immunotherapy) study is a randomized, double-blind and placebo controlled trial that will enroll patients with MAGE A-3-positive, non-small-cell lung cancers. The experimental vaccine targets MAGE-A3, a protein expressed in certain cancer cells but not in normal cells. Thirty-five percent of non-small-cell lung cancers have this protein which also is present in some melanomas and head and neck cancers.

The principle is that you can possibly teach a patient's immune system to eliminate cancer cells that express certain proteins such as the MAGE-A3 protein, said Dr. Anthony Kim, thoracic surgeon and principal investigator of the study at Rush. In a trial of early-stage lung cancer patients whose tumors expressed MAGE-A3, preliminary results showed that the vaccination reduced the risk of recurrence and the need for repeat surgery.

The vaccination may be a promising alternative treatment solution for lung cancer patients that may not be ideal candidates for chemotherapy. Many surgically treated lung cancer patients are not able to tolerate the side effects of chemotherapy.

Surgery is the standard treatment for patients with early-stage lung cancer, but approximately 50 percent of patients who have surgery ultimately die of lung cancer.

Adding the tumor vaccine to surgery has the potential to boost the survival rate by 10 percent, which was the figure that was observed in the initial phase of the MAGE-A3 trial, said Kim. This is a potential alternative for patients that otherwise would not undergo chemotherapy treatment either because of their tumor stage or other co-morbidities such as their age or other medical problems.

A total of 182 patients with non-small-cell lung cancers were included in the early phase of the study sponsored by GlaxoSmithKline, which is developing the vaccine therapy. All the patients had cancers expressing MAGE-A3, the tumor-specific antigen. After having surgery to remove the tumors, 122 patients were randomly assigned to treatment with the MAGE-A3-targeting vaccine and 60 patients received placebo vaccines. The preliminary research shows that the treatment was well tolerated by patients and the MAGE-A3-treated patients seemed less likely to have recurrences and die from their disease than the placebo-treated patients. Further studies need to be completed to test the safety and efficacy of the vaccine.

Patients were given five injections every three weeks at the beginning of treatment and then eight injections every three months later for a total of 27 months. Earlier phases of the study indicate the immunotherapy treatment was well tolerated by patients.

Environment plays role in complex heart defect

Mon, 30 Mar 2009 03:59:36 PST

( from http://www.rxpgnews.com ) A congenital heart disease that often leads to death in newborns is significantly more common during the summer, leading researchers to believe that the environment, and not just genes that affect the heart, may play a role in causing mini-epidemics of this disease.

A cardiac surgeon from Cincinnati Children's Hospital Medical Center presents this research today at the annual American College of Cardiology Meeting in Orlando, FL. The study is a finalist in the ACC's Best Poster Awards Competition.

Hypoplastic Left Heart Syndrome is one of the most complex cardiac defects seen in newborns and remains probably the most challenging to manage of all congenital heart defects. In a child with HLHS, all of the structures on the left side of the heart (the side which receives oxygen-rich blood from the lungs and pumps it out to the body) are severely underdeveloped. This results in the left side of the heart being completely unable to support the circulation needed by the body's organs.

The most common treatment for HLHS is staged reconstruction, in which a series of operations, usually three, are performed to reconfigure the child's cardiovascular system to be as efficient as possible despite the lack of an adequate left ventricle. Current management at major pediatric heart centers has resulted in survival rates of 75 percent or better.

Pirooz Eghtesady, MD, PhD, a cardiothoracic surgeon at Cincinnati Children's, led a study of nearly 1,500 newborns from 38 children's hospitals in the United States who had left-sided congenital heart diseases. Dr. Eghtesady and his colleagues found a seasonal occurrence of HLHS, but not other left-sided diseases, over a 10-year period, 1996 to 2006. Seasonal differences in HLHS occurred each year, with peaks between April and July and low points in January.

Strong seasonality is a clue that environmental factors may play an important role in this disease, as we see, for example, with such common childhood illnesses as asthma and croup, says Dr. Eghtesady. The study augments some prior epidemiologic studies and points the finger at the possibility of additional factors. It also opens the window for genetic studies to consider candidate genes not directly related to cardiac maldevelopment, such as those involved in immune responses, which really have not been considered in the past.

One potential environmental factor being studied by Dr. Eghtesady and colleagues is recurrent maternal exposure to the common agent strep throat, which is also responsible for the devastating condition known as rheumatic heart disease. Numerous studies have indicated that an immune reaction against strep in rheumatic heart disease can lead to injury on the left side of the heart, which is the side also affected in HLHS. Dr. Eghtesady's preliminary study suggests that many mothers whose newborns had left-sided heart injury had a significant history of problems related to strep throat.

Cincinnati Children's is involved in an ongoing clinical trial looking at maternal history of strep exposure compared to mothers with normal hearts and mothers affected by other cardiac defects. Researchers at Cincinnati Children' also are studying whether there are antibodies in the blood of mothers exposed to strep similar to ones found in patients with rheumatic heart disease

NF-κB mediated bioluminescence- sensitive and early indicator in auto-immune diseases

Wed, 25 Mar 2009 16:06:32 PST

( from http://www.rxpgnews.com ) Current research describes a new method to track the development of autoimmune diseases before the onset of symptoms. The related report by Zangani et al, "Tracking early autoimmune disease by bioluminescent imaging of NF-κB activation reveals pathology in multiple organ systems," appears in the April 2009 issue of The American Journal of Pathology.

Autoimmune diseases such as lupus, multiple sclerosis, rheumatoid arthritis and diabetes are caused when the immune system attacks the body's own cells. Normally, immune cells are prevented from attacking normal cells; however, in patients with autoimmune disease, this "tolerance" is lost. The immediate causes of autoimmune diseases remain unknown, partially due to the inability to detect disease before the onset of symptoms. Early detection of autoimmune disease is critical for assessing new treatments.

The molecule NF-κB is activated by inflammation, which plays a key role in autoimmune disease development, making NF-κB a prime candidate to track autoimmune activity. Researchers at the University of Oslo led by Drs. Ludvig Munthe and Bjarne Bogen in collaboration with Rune Blomhoff engineered NF-κB such that it would emit light when activated. Using a mouse model of systemic autoimmunity with features of lupus, they found that NF-κB activation signals were present in affected organs several weeks before the clinical manifestations of disease. The light signal intensity correlated with disease progression. NF-κB tracking may therefore provide a new tool in the evaluation of early autoimmune therapies.

The article from Zangani et al "indicate[s] that NF-κB mediated bioluminescence is a very sensitive and early indicator of inflammation and disease", allowing precise identification of incipient disease sites for biomedical and pathogenetic studies. In future studies, Drs. Munthe, Bogen, and colleagues will utilize this new model "for studies on early intervention, e.g. drug treatment, to prevent or treat autoimmune disease", and for studies of the development of B cell lymphoma.

Biotech company cofounded by BIDMC scientists targets natural killer T-cells

Thu, 19 Mar 2009 03:59:36 PST

( from http://www.rxpgnews.com ) BOSTON -- NKT Therapeutics, Inc., a Newton-based biotechnology company cofounded by Beth Israel Deaconess Medical Center (BIDMC) researchers Steven Balk, MD, PhD, and Mark Exley, PhD, has announced that it has closed an $8M Series A venture financing co-led by venture capital firms SV Life Sciences (SVLS) and MedImmune Ventures.

The company will work to develop therapies based on natural killer T-cells, with their first program focusing on treatments for asthma.

Doctors Balk and Exley [together with the company's third cofounder Brian Wilson, MD, PhD, of Massachusetts General Hospital] have extensive expertise in the applications of immunotherapeutic agents to human disease, explains Mark Chalek, Chief of Business Ventures at BIDMC. Their research has helped to establish the important role of NKT cells in the regulation of many immune responses.

Although NKT cells represent approximately .01 percent of the body's total lymphocyte population, they serve as a central regulator of the immune system, playing a critical role in health and disease, according to Balk, a member of the Division of Hematology/Oncology at BIDMC. By regulating the innate arm of the immune system, NKT cells help to destroy threatening pathogens and cancers, he explains. And by regulating the immune system's adaptive arm, they help to modulate antibody and cell-mediated immunity, which offers sustained protection over time.

Balk and Exley have been studying natural killer T cells since 1996. They were the first investigators to identify the NKT human subset, functionally define these immune cells, and demonstrate that they had defects in cancer patients. The scientists were also the first team to describe the cells' anti-viral roles and to characterize related populations of cells in liver and bone marrow, as well as to demonstrate their roles in various disease states.

NKT cells are a very potent source for good in some types of immune response, but in other instances can cause problems, adds Exley, who is also a member of BIDMC's Division of Hematology/Oncology. By selectively activating or depleting NKT function we plan to develop drugs that can target a wide range of diseases, from asthma and autoimmune disorders to cancers and infectious diseases. Asthma is one of the conditions in which NKT cells create an adverse immune response. Therefore, by downregulating NKT activity, we hope to create successful asthma treatments.

I am very excited to lead the development of this very promising technology whose broad potential for addressing major health care needs is underscored by this successful financing, adds Robert Mashal, MD, President and Chief Executive Officer of NKT Therapeutics.

NKT Therapeutics has licensed an extensive intellectual property portfolio from Beth Israel Deaconess Medical Center (BIDMC), Dana Farber Cancer Institute, and Massachusetts General Hospital. Stan Mah of BIDMC's Technology Ventures Office (TVO) had the lead role in organizing licensing on behalf of all parties.

Studies show children can complete treatment for peanut allergies and achieve long-term tolerance

Sun, 15 Mar 2009 03:59:36 PST

( from http://www.rxpgnews.com ) DURHAM, NC -- A carefully administered daily dose of peanuts has been so successful as a therapy for peanut allergies that a select group of children is now off treatment and eating peanuts daily, report doctors at Duke University Medical Center and Arkansas Children's Hospital.

It appears these children have lost their allergies, says Wesley Burks, MD, Chief of the Division of Pediatric Allergy and Immunology at Duke. This gives other parents and children hope that we'll soon have a safe, effective treatment that will halt allergies to certain foods.

Long-term tolerance in children with peanut allergies was documented for the first time by the presence of key immunologic changes, according to researchers at Duke and Arkansas Children's Hospital who presented their findings at the American Academy of Asthma and Immunology meeting in Washington, DC today.

Tests of several immunologic indicators suggest the body builds tolerance quickly.

At the start of the study, these participants couldn't tolerate one-sixth of a peanut, Burks said. Six months into it, they were ingesting 13 to 15 peanuts before they had a reaction.

About four million Americans have food allergies, and allergies to tree nuts and peanuts are the most common. Life-threatening reactions can occur from exposure to even a trace amount of peanuts, and nearly half of the 150 deaths attributed to food allergies each year are caused by peanut allergies.

Duke and Arkansas Children's Hospital began enrolling patients in studies five years ago to determine if incremental doses of peanut protein could change how the body's immune system responds to its presence. The doses start as small as 1/1000 of a peanut. Eight to 10 months later, the children are ingesting the equivalent of up to 15 peanuts per day. The children stay on that daily therapy for several years and are monitored closely.

Nine of the 33 children participating in the study have been on maintenance therapy for more than 2.5 years. After a series of food challenges, four of those children were taken off the treatment and continue to eat peanuts. Some have been off treatment for more than a year. Doctors keep tabs on any potential changes in their immune system via skin, blood and immune studies.

One of the tests used in the study looks at immunoglobulin E (IgE), a protein the body makes in response to peanut allergens. If you have it, you're likely allergic, if you don't, you aren't, explained Burks. Children in this study generally started with IgE levels greater than 25. At the end of the study, their peanut IgEs were less than 2 and have remained that way since we stopped the treatment, he said.

Because the pool of children now off treatment is so small, Burks says it's hard to say whether these children simply outgrew their allergies or if the therapy did something to enhance that outcome. The next step is a blinded study in which children on treatment are compared to a control group. First year results were presented at the meeting by Stacie M. Jones, MD, a pediatric allergist at Arkansas Children's Hospital. So far, the oral immune therapy appears to be working.

We see initial desensitization effects of the treatment are real, Burks says. Those children are now able to eat up to 15 peanuts with no reaction, but the children not on treatment have symptoms early on in the study.

Despite the news, Burks insists this research is still ongoing and cautions parents and professionals against trying any version on their own. In my clinic, I would do the same things I've always done. Once diagnosed with a food allergy, I would recommend they avoid the food. We have to wait for the studies to show the treatment is safe, and to see desensitization start to work. We also want to know the therapy works long term.

Burks also cautions that some people are too sensitive to peanut allergens to be able to undergo the therapy.

African-Americans aware and accepting, but often do not receive, the HPV vaccine

Wed, 04 Feb 2009 04:59:36 PST

( from http://www.rxpgnews.com ) CAREFREE, A.Z. - Although only 25 percent of eligible African-American adolescents have received the HPV vaccine, a new survey presented at the American Association for Cancer Research conference on the Science of Cancer Health Disparities, suggests they have a positive view of the treatment and might respond to more education.

The Pennsylvania Department of Public Health is funding research to develop ways to increase the rate of HPV vaccination among those at highest risk. HPV vaccination prevents cervical cancer by inoculating against the human papillomavirus.

The consensus among those surveyed in our study was that it would be a good, beneficial option, said Ian Frank, M.D., professor of medicine in the Infectious Diseases Division of the University of Pennsylvania.

The HPV vaccine, approved for use in the United States as Gardasil and manufactured by Merck and Co., has been shrouded in controversy since it was released in June 2006.

Frank said the controversies break down into four basic areas. Following approval, Merck pushed for mandatory vaccination, which is generally opposed by citizens in the United States who believe health care decisions should not be forced. Others were concerned about the long-term efficacy of the vaccine or its possible side effects.

Most famously, some groups insisted that if adolescents were aware that they could inoculate themselves against the human papillomavirus, which is spread through sexual contact, they would be more likely to have early sexual relations.

I doubt that whether or not she is at risk for cervical cancer is on an adolescent's mind in the heat of the moment, said Frank.

Frank said the African-Americans who participated in the survey conducted by his research group were aware of these controversies, but they did not outweigh their positive views of the vaccine as an option.

Researchers surveyed 71 females for the study; 94 percent were African-American and the mean age was 15.3 years. Approximately 60 percent of them had had their first sexual encounter when they were 14 years old.

Of those who had not received the vaccine, 43.9 percent said they were very likely or likely to do so soon. A majority believed it was a good or very good idea and they generally viewed the vaccine as safe, effective and a wise choice.

Forty-five caregivers of adolescents also participated in the study, all of whom were African-American, 94 percent were female and 47.9 percent had a high school diploma.

The caregivers agreed that the vaccine was safe, effective and a wise choice, but two-thirds of them could not recall their health care provider ever mentioning the HPV vaccine.

Many of these caregivers, most of whom were women, reported feeling overwhelmed by the challenges of raising an adolescent girl, but they wanted to protect their daughters from health and emotional risks, said Frank. This suggests they would respond positively to an increased effort to inoculate.

Ireland Cancer Center researcher finds most triple-negative breast cancers express muc-1 target

Fri, 12 Dec 2008 04:59:37 PST

( from http://www.rxpgnews.com ) CLEVELAND: Research out of the Ireland Cancer Center of University Hospitals Case Medical Center has found that the vast majority of triple negative breast cancers express the MUC-1 target. This first-of-its-kind finding, presented today at the San Antonio Breast Cancer Symposium, has paved the way for an upcoming vaccine trial for patients with early stage triple negative breast cancer that could potentially prevent recurrence of this aggressive type of breast cancer.

Joseph Baar, MD, PhD, Director of Breast Cancer Research at the Ireland Cancer Center, and colleagues analyzed 53 tumors and determined that 92 percent of them expressed MUC-1. These findings support their theory that this MUC-1 protein on breast cancer cells could be a target for a novel vaccine using the patient's immune system to target and kill cancer cells.

Dr. Baar has received a prestigious grant from the National Cancer Institute and the Avon Foundation to begin the vaccine trial in January 2009 for women with early stage triple negative breast cancer to see if this vaccine can raise their immune response against MUC-1. If it does, then a later study would be undertaken to determine whether the generation of such an immune response leads to an increase in patients' relapse-free survival rates, thereby preventing recurrence. The vaccine will be administered following standard therapy of surgery, radiation and chemotherapy.

This vaccine trial has the potential to rev up patients' immune response to the MUC-1 protein and shut down the tumor's ability to grow, says Dr. Baar. Women with this aggressive triple negative breast cancer have an increased risk of recurrence and we are hoping to provide them with protection against the return of this deadly disease. Our findings that have been presented at the San Antonio Breast Symposium provide us a strong basis for this trial.

Triple negative breast cancer is a highly aggressive form which comprises 10-15 percent of newly diagnosed early stage breast cancer. Most triple negative tumors are high grade and have a high incidence of recurrence and metastases (spreading to other organs). Unlike other types of breast cancer, there is no standard follow-up treatment for triple negative breast cancer to prevent recurrence.

This is an important study because there has traditionally been nothing to offer women with triple negative breast cancer beyond standard therapy, says Stanton Gerson, MD, Director of the Ireland Cancer Center. This vaccine trial has the potential to lay the groundwork for a new standard of care for women with this aggressive form of breast cancer.

K-State researcher finds correlation between childhood obesity and asthma

Fri, 12 Dec 2008 04:59:37 PST

( from http://www.rxpgnews.com ) MANHATTAN -- A Kansas State University graduate student has found a correlation between childhood obesity and asthma.

Sara Rosenkranz, doctoral student in human nutrition, Manhattan, conducted research that found that healthy children with higher levels of body fat and lower levels of physical activity had greater amounts of airway narrowing after exercise.

Kids who are overweight and inactive are having -- even at the age of 8 to 10 years old -- a negative response to exercise challenge tests, which might be contributing to the increase that we've been seeing over the past several decades in asthma prevalence as well as obesity prevalence, Rosenkranz said.

Rosenkranz worked with other K-State faculty and students to recruit 40 children in the 8- to 10-year-old age range to participate in exercise studies. All of the children were healthy, meaning none of took medication or had a diagnoses or history of acute or chronic disease, including asthma.

For Rosenkranz's project, the children completed pulmonary function tests, an exercise test that doctors often conduct to determine if children have asthma, and body composition tests.

The children also took questionnaires to determine if they were active or inactive compared to the standards of their age, gender and ethnicity.

After the exercise challenge, the researchers measured the children's FEV-1, which determines if the individual's airwaves narrow post-exercise. The researchers found that the higher the body fat and the lower the level of activity of the child, the more likely they were to have asthma-like symptoms following exercise. In fact, these specific children had FEV-1 measures that many consider to be classified as exercise-induced asthma.

It was pretty interesting. There's that whole idea that it's possible to be fit and fat in adults, but that really hasn't been looked at closely in kids, Rosenkranz said. That's what spurred the idea for this research.

At the completion of the project, a follow-up letter was sent to the parents that showed their child's pulmonary test results and body fat percentage, which also had the corresponding fat group based on the child's age, gender and ethnicity.

It's important for parents to know what's going on with their children at a young age so that they can help do something to maybe stop a downward cycle, Rosenkranz said. It's especially important for those kids who already are overweight and are very physically inactive.

For many of the students that had higher levels of body fat and lower levels of activity, Rosenkranz said it is possible that they had the early stages of asthma and they didn't know it.

They might not know it because they might not be doing anything that could ever trigger it, she said.

When an asthma diagnosis is made, Rosenkranz said it is important that the child remain active to prevent airway problems.

Before the study, little was known about the role body composition and physical activity have in airway health in children, Rosenkranz said. When considering childhood obesity, pulmonary function wasn't often considered, she said.

At K-State, we just started working with the childhood population, she said. We've been working more with college-age students because that's a handy group to have access to, but with kids, it's a whole new world and there's not much information out there.

Immunology Center will continue to drive standard methods, better science

Thu, 11 Dec 2008 04:59:37 PST

( from http://www.rxpgnews.com ) The Rochester Human Immunology Center (RHIC) has been awarded a $4 million renewal of its grant from the National Institute of Allergy and Infection Disease (NIAID). The renewal enables RHIC to continue leading the field of immunology in a worldwide effort to standardize how researchers use complex technologies like flow cytometry that are central to the discovery of new treatments.

When standardization is achieved, researchers will be better able to compare data collected worldwide, with the results of many studies combined into massive datasets to guide the construction of hyper-accurate computer models of the mechanisms of disease. Such simulations will yield scientific conclusions that are dramatically more valid and reproducible in areas like infectious disease, transplantation and cancer, researchers said. The resulting sophistication in understanding of the human immune system, and of how it responds to influenza, HIV or smallpox for instance, will guide the more precise design of near-future vaccines.

Since its founding four years ago, the RHIC has proven that it can drive the development of standard operating procedures, having helped more than 39 investigators and teams standardize their testing, and lending expertise that helped lead to the winning of 22 major grants. As an internationally known resource, the RHIC is part of working groups seeking to standardize methods for analyzing flu viruses and HIV in partnership with the Division of Microbiology and Infectious Diseases at NIAID, the HIV Vaccine Trials Network and the New York Influenza Center of Excellence.

Standardizing test methods to achieve comparable results goes far beyond being able to compare apples to apples, said Sally Quataert, Ph.D., director of Core Facilities for the University of Rochester School of Medicine and Dentistry, and co-principle investigator for the grant renewal. Validated methods assure researchers that their experimental results are good science, and truly meaningful. Standard methods also directly contribute to translational science, where the results of studies are more readily affirmed by regulatory bodies, and with fewer conflicting studies.

Prior to 2004, Quataert was director of Immunobiological Laboratory Services at Wyeth Vaccines Research in Rochester for seven years. Her industry background prepared her to apply Good Laboratory Practice (GLP) standards to academic studies, making them more likely to withstand scrutiny by the U.S. Food and Drug Administration as sound evidence that new treatments are safe and effective. If applied internationally, such standards would make drug candidates discovered at universities much easier to license to industry, with potential to increase the number of new drugs becoming available.

Also recently joining the RHIC executive committee was Tim Bushnell, Ph.D., director of the Flow Cytometry Core at the University of Rochester Medical Center. Bushnell's active role in the International Society of Analytical Cytology (ISAC) has positioned RHIC, not just to develop expertise, but also to take a leading role in the groups that are shaping related standards worldwide.

Flow cytometry is a method of counting and sorting cells that have been labeled by fluorescent markers which correspond with physical and chemical qualities of the cell. Modern flow cytometers can analyze thousands of cells in real time to unravel the complex interactions driving disease processes. The devices beam laser light into a stream of liquid which carries the cells to be analyzed. Detectors catch the patterns of fluorescent light that bounce off single cells as they pass through the laser. The cells have been prepared with fluorescent dyes that absorb the laser light and emit light at lower frequencies in scatter patterns that reveal information about the cell.

Modern instruments have multiple lasers and fluorescence detectors, with 18 fluorescence detectors now commonplace in larger research institutions. Increasing the number of lasers and detectors enables more precise identification of target cell populations by their characteristics. Four years ago, the RHIC had eight-color flow cytometry, but has since upgraded to 11- and 18-color cytometers with support from the Medical Center and its Clinical Translational Science Institute (CTSI). Researchers receive training on flow cytometry and other key discovery techniques and gain access to a growing suite of RHIC equipment. With the renewal of the NIAID grant, the center will continue to develop and standardize immunological methods.

Beyond general leadership and standard setting, the center will take the lead in the next five years in helping the field to make better use of three cutting-edge technologies of immense importance. The goal is to advance technologies to maturity so that they can be applied widely, with the new standards communicated through publications, the RHIC Web site and symposia.

The first technology is arrayed image reflectometry, which promises to be very useful in large-scale analysis of immune responses against multiple disease-causing proteins like those encountered during influenza outbreaks. Immune system proteins can be coated with a thin film that prevents light from reflecting off of them, but that become more reflective as the proteins bind to disease-related proteins. When several proteins to be tested are attached to a biochip, a great many proteins can be analyzed for little cost.

The grant renewal will also bring together RHIC experts in cytometry and in a second new technology: quantum dot nanostructures. These microscopic machines have optical qualities that can be harnessed to measure cellular qualities via flow cytometry with more precision than fluorescent dyes. Like dyes, the dots can be designed to inhabit certain regions of the cell, or cling to certain proteins, so that their number and characteristics can be measured. Dyes are an older technology, limited in number and with overlapping emission spectra, which means they interfere with each other. RHIC teams will seek to establish new Q-dot production methods to replace and extend dye capability. As RHIC machinery gets more complex, it will become increasingly able to pick apart and to build accurate immune cell models.

Thirdly, the team will seek to design better gating procedures. Flow cytometry separates cell types by brightness into groups, and gating is the process by which researchers select which cells go into each group. The current process in many labs is arbitrary, tedious and has poor reproducibility between operators because research teams select patterns of cell characteristics by eye. The field of flow cytometry is in desperate need of high-speed automation to process the mountains of data generated by the tests, and when gating the results, researchers said. The current process is greatly slowing the pace of discovery as research teams do double duty with lab work and time-consuming computational work.

One unique capability that drove the RHIC renewal was that the Medical Center has a world-leading core of biostatisticians along with leading immunologists. Led by Hulin Wu, Ph.D., chief of the Department of Biostatistics and Computational Biology, the biostatistics team within RHIC will seek to establish statistically-rigorous, automated gating protocols for flow cytometry analysis that will greatly increase the reproducibility of data and the speed of flow cytometry lab by lab.

Allergies could be a blessing in disguise, against cancers

Sat, 15 Nov 2008 14:06:01 PST

( from http://www.rxpgnews.com ) Washington, Nov 12 - Sneezing, coughing and itching may just help prevent cancer affecting colon, skin, bladder, mouth, throat, uterus and cervix, lung and gastrointestinal tract, according to a new study.

These cancers involve organs that are exposed to the external environment, said Paul Sherman, professor of neurobiology and behaviour at Cornell University, who led the study.

He and colleagues analysed 646 studies on allergies and cancers published over the past 50 years, putting together 'the most comprehensive database yet available' on allergies and cancers.

The study revealed 'a strong relationship' between allergies and cancer in environmentally exposed tissues, Sherman said.

This relationship seldom exists, he noted, between allergies and cancers of tissues that are not directly exposed to environment, particularly breast and prostate cancers, myelocytic leukemia and myeloma, said a Cornell report by Susan Lang.

The study has been co-authored with Erica Holland, a medical student at the University of Massachusetts, and Janet Shellman Sherman, a Cornell research scientist.

'Sherman believes that allergy symptoms may help protect against cancer by shedding foreign particles from the body. Some of those particles, he said, might be carcinogenic or carry carcinogens.

Asthma is linked to higher rates of lung cancer. Unlike other allergies, however, asthma reduces the ability to expel mucus, while other allergies facilitate mucus expulsion and are correlated with lower rates of lung cancer.

These findings are scheduled for publication in the December issue of The Quarterly Review of Biology.

Researchers aim to over-stress already taxed mantle cell lymphoma cells

Mon, 10 Nov 2008 04:59:37 PST

( from http://www.rxpgnews.com ) AUGUSTA, Ga. - Cancer cells are already stressed by the fast pace they require to grow and spread and scientists believe a little more stress just may kill them.

Think about an assembly line in a factory that is working five times faster than normal, said Dr. Kapil Bhalla, director of the Medical College of Georgia Cancer Center. There is a lot of stress but you need workers to keep going. Some of them fall out, some get bent out of shape.

His research team believes they can disrupt the over-stressed assembly line of mantle cell lymphoma and possibly similar cancers such as pancreatic, liver and breast, by taking away support needed for rapid protein turnover and by clogging up the mechanism for eliminating poorly made ones.

Mantle cell lymphoma, an aggressive cancer of the lymphatic system that mostly occurs in middle age, responds initially to chemotherapy and antibiotics, but often returns, said Dr. Bhalla. Patients have a median survival of three to four years. This cancer affects b lymphocytes, immune cells which make antibodies to fight infection. Ironically, in the process of rearranging genes to make antibodies to a specific invader, mistakes happen, and a would-be protector becomes cancer.

MCG researchers found that to keep their fast pace, these now-malignant cells need increased activity of heat shock protein 90. Cancer cells require hsp90 for keeping their proteins in active conformation to do their job. That is what cancer is addicted to, said Dr. Bhalla, Cecil F. Whitaker, Jr., M.D./Georgia Research Alliance Eminent Scholar in Cancer and Georgia Cancer Coalition Distinguished Cancer Scholar. Hsp90 is one of the more common molecular chaperones, which help proteins get made, moved, folded and function. Its levels and activity are upregulated in response to stress.

They also found that the usually busy endoplasmic reticulum of these cells, which is supposed to be making normal antibodies, is stressed by making hyperactive, cancer-associated proteins. Stepped-up protein production also means more misfolded proteins that the proteasome must deal with. It's all stressed-out machinery, Dr. Bhalla said.

To help push cancer cells over the edge, the researchers are inhibiting hsp90, so the cells lose the molecular chaperone function required to maintain their fast pace. This also puts more stress on the endoplasmic reticulum. Independently hsp90 inhibitors are known to selectively kill cancer cells. But researchers also are clogging up the proteasome, the machinery for chopping up misfolded proteins, recycling some products and eliminating what's left. Much like a sink won't work with a clogged garbage disposal, mantle cell lymphoma cells will start backing up. When a cell detects excessive misfolded proteins, it first has a protective response, but if the problem persists, it commits suicide.

With support from a five-year, $1.5 million grant from the National Cancer Institute, the researchers are using hsp90 and proteasome inhibitors to study protective versus lethal endoplasmic reticulum stress as a way to get rid of mantel cell lymphoma cells. The laboratory studies are being done in human mantle cell lymphoma cells as well as an animal model the researchers developed.

The drugs they are using already are in early clinical trials for a variety of cancers but have not yet been packaged together, Dr. Bhalla said. We kill cancer cells and a lot of them with this strategy. Still, at least one more inhibitor may get added to the mix. After the rather brutal attack at the cancer's molecular underpinnings, the immune system comes in to essentially mop the floor, but researchers have found cancer cells can still get a pass from an enzyme called IDO. A team of MCG researchers led by Dr. David Munn is exploring IDO's therapeutic potential in cancer. Fetuses use IDO to avoid rejection by the mother's immune system and tumors appear to use it as well. Dr. Bhalla suspects an IDO inhibitor, already under study for lung cancer and other tumors, likely will get a shot at mantle cell lymphoma as well.

New hope for HIV treatment: Cells exhausted from fighting HIV infection can be revitalized

Mon, 10 Nov 2008 04:59:37 PST

( from http://www.rxpgnews.com ) Researchers at the University of Toronto and the University of California, San Francisco, have revealed new hope for HIV treatment with the discovery of a way to 'rescue' immune cells that are exhausted from fighting off HIV infection.

The team lead by Drs. Mario Ostrowski, of the University of Toronto's Faculty of Medicine, and Douglas Nixon, of the Division of Experimental Medicine at the University of California, San Francisco, has discovered that a molecule called Tim-3 is present at high levels on poorly functional immune system cells which are 'exhausted' from fighting HIV infection. The researchers found that blocking the activity of Tim-3 on these cells improved their function and allowed them to rejoin the battle against HIV.

In the typical course of HIV infection, an initial burst of very high levels of the HIV virus is brought partially under control by the infected person's immune system, specifically by an immune system cell called a CD8+ killer T cell. In the majority of cases without antiretroviral drug treatment, the immune system is eventually overwhelmed and progression to AIDS occurs, said co-principal author Brad Jones, a PhD candidate in Immunology at the University of Toronto.

Progression to AIDS is associated with a breakdown in those CD8+ T immune system cells. In a typical viral infection, those cells rapidly multiply, kill off virus-infected cells and stimulate other cells in the immune system. But over time, in the battle to fight off HIV infection these CD8+T cells become less functional and enter into a state known as 'exhaustion.' The mechanisms that lead to this exhausted state are not well known, said Jones. We felt that if we could understand these mechanisms then we may be able to intervene and re-energize the immune system. The research team theorized that this exhausted state may result from the Tim-3 molecule sending a signal to shut down CD8+ T cells in HIV-infected individuals.

The researchers observed that Tim-3 expression on T cells, in particular the CD8+ T cells, associated remarkably strongly with clinical parameters of HIV disease progression in a diverse group of HIV-infected individuals. From these results we predicted that the Tim-3 pathway might be manipulated to potentially confer clinical benefit and serve as a promising new target for clinical intervention to decrease the severity of HIV infection, said co-principal author Lishomwa Ndhlovu, MD, PhD in the Division of Experimental Medicine, University of California, San Francisco.

To test this, we produced a molecule capable of blocking the Tim-3 signal and studied the effect that this had on CD8+ T cell function in vitro, said Mario Ostrowski, MD, Associate Professor in the Department of Immunology, University of Toronto. We observed that blocking the Tim-3 pathway rescued those cells and restored their ability to fight off infection.

This discovery, published in the November 24th issue of the

1918 Spanish flu records could hold the key to solving future pandemics

Sun, 09 Nov 2008 04:59:37 PST

( from http://www.rxpgnews.com ) Ninety years after Australian scientists began their race to stop the spread of Spanish flu in Australia, University of Melbourne researchers are hoping records from the 1918 epidemic may hold the key to preventing future deadly pandemic outbreaks.

This month marks the 90th anniversary of the return of Australian WWI troops from Europe, sparking Australian scientists' race to try and contain a local outbreak of the pandemic, which killed 50 million people worldwide.

Researchers from the University of Melbourne's Melbourne School of Population Health, supported by a National Health and Medical Research Council grant, are analysing UK data from the three waves of the pandemic in 1918 and 1919.

They hope that modern high-speed computing and mathematical modeling techniques will help them solve some of the questions about the pandemic which have puzzled scientists for close to a century.

Professorial Fellow John Mathews and colleagues are analysing the records of 24,000 people collected from 12 locations in the UK during the Spanish flu outbreak including Cambridge University, public boarding schools and elementary schools.

He says gaining a better understanding of how and why the virus spread will help health authorities make decisions about how to tackle future pandemics.

In the 1918/19 pandemic, mortality was greatest among previously healthy young adults, when normally you would expect that elderly people would be the most likely to die,'' Professor Mathews says We don't really understand why children and older adults were at lesser risk.

One explanation may be that children were protected by innate immunity while older people may have been exposed to a similar virus in the decades before 1890 which gave them partial but long-lasting protection.

Those born after 1890 were young adults in 1918. They did not have the innate immunity of children and as they weren't exposed to the pre-1890 virus they had little or no immunity against the 1918 virus. We can't prove it but it is a plausible explanation.

Another striking feature is that the pandemic appeared in three waves, in the summer and autumn of 1918 and then the following winter.

One theory being examined to explain why some people were only affected in the second or third wave is that because of recent exposure to seasonal influenza virus they had short-lived protection against the new pandemic virus.

The attack rates in the big cities weren't as high and this is probably because many people had been exposed to ordinary flu viruses, giving short-lived immunity,'' he says.

In the English boarding schools, where there was social demarcation, children were probably less exposed to seasonal influenza viruses in earlier years; without that protection, pandemic attack rates were much higher than in ordinary government elementary schools.

If we can provide a detailed time course of epidemics and the attack rates at different times, that information can be extremely useful in determining how a future pandemic might progress,'' says Professor Mathews.

He says initial findings point strongly to the value of short-lived immunity to provide protection or partial protection against the early waves of a virus.

This is particularly important when considering the stockpiling of drugs and vaccines to protect the community against a virus.

The early implications of our study are that there may be benefit in providing short-lived immunity that is broadly based rather than specific,'' he says.

If another flu pandemic were to come along and you have a vaccine, it may be better to use it even if it is against a different sub-type of the virus.

Pneumococcal vaccine could prevent numerous deaths, save costs during a flu pandemic, model predicts

Tue, 28 Oct 2008 03:59:37 PST

( from http://www.rxpgnews.com ) A new predictive model shows that vaccinating infants with 7 valent pneumococcal conjugate vaccine (PCV7)--the current recommendation--not only saves lives and money during a normal flu season by preventing related bacterial infections; it also would prevent more than 357,000 deaths during an influenza pandemic, while saving $7 billion in costs.

Keith P. Klugman, PhD, professor of global health at Emory University's Rollins School of Public Health, will present results of the research using the predictive model at the joint ICAAC/IDSA meeting in Washington, DC, Oct. 25-28. (Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Disease Society of America.

Bacterial infections, particularly pneumococcal disease, can follow a viral illness such as flu and cause secondary infections that worsen flu symptoms and increase influenza-related risk. Bacterial infections may have been the cause of nearly half of the deaths of young soldiers during the 1918 flu pandemic.

We've known for years that bacterial infections can develop after influenza, says Klugman. Unlike the 1918 flu pandemic, which preceded the antibiotic era, we now have vaccines that can prevent these types of pneumococcal infections. This model shows what a dramatically different outcome we could expect with standard PCV vaccination.

Klugman and colleagues at Harvard University, i3 Innovus in Medford, Ma. and Wyeth Research constructed a model to estimate the public health and economic impact of current pneumococcal vaccination practices in the context of an influenza pandemic.

Since 2000 the Centers for Disease Control and Prevention (CDC) Immunization Practices Advisory Committee (ACIP) has been recommending PCV vaccinations for infants and children.

The new predictive model was used to compare the results of no PCV vaccination to the current routine vaccination of infants less than two years old. The researchers assessed the effect of vaccination policies under both normal and pandemic influenza conditions. They included both direct vaccination effects in vaccinated individuals and indirect vaccination effects (called herd immunity) in the unvaccinated. For manifestations of pneumococcal disease, they included invasive pneumococcal disease (meningitis or bacteremia), all-cause pneumonia and all-cause acute otitis media (ear infections). The model's estimates were based on the 1918 pandemic.

The new model predicted that current pneumococcal vaccination practices reduce costs in a typical flu season by $1.4 billion and would reduce costs by $7 billion in a pandemic. In a pandemic, they would prevent 1.24 million cases of pneumonia and 357,000 pneumococcal-related deaths.

Our research shows that routine pneumococcal vaccination is a proactive approach that can greatly reduce the effects of a future flu pandemic, says Klugman. Countries that have not yet implemented a pneumococcal vaccination program may want to consider this as part of their pandemic flu preparedness.

First international guidelines for treatment of psoriatic arthritis

Sun, 26 Oct 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Rheumatologists, dermatologists, and patient advocates have come together to publish the first-ever international guidelines for the treatment of psoriatic arthritis, a disease that mainly affects people who have psoriasis but also some people without it.

The guidelines by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) were presented at the annual meeting of the American College of Rheumatology. The group was headed by Christopher Ritchlin, M.D., M.P.H., professor of Medicine at the University of Rochester Medical Center, who presented the guidelines Sunday, Oct. 26.

In the past few years, new medications have become available that are incredibly effective for the various manifestations of psoriatic arthritis, said Ritchlin, who treats about 250 patients with the disease. Many patients' find their lives changed for the better within just a couple of weeks. These guidelines are designed as a platform to make sure physicians around the world are aware of what's available for their patients and to help them make sound treatment decisions.

Psoriatic arthritis is an oft-forgotten cousin to its better known counterparts, osteoarthritis and rheumatoid arthritis. Doctors estimate that somewhere between 500,000 to 1 million people in the United States have psoriatic arthritis. Doctors say that about one out of four patients with psoriasis also gets psoriatic arthritis, and that conversely, about 15 percent of people who get the disease don't have psoriasis.

It's an autoimmune disease in which errant signaling molecules causes a person's body to attack itself. The disease literally eats away at patients' joints, causing some bones or digits such as fingers or toes to shrink or literally disappear while also triggering abnormal, disfiguring and disabling bone growth in their hands, feet, spine, and other joints. Doctors are also finding that patients with psoriasis are more prone that others to several ailments, including diabetes, high blood pressure, and heart attacks.

The presenting symptoms of psoriatic arthritis vary tremendously from patient to patient, said Ritchlin. It's a very challenging disease to treat, because so many different parts of the body can be involved. The skin can be inflamed, a particular joint or tendon can hurt tremendously, the patient might have back pain, or a single swollen finger or toe.

Oftentimes a patient will come in with something you might call 'tennis elbow,' or they might have a sore Achilles heel, and that's their only symptom. It can be very difficult to diagnose, said Ritchlin, who is director of the Clinical Immunology Research Unit at the Medical Center. He has served as a consultant to Amgen, Wyeth, Abbott, and Centocor, and has received research funding from Centocor, Abbott, and Amgen.

A broad range of treatments is available to treat the disease. Options include non-steroidal anti-inflammatory drugs like ibuprofen and steroids injected into joints or tendons.

Other anti-inflammatory medications known as disease-modifying antirheumatic drugs, such as methotrexate, are often used, but GRAPPA found that the medications are often not effective for psoriatic arthritis, even though they can be very useful for treating rheumatoid arthritis, Ritchlin said.

The group recommended that patients see a specialist, such as a dermatologist or rheumatologist, as soon as psoriasis or psoriatic arthritis is suspected. Currently a large number of patients with psoriatic arthritis never see a rheumatologist, and many patients go undiagnosed, Ritchlin said.

The group also recommended that newer medications that inhibit a molecule known as TNF (tumor necrosis factor) be considered by physicians. The first anti-TNF compound, etanercept, was approved by FDA in 1998 to treat rheumatoid arthritis, and then was approved in 2002 to treat psoriatic arthritis. Similar drugs include infliximab and adalimumab.

Most people respond rapidly and dramatically to these medications, said Ritchlin, who led a research team at Rochester that described the central role of TNF in the bone damage that occurs in psoriatic arthritis. Recent estimates indicate that less than 20 percent of psoriatic arthritis patients are on anti-TNF medications.

A reversal of thinking: How women with lupus can increase chance for healthy pregnancies

Sat, 25 Oct 2008 03:59:37 PST

( from http://www.rxpgnews.com ) In the not so distant past, women with systemic lupus erythematosus (SLE), an autoimmune disease, were advised not to have children, and if they became pregnant, to have therapeutic abortions to prevent severe flares of their lupus. Research by rheumatologists at Hospital for Special Surgery in New York, in patients with lupus who have had successful pregnancies is yielding insights that support a reversal of that thinking.

The research effort, a multi-center research initiative lead by Jane Salmon, M.D., attending physician at Hospital for Special Surgery, is known as the PROMISSE (Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus) Study.

Two research projects will be presented at this year's American College of Rheumatology meeting in San Francisco on October 24-29 by Dr. Salmon, based on data gathered from the PROMISSE Study. She and her collaborators identified factors that help a woman and her doctor plan for a healthy pregnancy.

Patients with lupus can live free of symptoms for long periods of time and then experience a disease flare, when symptoms such as a red rash across the nose and cheeks, painful or swollen joints, swollen legs or extreme fatigue suddenly appear. The first presentation will examine whether problems during pregnancy can be correlated to the severity, frequency and timing of disease flares. Dr. Salmon and her colleagues followed 198 pregnant patients with lupus. The investigators found that women who conceived while their disease was stable or only mildly active had relatively infrequent flares during their pregnancies and delivered healthy babies. This held true regardless of past disease severity or past kidney disease (a frequent consequence of lupus). The findings inform women with lupus on how to plan when to conceive to have a low risk pregnancy.

Lupus patients, as well as other patients with the antiphospholipid syndrome, produce special types of proteins called antiphospholipid antibodies that can attack their own tissues and cause pregnancy complications. The second study to be presented by Dr. Salmon showed that the presence of a specific subset of these autoantibodies is highly associated with poor pregnancy outcomes. Specifically, the researchers found that women who tested positive for an autoantibody called lupus anticoagulant were more likely to have complications such as miscarriage or preeclampsia during pregnancy.

These results can help doctors identify patients at high risk for complications by obtaining a blood test to determine if they are positive or negative for the lupus anticoagulant autoantibody. While women with lupus or the antiphospholipid syndrome who are positive for this protein can still have successful pregnancies, their doctors should monitor them more closely for early signs of pregnancy complications.

Based on our new data, we believe we are in a position to help doctors counsel and care for their patients, says Dr. Salmon, Collette Kean Research Chair and co-director, Mary Kirkland Center for Lupus Research at HSS. In the past, women were discouraged from becoming pregnant because of a very high risk to the mother and the baby. Our findings from the PROMISSE study show that women with lupus can have normal pregnancies when they work together with their doctors, beginning with the decision of when it is safe to conceive and continuing with close follow-up to anticipate potential problems.

Groundbreaking, lifesaving TB vaccine a step closer

Tue, 07 Oct 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers at Aberystwyth University, following a number of years of investment by the Biotechnology and Biological Sciences Research Council (BBSRC), have licensed ground-breaking research to a non-profit product development partnership working to develop new, more effective vaccines against Tuberculosis (TB). This development will give hope that significantly better prevention and treatment of TB will be available within the next few years.

The Aeras Global TB Vaccine Foundation, which was founded to develop new, cost-effective TB vaccines for use in the developing world, has licensed a discovery of a protein that is able to 'wake up' dormant Mycobacterium tuberculosis bacteria that cause TB. The research and the fundamental knowledge that came out of it could be used to develop a vaccine that either stops infecting TB bacteria from taking hold or, for the one in every three people world-wide who are already carrying a latent TB infection, prevents dormant bacteria from 'waking up'. Another possible strategy could be to deliberately 'wake up' dormant bacteria in a controlled way so they can be destroyed with antibiotics.

In the late 1990s, researchers funded by BBSRC discovered a new family of proteins that were able to resuscitate bacteria found harmlessly in and around the human body. When 'awoken' from dormancy the bacteria were then much more susceptible to attack from antibiotics. The team led by Professors Mike Young and Doug Kell at Aberystwyth University together with Prof Arseny Kaprelyants of the Bakh Institute of Biochemistry, Russian Academy of Sciences, Moscow, identified the gene in the bacterium that produced the protein and went on to discover the corresponding genes in M. tuberculosis. This research has now been licensed by Aeras after years of development. Aeras plans to take its recombinant BCG (AERAS-407) vaccine, based in part on the Aberystwyth work, to clinical trial in 2009.

Prof Young, now based in Aberystwyth University's newly formed Institute of Biological, Rural and Environmental Studies, said: Current TB treatments can go on for over six months and can still leave bacteria in the body that can cause the disease when they resume active growth and multiplication. Our discovery, which is now being developed into a vaccine, might help prevent the establishment of persistent infections in the first place or, alternatively, it might prevent persisting organisms in individuals with latent TB from reawakening at all.

TB kills around 1.7 million people around the world every year. I hope that our research will now be rapidly translated into a vaccine that can help as many of these people as possible.

Dr Alf Game, BBSRC Deputy Director of Research, said: This discovery came out of research in the basic biology of a different bacterium. It shows that we need to strive to understand the fundamental workings of the world around us and from that we can identify how to tackle challenges, such as dangerous diseases, that we all face.

Multiple disease-related research gets green light from the NIH

Tue, 16 Sep 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Saranac Lake, N.Y. - Stephen Smiley, Ph.D., a member of the scientific faculty at the Trudeau Institute, whose research could lead to new treatments for several common diseases, has been awarded a research grant from the National Institutes of Health (NIH) for nearly $2 million.

Dr. Smiley and members of his laboratory are working to develop treatments for a number of diseases where an abnormal activation of blood coagulation pathways causes damage to the body. The diseases include multiple sclerosis (MS), rheumatoid arthritis, transplant rejection and sepsis, a leading cause of hospital deaths. In particular, Dr. Smiley's laboratory is studying fibrin, a blood-clotting protein that frequently accumulates at high levels in diseased tissues. These high levels of fibrin are thought to clog blood vessels and cause inflammation, thereby starving tissues of oxygen and increasing the severity of disease.

With prior funding from the NIH, Dr. Smiley's laboratory collaborated with Trudeau colleague Larry Johnson to demonstrate that, despite the risks it poses, fibrin also performs critical protective functions during immune responses.

The researchers showed that fibrin deposition is essential for survival during certain infections. Specifically, they found that fibrin staunches bleeding caused by protective immune cells as they rid the body of infected cells. In addition to protecting against this collateral damage caused by the immune system itself, Drs. Smiley and Johnson also discovered that fibrin suppresses the growth of some unhealthy bacteria.

These prior studies led the scientists to hypothesize that the human body needs to maintain a careful balance of proper fibrin levels during immune responses: Some fibrin deposition is essential for good health, while too much can be dangerous and harmful, explained Dr. Smiley.

I'm very pleased the NIH is continuing to support Dr. Smiley's research, said David L. Woodland, Ph.D., president and director of the Trudeau Institute. Cutting-edge research of this caliber has the potential to lead to improved treatments for people afflicted with a number of debilitating diseases, in addition to those who suffer transplant rejections.

Dr. Smiley believes that prior attempts to treat patients suffering from sepsis by removing fibrin failed because those treatments most likely removed both unhealthy and healthy fibrin. With this infusion of research funds, Dr. Smiley's laboratory will now seek to identify what exactly tips the balance between healthy and unhealthy levels of fibrin. They recently discovered that cytokines, soluble signaling molecules within the immune system, play a primary role in regulating this balance. Now they are using a variety of models and methods to delineate precisely how cytokines regulate fibrin levels.

The NIH funds will support Dr. Smiley's research efforts over a four-year period.

UT Medical School receives $6 million NIH grant to study scleroderma

Wed, 10 Sep 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Within five years, researchers at The University of Texas Health Science Center at Houston expect to have identified the genetic clues to scleroderma, a chronic, often progressive, autoimmune disease.

The National Institutes of Health awarded a rheumatologist at the health science center's University of Texas Medical School at Houston a $6 million, five-year grant to conduct a genome-wide association study. The study's goal is to identify gene regions that influence a patient's susceptibility to a serious form of scleroderma known as systemic sclerosis.

Scleroderma, a condition that causes the immune system to attack its own body, affects an estimated 300,000 patients nationwide, mostly women ages 25-55. The disease can result in thickening and tightening of the skin and, in systemic cases, causes serious damage to internal organs, oftentimes targeting the lungs.

I've been studying scleroderma for 20 years, and to see the research field mature to the point where we can do this genotyping, and at the end of five years have an answer is very exciting, said principal investigator Maureen D. Mayes, M.D., MPH, professor of internal medicine in the Division of Rheumatology and Clinical Immunogenetics. Right now we don't know what causes scleroderma, and there is no cure. With this genetic information, we can change that. We can develop better treatments and improve or eliminate symptoms.

For the first phase of the research, which is supported in part by the UT Health Science Center at Houston's Center for Clinical and Translational Sciences, Mayes and collaborators will study the genes of 1,500 patients with scleroderma, plus 3,000 in a control group. Most patients from scleroderma centers at the UT Medical School at Houston, Johns Hopkins School of Medicine and Fred Hutchinson Cancer Research Center have already been identified, and Mayes estimates that the genotyping can be completed as soon as the end of this year. Olga Gorlova, Ph.D., a co-investigator at The University of Texas M. D. Anderson Cancer Center, will then conduct an in-depth statistical analysis of the genome-wide association scan.

During the second phase of the study, to validate the results from the first patient group, Mayes will lead efforts to collect and analyze another 1,500 genetic samples from patients at 10 scleroderma centers in the United States and Canada. Genetic data from a control group of 3,000 healthy individuals will be used for comparison.

This is the tip of the iceberg. With this study, we'll be able to identify gene regions, and from those regions, we will be able to identify specific genes, Mayes said. This provides us a map to the pathways that cause scleroderma, and if we know the pathways, we could interrupt them and prevent disease.

In addition, the study could help investigators identify genes that are markers of severe disease, as well as genes that are indicators of mild disease that is not likely to progress. This, Mayes said, would help physicians determine the best course of treatment. For those with genes that indicate mild disease, rheumatologists could treat their symptoms, which often include joint pain and heartburn. Physicians could pursue a more aggressive approach to treatment, including chemotherapy, for patients with genes that are identified to increase likelihood of severe disease.

The goal is to improve their quality of life, and one of the most important ways we can do that is to first identify and learn more about the genes that influence scleroderma, Mayes said.

Survivors of 1918 flu pandemic protected with a lifetime immunity to virus

Sun, 17 Aug 2008 03:59:37 PST

( from http://www.rxpgnews.com ) New research has discovered that infection and natural exposure to the 1918 influenza virus made survivors immune to the disease for the remaining of their lives. Antibodies produced by cells isolated from these survivors served as an effective therapy to protect mice from the highly lethal 1918 infection. The study entitled Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors, was released for advanced online publication by the journal Nature. Researchers at Mount Sinai School of Medicine's Department of Microbiology contributed to the research findings. An estimated 50 million people were killed by the 1918 flu pandemic worldwide.

Ninety years after survivors encountered the 1918 pandemic influenza virus, we collected antibody-producing B cells from them, and successfully isolated B cells that produce antibodies that block the viral infection, said contributing author Dr. Christopher Basler, PhD, Associate Professor of Microbiology at Mount Sinai School of Medicine. The antibodies produced by these cells demonstrated remarkable power to block 1918 flu virus infection in mice, proving that, even nine decades after infection with this virus, survivors retain protection from it.

The fact that you can isolate these anti-1918 memory B cells so long after infection will hopefully provide the impetus to further study the mechanisms behind long lived immunity, said Dr. Osvaldo Martinez, post-doctoral fellow at Mount Sinai School of Medicine.

For this study, 32 individuals who were born before 1918 and lived through the influenza pandemic were recruited by Dr. Eric Altschuler at the University of Medicine and Dentistry of New Jersey to donate blood which was tested by Dr. Basler's lab for the presence of antibodies that recognize the 1918 virus. Dr. James Crowe and colleagues at Vanderbilt University produced antibodies from these individuals' blood cells and provided these to Dr. Basler's lab where the potent neutralizing activity against 1918 virus was demonstrated. Antibodies were also provided to Dr. Terrence Tumpey at the CDC to test in mice the strength of the antibodies derived from the 1918 survivors.

Our findings show that survivors of the pandemic have highly effective, virus neutralizing antibodies to this powerful virus, and humans can sustain circulating B memory cells to viruses for up to 9 decades after exposure, said Dr. Tshidi Tsibane, post-doctoral fellow, Department of Microbiology, Mount Sinai School of Medicine. These findings could serve as potential therapy for another 1918-like virus.

Vanderbilt University, Mount Sinai School of Medicine, University of Medicine and Dentistry of New Jersey, Centers for Disease Control and Prevention and The Scripps Research Institute collaborated on this research study.

About The Mount Sinai Medical Center The Mount Sinai Medical Center encompasses The Mount Sinai Hospital and Mount Sinai School of Medicine. The Mount Sinai Hospital is one of the nation's oldest, largest and most-respected voluntary hospitals. Founded in 1852, Mount Sinai today is a 1,171-bed tertiary-care teaching facility that is internationally acclaimed for excellence in clinical care. Last year, nearly 50,000 people were treated at Mount Sinai as inpatients, and there were nearly 450,000 outpatient visits to the Medical Center.

Mount Sinai School of Medicine is internationally recognized as a leader in groundbreaking clinical and basic-science research, as well as having an innovative approach to medical education. With a faculty of more than 3,400 in 38 clinical and basic science departments and centers, Mount Sinai ranks among the top 20 medical schools in receipt of National Institute of Health (NIH) grants.

UGA researchers win $9.2 million stem cell grant from NIH

Mon, 04 Aug 2008 03:59:37 PST

( from http://www.rxpgnews.com ) A research group led by Stephen Dalton, professor and Georgia Research Alliance Eminent Scholar of Molecular Biology at the University of Georgia, has been awarded $9.2 million as part of a major new research grant by the National Institute of General Medical Sciences, part of the National Institutes of Health.

Dalton's group, headquartered in the department of biochemistry and molecular biology, will address the molecular underpinnings of the early steps that stem cells take in becoming specialized cell types. The scientists will also seek to identify the genetic and protein modification patterns that accompany this process of differentiation.

The new grant in UGA's Franklin College of Arts and Sciences is part of $27 million in funding awarded to the University of Wisconsin, UCLA and UGA that NIGMS has added to its ongoing effort to uncover the basic biology of human embryonic stem cells.

Our program will offer training for scientists seeking to gain expertise in the specialized techniques needed to work with embryonic stem cells and will serve as a source of reagents, technical support and methodology development, said Dalton, who is also a Georgia Cancer Coalition Distinguished Scholar and a member of UGA's developmental biology program.

The results of all three new programs are expected to deepen existing knowledge of the unique properties of stem cells and will be important to researchers trying to develop stem-cell-based therapies.

This program project grant is important for a number of reasons, said David Lee, UGA vice president for research. Certainly it highlights the expertise in stem cell biology and glycomics at the University of Georgia. But perhaps more important, it is cleverly designed to promote stem cell research throughout the Southeast. One of the core facilities funded by the grant is specifically tasked with developing new stem cell technologies that will be disseminated to researchers across the region via the new Southeast Stem Cell Consortium, which Professor Dalton chairs. We are extremely pleased by the leadership provided by Dr. Dalton in an area that offers so much promise for human health.

Dalton's position as a leader in stem-cell research has been solidified with the recent establishment of the Southeast Stem Cell Consortium. The consortium has strong interests in the basic biology of stem cells, their utility as a model for studying mammalian development and their potential as a cell source to develop therapies for degenerative disease and repair of chronic injury. Focus areas include diabetes, cardiovascular disease, spinal cord injury and neurodegenerative disease.

This is an innovative program that focuses on an understudied area of stem cell biology, said Marion Zatz, Ph.D., who oversees stem cell grants at the National Institute of General Medical Sciences of the National Institutes of Health. By looking at how proteins are modified by sugar molecules as stem cells differentiate, Dalton's team could help us understand how the many distinct cell types in our bodies are formed.

Dalton's research group at UGA focuses on the uses of stem cells in understanding diabetes and cardiovascular disease. One current project involves finding ways to use stem cells to repair the human heart.

The heart is an organ that doesn't repair itself, said Dalton. But we're studying a resident population of stem cells that have the capability of dividing and turning into cardiac cells. Theoretically, they could be used to help the heart repair itself after a heart attack.

The new programs join an NIGMS effort launched in 2003 to explore the basic molecular and genetic features of human embryonic stem cells. Prior to the latest awards, the initiative has included six exploratory centers, two multidisciplinary research programs and several independent research projects and supplements.

String probes for devastating childhood digestive disease

Wed, 30 Jul 2008 03:59:37 PST

( from http://www.rxpgnews.com ) A swallowed string may someday replace the invasive, uncomfortable endoscope now used to diagnose a devastating childhood disease of the esophagus.

Steven J. Ackerman of University of Illinois at Chicago College of Medicine and Dr. Glenn T. Furuta, his colleague at the University of Colorado Denver, were recently awarded three grants for an all-fronts attack on eosinophilic esophagitis, an inflammatory disease in which defense cells called eosinophils mistakenly attack the esophagus, causing it to narrow until food can't pass.

Most cases are first encountered in the emergency room, where a child is brought in because something he ate is caught in his esophagus, said Ackerman, professor of biochemistry and molecular genetics at UIC.

To diagnose the disease, doctors insert an instrument called an endoscope down the esophagus and take six to eight samples of tissue, from the top, middle and distal end, near the stomach. Under a microscope, they count the number of eosinophils, which are not normally present in the esophagus at all, Ackerman said. The procedure, he said, is not only expensive but uncomfortable and carries some risks. And because repeat testing is needed over the course of treatment, a child may need to undergo as many as 20 endoscopies within three or four years.

Ackerman and his colleagues hope they can replace the endoscope by having children swallow a string encased in a gelatin capsule. As the capsule travels down the esophagus, the string plays out of the dissolving capsule, stretching through the esophagus, the stomach and the small intestine. The string is left in place overnight, then pulled out.

We can determine which part of the string was in the esophagus, versus in the stomach, mouth or small intestine, said Ackerman. They then look on the string for certain inflammatory proteins that are expressed only by eosinophils.

The test will be done the day before an endoscopic test is planned. The researchers will compare the thread's measures of the eosinophil proteins with the cell counts obtained by endoscopy.

Eventually, of course, our hope is to replace these repeated endoscopies with this simple procedure, Ackerman said.

The study, funded by the National Institute of Allergy and Infectious Diseases (one of the National Institutes of Health), will be done at two sites, UIC and Denver. Ackerman and Furuta are co-principal investigators on the team, which also includes Dr. Amir Kagalwalla of the UIC Department of Pediatrics.

The two other grants are from the American Gastroenterological Association (AGA) and the CURED Foundation (Campaign Urging Research for Eosinophilic Diseases).

The AGA awarded Ackerman and Furuta its 2008 translational research award to determine the mechanisms that regulate changes in the esophagus caused by the disease, including the growth of scar tissue. The researchers will use the string test to look for biomarkers of the changes that characterize the disease.

CURED awarded the team an unrestricted gift for research to investigate pathogenic mechanisms in eosinophilic esophagitis and related gastrointestinal diseases. CURED has raised more than $1.4 million over the past five years, most recently as the beneficiary charity of the annual Highland Park (Ill.) High School fund-raising event, which raised $500,000 this year.

The investigators are also planning a proteomics study that will measure all the proteins on the string to develop a more complete diagnostic profile of the disease, Ackerman said.

These grants present us with an exciting opportunity to increase our understanding of this difficult, newly emerging disease, which has increased in detection, and also possibly in incidence.

Heart researchers receive grant to study asthma

Fri, 25 Jul 2008 03:59:37 PST

( from http://www.rxpgnews.com ) A research grant program that encourages thinking outside the box will allow a team of University of Iowa investigators to apply findings from heart research to the study of asthma.

Specifically, the team has received a three-year, $750,000 grant from the Strategic Program for Asthma Research, known as SPAR, to see if an enzyme known to play a role in heart failure might also affect smooth muscle cells in the airway and thus play a role in asthma. The basic science research focuses on CaM kinase II, which has been under scrutiny in other UI research.

We are taking a fresh look at the role of calcium signaling in asthma, and are applying some ideas and results from the cardiovascular field that have never before been considered in the field of asthma, said study investigator Isabella Grumbach, M.D., Ph.D., assistant professor of internal medicine in the UI Roy J. and Lucille A. Carver College of Medicine.

The study team includes five UI faculty members, four of whom are based in cardiology and have never studied asthma, and only one whose field of expertise is asthma. The team aims to learn more about airway smooth muscle cells.

Grumbach's lab will grow the cells and monitor their response (for example, for inflammation) to the enzyme. She also will supply mouse models to investigate the response of airway smooth muscle cells to CaM kinase II inhibition.

The study will be led by Mark Anderson, M.D., Ph.D., UI professor of internal medicine and molecular physiology and biophysics, who has previously published, and has other studies underway, on CaM kinase II as it relates to heart issues.

Competition for the award was considerable, noted Anderson, with only 17 projects out of 255 applications funded this year.

This kind of research is meant to help examine 'holes' in the paradigm of current asthma understanding. We're not asking safe, predictable questions, but getting involved because sometimes people from outside a field can help with a paradigm shift, said Anderson, who also holds the Potter-Lambert Chair in Cardiology.

In addition to Grumbach and Anderson, the team includes Joel Kline, M.D., professor of internal medicine; Peter Mohler, Ph.D., associate professor of internal medicine; and Long-Sheng Song, M.D., assistant professor of internal medicine. Anderson, Grumbach, Mohler and Song also are members of the UI Heart and Vascular Center.

Kline is an asthma expert and provided precursor data to help the team apply for the study. Mohler has expertise in helping determine the mechanical and electrical function of cells, while Song brings expertise in measuring calcium responses.

It's a great partnership, and another example of what can happen when there is a focus on innovative scientific collaboration by generous funders and motivated researchers, Anderson said.

USU researchers awarded $5.6 million NIH grant to fight deadly viruses

Fri, 27 Jun 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers at the Uniformed Services University of the Health Sciences (USU) have been awarded a $5.6 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) to develop and test vaccines and treatments for the deadly Nipah and Hendra viruses.

Christopher C. Broder, Ph.D., USU professor of microbiology and immunology and director of the university's interdisciplinary program in Emerging Infectious Diseases, is the principal investigator of the grant from NIAID. The grant was awarded to continue work on vaccines and therapeutics for Nipah and Hendra that his group has been working on for the past several years. The award will support a continued collaboration with investigators at Australia's Commonwealth Scientific and Industrial Research Organization (CSIRO) Livestock Industries, Australian Animal Health Laboratory (AAHL) and Australian Biosecurity Cooperative Research Center (AB-CRC) in Geelong, Victoria.

Hendra and Nipah are recently emerged paramyxoviruses that are highly pathogenic and can cause lethal infections in several animals and in humans. Since their initial discovery in Australia and Malaysia, sporadic Hendra outbreaks have been reported from 1995 to 2007, while Nipah has caused at least nine outbreaks between 1998 and 2008. Human case fatality rates have approached 75 percent, and there has been evidence of human-human transmission. The most recent appearance of Nipah in 2008 claimed the lives of several children.

In earlier work, Katharine Bossart, Ph.D., a former graduate student in Broder's laboratory who now works with the Australian Animal Health Laboratory in Geelong, developed a subunit vaccine for Nipah and Hendra composed of a piece of the virus known as the G glycoprotein. In other recent studies, Broder's group, in collaboration with researchers from the National Cancer Institute, developed a potent Nipah and Hendra virus neutralizing human monoclonal antibody (m102.4).

We now have the critical resources needed to evaluate the therapeutic potential of both vaccines and perhaps more importantly a potent human antibody against both Nipah virus and Hendra virus, that could help control outbreaks in geographical regions susceptible to these emerging viruses, and result in a real benefit to those people at risk of infection and disease caused by these deadly agents, said Broder.

Previously, Broder and colleagues demonstrated that a cell surface protein called Ephrin-B2 is a functional receptor for both the Hendra and Nipah viruses. Ephrin-B2 is highly conserved in animals, and this finding shed light on how the viruses can infect such a wide range of hosts. The receptor is found on cells in the central nervous system, as well as in cells lining blood vessels. It is essential for central nervous system development and blood vessel growth in the embryos of humans and other mammals.

The research has led to four inventions on which USU and HJF have filed patent applications. The first patent application, Soluble forms of Hendra Virus and Nipah Virus G glycoprotein, covers the production and use of a recombinant soluble G glycoprotein. This protein has utility as a vaccine, in the development of pharmaceutical compositions and in diagnostic assays.

The second patent application, Compositions and Methods for the Inhibition of Membrane Fusion by Paramyxoviruses, covers the use of a novel peptide sequence of the soluble F glycoprotein, to block fusion of the virus with the host cell. This peptide can be used as a prophylactic, and/or to treat infections, and antibodies developed using this peptide can be utilized in diagnostic assays.

A third patent application, Soluble forms of Hendra and Nipah Virus F glycoprotein covers the production and use of a new recombinant soluble F protein. The remaining patent application, Human Monoclonal Antibodies Against Hendra and Nipah, filed in conjunction with the National Institutes of Health, covers the production and use of monoclonal antibodies which could be used as a therapeutic for people already infected with the disease.

Pharmacists as educators can improve asthma outcomes

Mon, 23 Jun 2008 03:59:37 PST

( from http://www.rxpgnews.com ) New research has shown that up to 90 per cent of people on asthma medications are using their inhalers incorrectly leading to poor asthma control, increased hospital visits and increased cost of treatment.

The study then went on to show how a brief educational chat with a pharmacist about inhaler technique and stickers on the medication can lead to improved asthma control in the patients.

Woolcock Institute of Medical Research spokesperson, Associate Professor Helen Reddel said, Pharmacists and other health care professionals need to effectively show patients how to use inhalers correctly and to promote the importance of inhaler technique on patient outcomes, she said.

By educating pharmacists on correct technique and then putting in place an easy system for them to relay this knowledge, our research was able to demonstrate a real effect on patient behaviour.

The inhaler technique intervention took an average of 2.5 minutes per visit, which is short enough to be feasible during routine dispensing procedures, she said.

The research carried out by Dr Iman Basheti of the Faculty of Pharmacy is the first to report on the effect of inhaler technique education alone on asthma outcomes.

All pharmacists who took part in the study attended a general workshop about asthma, inhaled medications and peak flow meter technique. However only pharmacists in the active group were trained to assess and teach dry powder inhaler technique, with the aid of a simple education tool.

The active group pharmacists then delivered interventions to patients at four visits over six months.

An additional component of the intervention was the use of innovative stickers applied to the outside of inhalers to remind patients about the correct technique. Stickers were personalised to highlight each patient's most problematic steps with their inhaler. They were updated at each visit.

At six months improvement in inhaler technique score was significantly greater in the active group, and asthma severity was significantly improved.

Professor Reddel explains the findings of the study reinforce the need for regular assessment and education about inhaler technique.

The inhaler labels provided a simple visual aid, acting as both a daily reminder of correct technique and as visit-by-visit evidence of progress.

For people with asthma to obtain the full benefit of medication they must not only use their preventer inhaler regularly, which is itself a challenge, but do so correctly.

Pharmacist education represents an inexpensive yet effective way of improving asthma control in the community.

If the results of this study are confirmed in broader populations, this simple pharmacist intervention should be instituted as a routine part of the dispensing of inhaled asthma medications, Associate Professor Helen Reddel concluded.

Weizmann Institute scientists develop a new approach to treating autoimmune disease

Mon, 02 Jun 2008 03:59:37 PST

( from http://www.rxpgnews.com ) In autoimmune diseases, the immune system turns against the body's own tissues and organs, wreaking havoc and destruction for no apparent reason. Partly because the origins of these diseases are so obscure, no effective treatment exists, and the suffering they inflict is enormous. Now Weizmann Institute scientists have developed a method that in the future may make it possible to treat autoimmune diseases effectively without necessarily knowing their exact cause. Their approach is equivalent to sending a police force to suppress a riot without seeking out the individuals who instigated the unrest.

In healthy people, a small but crucial group of immune cells called regulatory T cells, or T-regs, keeps autoimmunity in check, but in people with inflammatory bowel disease (IBD), one of the most common autoimmune disorders, too few of these cells appear in the diseased intestine, and the ones that do fail to function properly. The new Weizmann Institute approach consists of delivering highly selective, genetically engineered functioning T-regs to the intestine. The study was conducted by Dr. Eran Elinav, a physician from Tel Aviv Sourasky Medical Center's gastroenterology institute who is working toward his Ph.D. at the Weizmann Institute, and lab assistant Tova Waks, in the laboratory of Prof. Zelig Eshhar of the Immunology Department.

Relying on Eshhar's earlier work in which he equipped a different type of T cell to zero in on cancerous tumors, the team genetically engineered T-regs, outfitting these cells with a modular receptor consisting of three units. One of these units directed the cells to the intestine while the other two made sure they became duly activated. As reported in the journal Gastroenterology, the approach proved effective in laboratory mice with a disease that simulates human IBD: Most of the mice treated with the genetically-engineered T-regs developed only mild inflammation or no inflammation at all.

The cells produced what the scientists called a 'bystander' effect: They were directed to the diseased tissue using neighboring, or 'bystander' markers that identified the area as a site of inflammation, and suppressed the inflammatory cells in the vicinity by secreting soluble suppressive substances.

The scientists are currently experimenting with human T-regs for curing ulcerative colitis and believe that in addition to IBD, their 'bystander' approach could work in other autoimmune disorders, even if their causes remain unknown. They also think the method could be valuable in suppressing unwanted inflammation in diseases unrelated to autoimmunity, as well as in preventing graft rejection and certain complications in bone marrow and organ transplantation, in which inflammation is believed to play a major role.

Hayfever hope

Mon, 02 Jun 2008 03:59:37 PST

( from http://www.rxpgnews.com ) With the peak grass pollen season approaching, scientists can reveal that a daily dose of probiotic can change the immune status of people with hay fever.

In the first human study of its kind, scientists at the Institute of Food Research found that probiotic bacteria in a daily drink can modify the immune system's response to grass pollen, a common cause of seasonal hay fever.

But they are not recommending that sufferers rush to the supermarket shelves just yet. The changes found may not have an immediate effect on symptoms.

This was a pilot study based on small numbers of patients, but we were fascinated to discover a response, says research leader Professor Claudio Nicoletti. The probiotic significantly reduced the production of molecules associated with allergy.

Hayfever is an allergic reaction to pollen or fungal spores, most commonly grass pollen. The immune system mistakes the spores for harmful invaders and produces excessive amounts of the antibody IgE to bind to them and fight them off.

IgE stimulates the release of histamine to flush out the spores, and this irritates the airways making them swell and producing the symptoms of hayfever.

In this study, volunteers with a history of seasonal hay fever drank a daily milk drink with or without live bacteria over 5 months. The study was double-blinded and placebo controlled, so neither the volunteers nor the scientists knew who had been assigned the probiotic drinks. The probiotic drinks contained Lactobacillus casei, a bacterial species that has been widely studied for its health promoting properties.

Blood samples were taken before the grass pollen season, then again when it was at its peak (June), and 4 weeks after the end of season. There were no significant differences in levels of IgE in the blood between the two groups at the start of the study, but IgE levels were lower in the probiotic group both at the peak season and afterwards.

At the same times, levels of the antibody IgG were higher, a type of antibody that in contrast to IgE is thought to play a protective role against allergic reactions.

The probiotic strain we tested changed the way the body's immune cells respond to grass pollen, restoring a more balanced immune response, says Dr Kamal Ivory, a senior member of the group.

The changes observed may also reduce the severity of symptoms, but clinical symptoms were not measured in this study. That is one aim of further research.

These are really interesting results, says Dr Linda Thomas, head of science at Yakult UK, who provided the drinks and some of the funding. We are delighted that independent scientists found evidence of this biological activity. The project was part of ongoing research into the benefits of our probiotic strain. The Institute of Food Research is well positioned to do this kind of fundamental research, as it is unique in having the right combination of expertise in microbiology, immunology, flow cytometry and human nutrition research.

Professor Nicoletti's group intend to perform a similar study in the near future to see if the immunological changes translate into a real reduction in the clinical symptoms of hayfever. They would also like to examine the mechanisms involved.

New HIV browser gives researchers access to valuable data from vaccine trials

Thu, 29 May 2008 03:59:37 PST

( from http://www.rxpgnews.com ) SANTA CRUZ, CA--A new HIV data browser developed by the University of California, Santa Cruz, and the nonprofit organization Global Solutions for Infectious Diseases (GSID) will give researchers access to a wealth of data collected during clinical trials of an AIDS vaccine. Although the vaccine did not succeed in preventing infections, the clinical trial generated a huge amount of valuable data for researchers studying how the virus evolves and causes new infections.

Modeled on the UCSC Genome Browser, the GSID HIV Data Browser is the brainchild of Phillip Berman, professor and chair of biomolecular engineering in UCSC's Baskin School of Engineering. Berman helped oversee the clinical trials, which ended in 2003, when he was senior vice president for research and development at VaxGen, the company that developed the vaccine and conducted Phase III clinical trials in North America, Europe, and Thailand.

After the trials concluded, I spent a couple of years trying to think what was the most important thing I could do for HIV research, Berman said. I concluded it was using new technology to preserve the data from these clinical trials and present it in a form useful to the scientific community.

In 2004, Berman cofounded GSID, based in South San Francisco and dedicated to combining knowledge and expertise from the biotechnology industry and the public health sector to address infectious disease problems in the developing world. He joined the UCSC faculty in 2006.

Despite the fact that the vaccine trial didn't work, a huge amount of useful information was obtained, Berman said. The North American trial included about 60 different clinical sites in North America and one site in the Netherlands. Of particular value to researchers are the genetic sequences of the viruses that infected participants during the trial.

The trial represented the only up-to-date broad survey of virus sequences from new infections that had ever been carried out, Berman said. Every time there was a new infection in the vaccine or placebo group, the virus was sequenced. The sequence information provides the best picture we have about what the immune system sees when there is a new infection.

This is important, Berman said, because other major repositories of HIV sequence data are not annotated for the time after infection, the clinical status of the patient, or the histories of the specimens sequenced. That limits their usefulness for studying such a rapidly evolving virus.

HIV is highly mutable and evolves in response to attacks by the immune system. As a result, HIV isolated from a patient years after the initial infection is genetically different from the virus that caused the infection in the first place. A vaccine should target the most infectious form of the virus, Berman said. Yet all the vaccines tested so far have been based on viruses isolated from patients with longstanding infections.

A current hypothesis in HIV vaccine research is that the antigenic structures of HIV viruses that mediate new infections differ from those recovered from people long after infection, Berman explained. The specimens in this set represent the largest group from new infections that has ever been collected.

Besides viral genome-sequence data, the database links to a repository of preserved specimens (blood samples and cells) that researchers can access from GSID and the National Insitutes of Health (NIH) for further study.

This is the first time that an HIV sequence database has been linked to a specimen repository and a database of clinical information, Berman said. These clinical specimens are longitudinal, collected from the same person during a two-year follow-up period. This will allow investigators to study the evolution of the virus and the evolution of the immune response and clinical outcomes.

At UCSC, Berman teamed up with the Genome Browser group to develop a browser for the sensitive clinical data collected during the vaccine trial. Jim Kent, associate research scientist for the UCSC Genome Browser and principal investigator on the project, said it was the first time his group had worked with data from participants in a clinical trial.

This data must be handled differently and great care taken with confidentiality, Kent said. We learned from this project how to build the infrastructure to cope with that. This will be useful for other medical projects, such as cancer genomics, in the future.

Fan Hsu, director of proteomics for the UCSC Genome Browser, said the emphasis on security was very different from past projects. Before, everything we have worked on is totally open, totally public. With the GSID project, only authorized users can access the data, so we needed to set up special controls, Hsu said.

How to display the very large number of HIV sequences on the browser was another challenge. Our original genome browser has only one reference genome. For this HIV database, we have about 350 infected people and more than 1,000 sequences, he said.

Hsu and software developer Galt Barber adapted the genome browser software to accommodate the large number of HIV sequences and the data security along with interactive selection criteria for viewing the data. As the project evolved, Hsu also coordinated the transfer of the software to GSID. The UCSC team, which also included Erich Weiler, Robert Kuhn, and Ann Zweig, worked nights and weekends to bring the new browser online.

The resulting GSID HIV Data Browser is a customized version of the UCSC Genome Browser. It provides researchers with searchable demographic and clinical data from volunteers who became HIV infected during the VaxGen clinical trial. The browser allows users to align viral sequences with one another and with reference or consensus sequences.

This is something where the university can make a difference, because the private sector is not so interested in vaccines; they're not so profitable, Kent said. There is very little economic incentive to develop an AIDS vaccine, but there is a tremendous humanitarian incentive.

Kent hopes that just as the UCSC Genome Browser has continued to build the collaborative nature of the genomics research community, this HIV data browser will help motivate the AIDS research community to work together and pool their data.

Vaccine development efforts have been repeatedly frustrated. An HIV vaccine candidate developed by the pharmaceutical company Merck recently failed in clinical trials cosponsored by NIH. The recent failure of the Merck HIV vaccine has thrown the field into turmoil, Berman said. All the best ideas for an HIV vaccine in the past 20 years have failed. The information in this database is now more critical than anyone could have imagined. It tells us what's being transmitted.

The next phase of the HIV browser project involves releasing the sequence data from infected participants in the Phase III clinical trial that VaxGen conducted in Thailand.

In the future, the database will be expanded to allow associations between virus sequences, clinical data, immune response data, and host genetics, Berman said. We hope to eventually include data from other HIV vaccine trials sponsored by the NIH, private companies, and other HIV vaccine research organizations.

Getting better with a little help from our 'micro' friends

Wed, 28 May 2008 03:59:37 PST

( from http://www.rxpgnews.com ) PASADENA, Calif.-- A naturally occurring molecule made by symbiotic gut bacteria may offer a new type of treatment for inflammatory bowel disease, according to scientists at the California Institute of Technology.

Most people tend to think of bacteria as insidious organisms that only make us sick, says Sarkis K. Mazmanian, an assistant professor of biology at Caltech, whose laboratory examines the symbiotic relationship between good bacteria and their mammalian hosts. Instead, he says, bacteria can be beneficial and actively promote health.

For example, the 100 trillion bacteria occupying the human gut have evolved along with the human digestive and immune systems for millions of years. Some harmful microbes are responsible for infection and acute disease, while other bacteria, the more intelligent ones, have taken the evolutionary route of shaping their environment by positively interacting with the host immune system to promote health, which gives them an improved place to live; it's like creating bacterial nirvana, says Mazmanian.

If bacteria are actively modifying the gut, their work would have to be mediated by molecules. In their recent work, Mazmanian and his colleagues have identified one such molecule, a sugar called polysaccharide A, or PSA, which is produced by the symbiotic gut bacterium Bacteroides fragilis. They have termed this molecule a symbiosis factor, and predict that many other bacterial compounds with diverse beneficial activities await discovery.

To identify the molecule and its action, the scientists used experimental mice and induced changes to their intestinal bacteria by exposing them to a pathogenic bacterium called Helicobacter hepaticus. This microbe causes a disease in the mice that is similar to Crohn's disease and ulcerative colitis. However, when the animals were co-colonized with B. fragilis, they were protected from the disease--as were animals that were given oral doses of just the PSA molecule.

In particular, Mazmanian and his colleagues found that PSA induced particular immune-system cells called CD4+ T cells to produce interleukin-10 (IL-10), a molecule that has previously been shown to suppress inflammation--and offer protection from inflammatory bowel disease. Thus, bacteria help reprogram our own immune system to promote health, he says.

The most immediate and obvious implication is that PSA may potentially be developed as a natural therapeutic for inflammatory bowel disease, says Mazmanian.

Inflammatory bowel disease, a constellation of illnesses that cause inflammation in the intestines, including ulcerative colitis and Crohn's disease, is estimated to affect one million Americans. The rates of inflammatory bowel diseases have skyrocketed in recent years; for example, the incidence of Crohn's disease, a condition that causes debilitating pain, diarrhea, and other gastrointestinal symptoms, has increased by 400 percent over the past 20 years.

The current research, along with other work by Mazmanian and June L. Round, a Caltech postdoctoral researcher, suggests that the interplay between various groups of bacteria living in the intestines has profound effects on human health.

This notion gels with the so-called hygiene hypothesis. The hypothesis, first proposed two decades ago, links modern practices like sanitation, vaccination, a Western diet, and antibiotic use, which reduce bacterial infections, to the increased prevalence of a variety of illnesses in the developed world, including inflammatory bowel disease, asthma, multiple sclerosis, and Type 1 diabetes. However, it is now clear that increased living standards and antibacterial drugs affect not only infectious microbes, but all of the beneficial ones that we may depend on for our well-being.

Through societal measures we have changed our association with the microbial world in a very short time span. We don't have the same contact with microbes as we have for millions of years--we just live too clean now, Mazmanian says. So while it is useful to eliminate disease-causing organisms, perhaps disease results from the absence of beneficial bacteria and their good effects, he suggests. This study is the first demonstration of that. What it hopefully will do is allow people to re-evaluate our opinions of bacteria. Not all are bad and some, maybe many, are beneficial.

Suspected cause of type 1 diabetes caught 'red-handed' for the first time

Fri, 09 May 2008 03:59:37 PST

( from http://www.rxpgnews.com ) May 8, 2008 -- Scientists at Washington University School of Medicine in St. Louis working with diabetic mice have examined in unprecedented detail the immune cells long thought to be responsible for type 1 diabetes.

Researchers were able to examine the immune cells from isolated insulin-making structures in the pancreas known as the islets of Langerhans. They caught the immune cells, known as dendritic cells, red-handed: carrying insulin and fragments of insulin-producing cells known as beta cells. This can be the first step toward starting a misdirected immune system attack that destroys the beta cells, preventing the body from making insulin and causing type 1 diabetes.

The results, reported online in The Proceedings of the National Academy of Sciences, push scientists a step closer to finding ways to treat this condition.

Now that we've isolated dendritic cells from the pancreas, we can look at why they get into the pancreas and determine which of the materials that they pick up are most critical to causing this form of diabetes, says senior author Emil R. Unanue, M.D., the Paul and Ellen Lacy Professor of Pathology. That may allow us to find ways to inhibit dendritic cell function in order to block the disorder.

The American Diabetes Association estimates that 1 million to 2 million Americans suffer from type 1 diabetes, which is also called juvenile diabetes because it frequently develops in children.

Patients require insulin injections to survive because the immune system has destroyed the islets of Langerhans, which contain the body's only beta cells. The insulin these cells make is required for the critical task of regulating blood sugar levels.

Scientists detected dendritic cells in the islets years ago. Dendritic and other antigen-presenting cells are the sentinels of the immune system: They pick up bits of protein from around the body and present them to lymphocytes to initiate an immune system reaction. The lymphocytes lead immune attacks against foreign invaders like bacteria and viruses and eliminate them, clearing infections. But when interaction between an antigen-presenting cell and a lymphocyte leads to a part of the body being mistakenly identified as alien, the resulting attack harms the body, causing autoimmune diseases.

Although dendritic cells' presence in the islets and their ability to summon immune attacks made them likely suspects in type 1 diabetes, they were challenging to isolate from the pancreas for closer examination.

They're very tiny and there are only about 5 to 10 of them per islet, each of which contains approximately a thousand cells, explains Unanue. So the senior postdoctoral researcher in the lab who did this work, Boris Calderon, had to develop some sophisticated cellular assays to pick them up.

Calderon, M.D., found indications that the cells were carrying granules of insulin and pieces of proteins from beta cells on their cell surfaces. To test whether this cargo carried by the dendritic cells had the potential to trigger an immune attack on beta cells, Calderon exposed the dendritic cells to lymphocytes taken from diabetic mice. The lymphocytes were activated by the dendritic cells of the islets and switched into attack mode.

In a separate line of research, Unanue's lab has learned that dendritic cells in the pancreas may normally have beneficial effects on the health of beta cells. They've shown that when dendritic cells are absent from the pancreas, the beta cells are smaller, an indication that they're not as healthy.

We think these dendritic cells aren't in the pancreas by accident, says Unanue. We believe that in the normal individual they help maintain the health of beta cells. But in a person with autoimmune diabetes, they appear to start the problems that destroy beta cells.

The key distinction likely lies in a group of proteins called the major histocompatibility complex (MHC). Two decades ago, Unanue and Paul Allen, Ph.D., the Robert L. Kroc Professor of Pathology and Immunology, showed that the MHC provides the stage on which antigen-presenting cells show bits of protein or peptides to other immune system cells. Scientists believe autoimmune conditions like type 1 diabetes are caused by differences in what the MHC binds to and how it presents that material to immune attack cells. In support of this theory, Unanue's laboratory and that of Michael Gross, Ph.D., Washington University professor of chemistry, have collaboratively shown that the genes that encode the MHC proteins in the diabetic mouse are unique and bind to a set of very characteristic peptides.

In addition to studying what protein fragments carried by dendritic cells are essential for causing type 1 diabetes, Unanue and others are working to learn how genetic variations in the MHC alter the chances that the immune system will mistakenly attack the body.

Method for fast human antibodies against flu could find broad use

Wed, 30 Apr 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Scientists have developed a new, faster way to create human monoclonal antibodies against infectious disease by tapping the immune system at the peak of its powers.

Researchers from Emory University School of Medicine and Oklahoma Medical Research Foundation report that they can generate high-affinity monoclonal antibodies against influenza virus a month after vaccinating human volunteers.

Their results are described in an advance online publication in the journal Nature.

This method could find broad application towards almost any infectious disease, says Rafi Ahmed, PhD, director of the Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar.

As a first example, doctors could quickly generate human antibodies against a pandemic flu strain as a stop-gap therapy or to protect people from infection. In this study, the antibodies were not tested on influenza virus strains with pandemic potential, such as the H5N1 strain although such studies are underway.

Ahmed and postdoctoral fellow Jens Wrammert, PhD, from the Emory Vaccine Center and Emory University School of Medicine, collaborated with Don Capra, PhD, and Patrick Wilson, PhD, immunology researchers at the Oklahoma Medical Research Foundation.

With just a few tablespoons of blood, we can now rapidly generate human antibodies that can be used for immunization, diagnosis and treatment of newly emerging strains of influenza, Wilson says. In the face of a disease outbreak, the ability to quickly produce infection-fighting human monoclonal antibodies would be invaluable.

With a detailed look at the antibodies stimulated by booster vaccination, the scientists also were able to address an issue that confounds health authorities trying to predict which viral strains will prevail in the upcoming flu season.

Doctors have worried about a phenomenon called original antigenic sin, where immunizing someone against a certain strain can handicap them in responding to a related strain.

We found that these early B cell responses are able to focus on the new virus, even though the immune system has seen related viruses before, says Wrammert, who is the paper's first author. B cells are the white blood cells that make antibodies.

The authors conclude that original antigenic sin is uncommon for healthy adults receiving influenza vaccination.

The methods previously used to make human monoclonal antibodies can be relatively laborious, Ahmed says. They involve sifting through human B cells and looking for those that make the right antibodies, or vaccinating mice and humanizing the mouse antibody genes by altering them so that they resemble human antibodies.

To make human antibodies against influenza, the Emory and University of Oklahoma researchers isolated antibody-secreting cells (plasma cells) from volunteers' blood a week after vaccination and cloned the antibody genes from these antibody-secreting cells.

Specialized white blood cells coordinate first responders to viral infection

Thu, 24 Apr 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Just as fire engines arrive quickly at the scene to save people and property, the cells that fight viruses have to reach the site of an infection promptly to mount a protective response.

According to recent studies by University of Washington (UW) scientists, specialized types of white blood cells, a category called regulatory T cells, seem to help orchestrate this timely reaction to a virus invasion. Their findings appear in the April 24 edition of Science Express, a Web edition of selected Science papers published in advance of the print edition. The authors of the study, Coordination of Early Protective Immunity to Viral Infections by Regulatory T Cells, are Jennifer M. Lund, senior fellow in immunology; Lianne Hsing, immunology graduate student; Thuy T. Pham, senior biology major; and Alexander Y. Rudensky, professor of immunology.

The Rudensky laboratory is noted for many contributions to the superhot field of regulatory T cells. These cells are important in controlling autoimmunity, a cellular self-attack that can lead to diseases like reactive arthritis. UW researchers and other scientists have shown that young mice deficient in regulatory T cells die from an aggressive form of autoimmunity that damages several organs.

Rudensky noted the great clinical interest in the therapeutic potential of regulatory T cells. Evidence is growing on the role of regulatory T cells in keeping the body's immune responses in check. Studies in lab animals suggest these cells might be harnessed to treat autoimmune diseases or reduce rejection of transplanted organs.

Researchers think that regulatory T cells might call a halt to immune responses as the body nears success in eliminating an infection. This suppression as the fight draws to an end would reduce tissue damage from robust immune responses.

But what happens early in infection Does the immunity-suppressing function of regulatory T cells form an obstacle to organizing an attack on germs that have just invaded the body Do regulatory T cells temporarily lose their suppression ability in reaction to viral-sensing mechanisms or other signals In the recent Science Express study, researchers looked for a role for regulatory T cells during the start of a herpes simplex virus infection in mucus membranes.

When regulatory T cells are deficient in mice, the herpes simplex virus replicates rapidly in the mucus membranes and spreads to the spinal cord. Upon closer examination of these mice that lack regulatory T cells, the researchers found very little interferon, an anti-viral chemical that also boosts the immune response, at the infection site, even though it was found in the draining lymph nodes.

Also in the lymph nodes they noticed a sharp increase in certain chemokines, chemicals that stimulate immune cells to move in and cause inflammation. The presence of chemokines appeared to encourage the entry and retention of certain infection-fighting cells in the lymph nodes draining the site of infection, an ineffective place for the infection-fighting cells to be during the start of a viral attack.

The researchers also noticed a delay in killer cells, dendritic cells (the cells that capture and present foreign proteins to other immune cells), and T cells arriving at the site of infection, where they were supposed to go earlier to fulfill their virus-fighting roles. The researchers suggested that a possible reason for this tardiness is an alteration in the chemical cues necessary for these cells to migrate to the site of infection.

The authors described the finding of an immune-response promoting role for regulatory T cells during the early stages of a local infection as unexpected, considering the cells' suppressor roles during later stages of an immune response.

A simplified method of giving rabies vaccine

Tue, 22 Apr 2008 03:59:37 PST

( from http://www.rxpgnews.com ) A simplified economical method of giving rabies vaccine is just as effective as the expensive standard vaccine regimen at stimulating anti-rabies antibodies.

A clinical trial in healthy volunteers has found that a simpler and cheaper way of using rabies vaccines proved to be just as effective as the current most widely used method at stimulating antibodies against rabies. The trial is published in this week's PLoS Neglected Tropical Diseases.

Dr Mary Warrell (Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, United Kingdom) and colleagues, who conducted the trial with a vaccine in routine use, say that the simplified method has the advantages of requiring fewer clinic visits, being more practicable, and acceptable, and having a wider margin of safety, especially in inexperienced hands. It would therefore, they say, be suitable for use anywhere in the world where there are financial constraints, and especially where two or more patients are likely to be treated on the same day.

All human deaths from rabies result from failure to give adequate prophylaxis. After a rabid animal bite, immediate wound cleaning, rabies vaccine and injections of anti-rabies antibody (immunoglobulin) effectively prevent fatal infection. But anti-rabies immunoglobulin is very rarely available in developing countries, and so prevention relies on giving people bitten by rabid animals effective vaccine treatment.

The vaccines that are currently approved by the World Health Organization, which are usually injected into the muscle, are prohibitively expensive, and so are unaffordable in developing countries. In Africa, for example, the average cost of an intramuscular course of vaccine is $US 39.6, equivalent to 50 days' wages.

Two economical regimens, involving injecting small amounts of vaccine into the skin (intradermally) at 2 or 8 sites on the first day of the course, with subsequent booster doses are available in a few places. With the 8-site method, a large dose of vaccine is given on the first day only, whereas with the 2-site method the same dose is divided between the first and third days, entailing an extra visit to the clinic. However, practical or perceived difficulties have restricted widespread uptake of these economical methods. Dr Warrell and colleagues therefore set out to test a new, similar simplified regimen, involving injections at 4 sites on the first day.

They vaccinated healthy volunteers to compare the antibody levels induced by the 4-site intradermal regimen with those induced by the current 2-site and 8-site intradermal regimens and the gold standard intramuscular regimen favored internationally. All of the economical intradermal regimens worked just as well as the intramuscular method at stimulating anti-rabies antibodies.

The authors conclude that the results provide sufficient evidence that the simplified 4-site regimen now meets all the criteria necessary for its recommendation for use wherever the cost of vaccine is prohibitive.

New vaccine may give long-term defense against deadly bird flu and its variant forms

Thu, 17 Apr 2008 03:59:37 PST

( from http://www.rxpgnews.com ) WEST LAFAYETTE, Ind. - A new vaccine under development may provide protection against highly pathogenic bird flu and its evolving forms, according to researchers at Purdue University and the Centers for Disease Control and Prevention who discovered the new preventative drug and have tested it in mice.

Unlike traditional influenza vaccines, the new vaccine could be produced quickly and stored for long periods in preparation for a pandemic of dangerous disease-causing avian influenza - H5N1 - and its variants, said Suresh Mittal, a Purdue virologist. In an earlier study with mice, he and his colleagues found that the vaccine protected against H5N1 for a year or longer. Because the studies have only been done in mice, it's not yet known whether the same results will be obtained in humans.

We want to have a vaccine that can be stored in advance and have the potential to provide protection for a period of time until we can change the vaccine to match the latest form of avian influenza, Mittal said. The combination of flu genes that we've used to produce the vaccine, I think, will provide that capability.

The importance of having a long-lasting, broadly protective vaccine is that it would give some cross-protection against new viruses with pandemic potential caused by mutations in currently circulating H5N1 viruses. This would give scientists time to develop a better vaccine that would match the latest form of the bird flu.

Mittal and his colleagues, including Suryaprakash Sambhara, the CDC principal investigator on the project, report their findings on the vaccine in the April 15 issue of The Journal of Infectious Diseases. In the December issue of Clinical Pharmacology and Therapeutics, Mittal, Sambhara and their collaborators published their findings of the long-lasting capabilities of the vaccine.

In humans we want a vaccine to be fully effective for at least a year, said Mittal, a professor of comparative pathobiology. How long it will last in humans, we don't know yet.

To produce the new vaccine, the scientists used a mutated common cold virus, known as an adenovirus, as a delivery system for important genes from two types of the H5N1 avian influenza. The adenovirus is incapable of multiplying and so cannot cause illness to people. By using the adenovirus vector technology, a couple of problems with existing vaccines used to fight annual flu outbreaks are solved.

Problems with current influenza vaccines include that they are made from eggs, a process that can take as long as six months. The vaccine Mittal and his research team has developed isn't grown in eggs, making vaccine production much faster.

Additionally it would be difficult under normal conditions to produce the hundreds of millions of doses needed to protect everyone at risk for highly pathogenic forms of bird flu. With the beginning of a pandemic, since H5N1 decimates poultry populations, the egg supply needed to produce vaccines would be drastically cut.

The new vaccine uses an adjuvant, molecules added to the vaccine that stimulate the body's immune system, so that lower doses of the vaccine can be used. The adjuvant also allows the vaccine to be stockpiled so more people can be vaccinated, and it helps the vaccine protect against variant forms of the H5N1. The only FDA-approved H5N1 vaccine protects against only that specific strain of flu and only works in about 60 percent of those immunized with a high dose.

Adenoviral vector-based pandemic vaccines are an attractive option for developing countries where egg-independent cell-based vaccine technologies for other vaccines already are available, Sambhara said. Since this process is already in place, our vaccine could be produced locally at an affordable price.

Since H5N1 has been known, it has changed so that there are now two main subgroups, called clades. Within one of the clades, five subclades have emerged. This has complicated the task of developing a perfect match vaccine for the highly pathogenic bird flu. Other avian influenza viruses exist, but they have not proved to be as lethal to humans or other animals as has H5N1.

Influenza viruses are classified according to the combination of two types of proteins found on the virus cell surface. Different combinations of the 16 types of hemagglutinin (H) protein and nine types of neuraminidase (N) protein form a large number of influenza viruses for which birds are the natural hosts.

New, often more dangerous flu strains develop when the H and N combinations change and combine with other genes from circulating influenza viruses. When the genes of a human or swine influenza mix with an avian variety, a highly pathogenic human flu likely will result, Mittal said.

The first bird-to-human H5N1 case was recorded in 1997 in Hong Kong. The deadly virus has been documented in more than 60 countries, according to the World Health Organization (WHO). Though it mainly has struck wild birds and poultry, there have been more than 300 human cases in 14 countries in the past decade with a 60 percent fatality rate. Most of the human cases have occurred in people who live and work closely with their poultry, but a few cases have been documented of the disease spreading from person to person.

In a typical case, WHO this week reported the most recent fatality - the death of a 30-year-old Egyptian woman who became ill on April 2 after handling sick birds. She did not respond to the antiviral treatment Tamiflu, which can be given after contact with a flu carrier.

The next step in the bird flu vaccine project will be to test the vaccine on new viruses that are appearing, Mittal said.

The scientific team's vaccine work is being developed by PaxVax Inc., which has licensed the technology. Mittal is a scientific adviser for the company but has no financial stake in the commercial development of the vaccine, nor do his colleagues.

Blood pressure enzyme can have tumor-sensing role

Mon, 07 Apr 2008 03:59:37 PST

( from http://www.rxpgnews.com ) By increasing production of a blood pressure-regulating enzyme in mice, researchers have found they can enhance the mouse immune system's ability to sense tumor growth.

When scientists at Emory University School of Medicine engineered mice that make more angiotensin-converting enzyme in white blood cells called macrophages, the mice could more effectively limit the growth of injected tumors.

The enzyme works by trimming small bits of protein that originate from the tumors, allowing the immune system to identify the tumors and mount a response more efficiently.

The results are published online in the Journal of Biological Chemistry (JBC).

Senior author Kenneth Bernstein, MD, Emory distinguished service professor of pathology and laboratory medicine, says his group's findings suggest a strategy for amplifying immune system function in humans.

We think we've discovered a means of tweaking the immune response by modifying the process of antigen presentation, Dr. Bernstein says.

In the clinic, doctors might be able to enhance a cancer patient's ability to resist a tumor by removing his or her white blood cells, boosting their production of angiotensin-converting enzyme, and re-infusing them, he says.

Antigen presentation refers to how proteins from within the body are constantly recycled and chewed up into small bits called peptides, which appear on the surfaces of cells. While the immune system generally ignores peptides from proteins in the body, it can respond to the peptides from foreign invaders.

Angiotensin-converting enzyme, or ACE, plays a critical role in controlling blood pressure and is the target of common medications. The hormone angiotensin (a peptide) constricts blood vessels, increases the brain's perception of thirst and indirectly causes the kidneys to retain sodium, thus limiting its production can reduce blood pressure.

ACE acts chemically by removing amino acids, the building blocks of proteins, from one end of a larger protein. In the body, ACE converts an inactive form of angiotensin into an active form by clipping off two amino acids.

But angiotensin is not ACE's only target. In previous studies, Bernstein and his co-workers found that manipulating its activity also affects processes such as fertility and the generation of red blood cells in the bone marrow.

To dissect out ACE's role in the immune system, they created mice with a genetic alteration in the ACE gene, forcing the gene to be turned on only in macrophages.

Macrophages are especially good at displaying peptides on their surfaces to other white blood cells called T cells so that the T cells are stimulated to grow. The T cells in turn kill virally infected cells. Depending on the situation, they can sometimes kill tumor cells as well.

When injected with several types of melanoma or lymphoma, the altered mice developed smaller tumors than normal mice. The tumors they did have contained more white blood cells attacking the cancerous cells.

In the JBC paper, the researchers show that ACE boosts cells' ability to display some foreign peptides, increasing their ability to stimulate T cells by several-fold.

Bernstein cautions that normally, macrophages make little ACE, so its effects must be seen as artificial. He notes that ACE inhibitors such as enalapril and lisinopril are taken by millions of people with high blood pressure and have not been reported to weaken the immune system.

However, cells similar to macrophages have been shown to produce ACE in response to pathogens such as sarcoid or leprosy, he says.

Researchers uncover new genetic links to psoriasis

Thu, 03 Apr 2008 03:59:37 PST

( from http://www.rxpgnews.com ) In the first comprehensive study of the genetic basis of psoriasis, researchers at Washington University School of Medicine in St. Louis have discovered seven new sites of common DNA variation that increase the risk of the troublesome skin condition. They also found that variations in one genetic region link psoriasis and a related joint disorder, psoriatic arthritis, to four autoimmune diseases: type 1 diabetes, Grave's disease, celiac disease and rheumatoid arthritis.

The study's results appear April 4 in the open-access journal PLoS Genetics.

Common diseases like psoriasis are incredibly complex at the genetic level, says lead investigator Anne Bowcock, Ph.D., professor of genetics at the School of Medicine. Our research shows that small but common DNA differences are important in the development of psoriasis. Although each variation makes only a small contribution to the disease, patients usually have a number of different genetic variations that increases their risk of psoriasis and psoriatic arthritis.

The DNA variations uncovered by the researchers point to different biological pathways that underlie psoriasis and may eventually lead to new targeted drugs and treatments that hit specific pathways, Bowcock says.

An estimated 7 million Americans have psoriasis, an autoimmune disease that occurs when the body's immune cells mistakenly attack the skin. The condition is characterized by red, scaly patches that can be itchy, painful or both. Some 10 to 30 percent of patients with psoriasis develop psoriatic arthritis, a condition that is often excruciatingly painful and debilitating.

The Washington University researchers focused on points of common variation in the genome called single nucleotide polymorphisms, or SNPs. While most of the 3 billion nucleotides that comprise DNA are thought to be identical from one person to the next, some 10 million SNPs build variation into the genome and make each individual unique. Some of these SNPs play a crucial role in a person's predisposition to disease or good health.

Using an approach known as whole genome association, the investigators scanned more than 300,000 SNPs in the genomes of 223 psoriasis patients, including 91 who had psoriatic arthritis. They compared the DNA variations in people with psoriasis to those found in 519 healthy control patients, looking for specific differences that may be linked to the disease. They then replicated their findings in a larger set of patients -- 577 with psoriasis and 576 with psoriatic arthritis -- and more than 1,200 healthy controls.

Bowcock and her team found seven novel DNA variations linked to psoriasis. Four other variations associated with the disease that had been identified previously by other researchers also were confirmed by the current study.

Whole genome association studies have recently been used to identify common genetic variations that increase the risk of diseases such as breast cancer, heart disease and type 2 diabetes. They typically involve more than 1,000 patients with a particular disease to help ensure that the genetic variations identified in the study do not occur by chance. While the current study included fewer patients, nearly half of them had a sibling and, in some cases, a parent with psoriasis, which increases the odds of finding genetic variations that contribute to the disease.

The researchers found the strongest genetic risk for psoriasis lies in a region of the genome that contains the major histocompatibility complex, a collection of genes involved in distinguishing the body's own cells from foreign invaders. Although this region has been known to play a major role in psoriasis, DNA variations in the MHC alone have been known to not be enough to trigger disease, Bowcock says. Only 10 percent of patients with variations in the major histocompatibility complex developed psoriasis. This tells us that other genetic or environmental factors also contribute to the disease.

One MHC variation linked to psoriasis and psoriatic arthritis occurs in the gene HCP5, the scientists noted. That variation was recently reported to delay the onset of AIDS in people infected with HIV. This is particularly interesting, Bowcock says, because psoriasis can be triggered by infection with HIV or other viruses. It may be that in people with this SNP variant, viral infection triggers a larger immune response that slows the development of AIDS but also leads to excessive inflammation in the skin and bone joints in genetically susceptible individuals, leading to the onset of psoriasis and psoriatic arthritis.

Notably, DNA variations on chromosome 4 were strongly linked to psoriatic arthritis. These same variations were also associated with psoriasis and had been previously linked to type 1 diabetes, rheumatoid arthritis, Grave's disease (caused by an overproductive thyroid gland) and celiac disease (caused by the inability to digest gluten). Doctors have noticed that some psoriasis patients have autoimmune diseases such as celiac disease, Grave's disease, and type 1 diabetes, Bowcock says. But we didn't know whether this was a coincidence. Now we know there is a genetic component underlying all of these diseases.

The same region of chromosome 4 contains genes that code for the signaling molecules IL2 and IL21. This opens the door to investigating whether existing drugs that block either molecule may be effective in some psoriasis patients, especially those with psoriatic arthritis.

The researchers also uncovered significant DNA variations on chromosome 13 in a genetic region involved in modifying proteins, and on chromosome 15, in a region responsible for producing a protein that activates TNF alpha (tumor necrosis factor-alpha) in a specialized immune cell known as a dendritic cell. While TNF alpha normally helps fight infections, it is thought to be a major player in psoriasis and psoriatic arthritis. Several FDA-approved psoriasis medications work by binding to TNF-alpha, thereby preventing it from communicating with cells.

Bowcock is now involved in a larger genome-wide association study of psoriasis patients and says she expects it will uncover additional genetic variations that are associated with psoriasis.

Eventually, she predicts, such studies will lead to more effective, better-targeted therapies.

The goal of this study and other genome-association studies is to get to personalized medicine, where you can diagnose a disease and ask what genetic risk factors this person has that points to altered pathways, she says. Then, we can target those pathways for specific therapeutic interventions.

Findings reveal how dengue virus matures, becomes infectious

Thu, 27 Mar 2008 03:59:37 PST

( from http://www.rxpgnews.com ) WEST LAFAYETTE, Ind. - Biologists at Purdue University have determined why dengue virus particles undergo structural changes as they mature in host cells and how the changes are critical for enabling the virus to infect new host cells.

The findings pertain to all viruses in the family of flaviviruses, which includes a number of dangerous insect-borne diseases such as dengue, West Nile, yellow fever and St. Louis encephalitis. Dengue is prevalent in Southeast Asia, Central America and South America. The virus, which is spread by mosquitoes, infects more than 50 million people annually, killing about 24,000 each year, primarily in tropical regions.

The researchers detailed critical changes that take place as the virus is assembled and moves from the inner to the outer portions of its host cell before being secreted so that it can infect other cells. Virus particles are exposed to progressively less acidic conditions as they traverse this secretory pathway, and this changing acidity plays a vital role in the maturation of the virus.

This is possibly the most detailed understanding of how any virus matures, said Michael Rossmann, the Hanley Distinguished Professor of Biological Sciences.

The research is a collaboration of work in two laboratories at Purdue, one operated by Rossmann and other operated by Jue Chen, an associate professor of biological sciences. They led the research with I-Mei Yu, a postdoctoral research associate working with Chen; and Long Li, a doctoral student working with Rossmann.

Findings are detailed in two back-to-back research papers appearing Friday (March 28) in the journal Science. The papers' co-authors include Yu, Li, Rossmann, Chen and Richard J. Kuhn, a professor and head of Purdue's Department of Biological Sciences.

Whereas the pathway for viruses entering new host cells has been studied extensively, the route for viruses moving out of their original host cells is not well-understood, Rossmann said.

These two papers concern that route and compare the differences between both pathways, he said.

The virus moves through compartments inside the cell called the endoplasmic reticulum and the trans-Golgi network. While immature, virus particles are incapable of fusing with cell membranes, preventing them from infecting their own host cells and ensuring their maturation. Once mature, however, the virus is able to fuse to cell membranes, a trait that enables virus particles to infect new host cells, Chen said.

There are many membranes in this trans-Golgi network, so the immature virus is always surrounded by membranes, Chen said. In fact, the environment of the secretory pathway is very similar to what the virus encounters while it enters and infects a new host cell. So the question is, why doesn't the virus fuse to membranes on the way out

The researchers have examined the crucial role played by the changing acidity as the immature virus travels through the compartments.

This change in acidity was already known, but its impact on the maturation process was not known until these new findings, Rossmann said.

As a virus particle matures along the pathway through the host cell, it changes the protein structure, or conformation, in its outer shell.

Yu mimicked the trans-Golgi network environment in test tubes, enabling the researchers to study the virus's changing structure with increasing acidity.

The surface of each virus particle contains 180 copies of a component made of two linked proteins called precursor membrane protein and envelope protein.

The precursor membrane protein prevents the immature virus from fusing with membranes by covering an attachment site in the envelope protein. During maturation, an enzyme called furin snips the connection between the two proteins, eventually exposing the envelope protein site and enabling the virus to fuse with membranes.

Yu learned, however, that the precursor membrane protein remains in place until the virus is ready to exit the original host cell. The researchers used a technique called cryoelectron microscopy to gain a more detailed view of the virus.

So, the precursor membrane protein is retained on the virus surface even after the enzyme detaches the two proteins, Chen said. This is a critical step because the virus is ready to mature but still is incapable of fusing with membranes until after it exits its own cell.

The researchers also determined that the environment must be acidic before the enzyme will snip the two proteins, and they examined the structure to learn specifically why the increased acidity is needed.

Li used fruit fly cells to produce large quantities of the linked proteins so that researchers could study them with a method called X-ray crystallography. Using crystallography, the researchers were able to visualize and study the combined structure of the precursor membrane and envelope proteins.

Having a better understanding of this structure will enable us to learn why the immature form does not fuse with membranes, Rossmann said. Ultimately, researchers might want to find ways to treat or prevent viral infections, but in order to do that we first have to learn how viruses work, how they mature and initiate infection.

To produce the complex of the two proteins, Li first had to replace the insoluble transmembrane region of the protein with a soluble segment, a step essential for using the fruit fly cells to manufacture the proteins. He also had to mutate the protein to remove sites where furin normally attaches, preventing the proteins from being snipped apart.

The precursor membrane protein is about as wide as 50 nanometers, or billionths of a meter, and the envelope protein is about 3 nanometers, or nearly atomic-scale. A nanometer is about the size of 10 hydrogen atoms strung together.

The research has been funded primarily by the National Institutes of Health. Rossmann's and Chen's research laboratories are affiliated with Purdue's Markey Center for Structural Biology.

One of the papers was authored by Li, postdoctoral research associate Shee-Mei Lok, Yu, graduate student Ying Zhang, Kuhn, Chen and Rossmann. The other paper was authored by Yu, research scientist Wei Zhang, technician Heather A. Holdaway, Li, postdoctoral research associate Victor A. Kostyuchenko, electron microscopist Paul R. Chipman, Kuhn, Rossmann and Chen.

Future research may focus on determining the virus's changing structure in greater detail.

UT-ORNL and UCSD researchers find promise in HIV 'switch'

Sun, 16 Mar 2008 03:59:37 PST

( from http://www.rxpgnews.com ) KNOXVILLE -- If the battle against HIV, the virus that causes AIDS, is a chess match, then new research published today gives new insight into one of the virus' most important moves.

The findings, by University of Tennessee, Knoxville, and Oak Ridge National Laboratory researchers Michael Simpson and Roy Dar, with colleague Leor Weinberger who led the research at the University of California, San Diego, reveal new information about how a critical genetic switch in the virus operates. They are published as a letter in the upcoming issue of Nature Genetics.

When HIV infects an immune cell, it can enter one of two states: activation, where the virus replicates and then destroys the host cell; and latency, where the viral genetic material continues to exist in the cell, but there is no production of additional virus.

While latency is a ticking time bomb, said Simpson, a possible therapeutic goal could be to stably maintain latency indefinitely.

Previous work by Weinberger found that the genetic circuit that controls whether HIV chooses to go active or latent is not a simple on-off switch, but instead is controlled by a type of genetic pulse -- when the pulse lasts a certain amount of time, the switch will activate replication of the virus.

Now the three researchers have demonstrated that it is possible to manipulate the lengths of the pulses in a way that would favor the selection of latency.

This is vital, said Simpson, because the switch is a definitive factor in whether the virus will become active. If the pulse does not last long enough, he said, the virus cannot become active.

This is an early step, but an encouraging one, said Simpson. HIV has evolved a very effective infection strategy, so the name of the game is understanding how that strategy operates in order to find a way to defeat it.

A challenge of the work, according to Simpson, is that the process involved in how the switch operates cannot be directly observed. Instead, the researchers had to rely on an analysis of the noise created within the cell by the process to determine how it worked.

Simpson and Dar conducted their work in the Center for Nanophase Materials Science at ORNL, a recently opened facility that Simpson says has made this type of analysis possible.

Moving forward, the next step in the research is to determine whether it is viable to attempt to control the switch as part of therapeutic treatment for HIV. The researchers also hope to apply the techniques they used to understanding the operation of other types of human cells.

How do infections and toxins launch a cell's self-destruct and alarm system?

Mon, 10 Mar 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Cells are coded with several programs for self-destruction. Many cells die peacefully. Others cause a ruckus on their way out.

Some programmed cell death pathways simply and quietly remove unwanted cells, noted a team of University of Washington (UW) researchers who study the mechanisms of cell destruction.

Then there is the alarm-ringing death of a potentially dangerous cell, such as a cell infected with Salmonella, they added. These dying cells spill chemical signals and get a protective response. The resulting inflammation, which the body launches in self-defense, can at times backfire and damage vital tissues.

A research team lead by Dr. Brad T. Cookson, an associate professor of microbiology and laboratory medicine, named this type of cell death pyroptosis, Greek for going down in flames. Cell death that doesn't cause inflammation is called apoptosis: to drop gently like leaves from a tree.

An enzyme inside cells, called caspase-1, plays a critical role in both harmful inflammation and in resistance to infection, Cookson and his colleagues noted. It's not just responsible for cell death, but also for the production of inflammatory proteins that are released from the dying cell. Mice deficient in caspase-1 are susceptible to infection, yet resistant to toxic shock, tissue injury from lack of oxygen, and inflammatory bowel disease.

The Cookson lab has done many studies of caspase-1 and how it mediates the pathway of pro-inflammatory programmed cell death. The lab's most recent study will be published the week of March 10 to March 14 in the online Early Edition of the Proceedings of the National Academy of Sciences. The study looked at how two different noxious stimuli, anthrax toxin and Salmonella infection, trigger the caspase-1-mediated cell death pathway. UW graduate students Susan Fink and Tessa Bergsbaken conducted this study.

The researchers found that each of these stimuli took an independent route to activate caspase-1; however, these two distinct mechanisms of activation eventually converged on a common pathway of cell death. This common pathway featured cleavage of the cell's DNA, activation of inflammatory chemical messengers, and the final jettison of the cells contents. The spillage occurs after nano-scale pores form in the cell membrane, much like punctures in a water balloon.

According to Cookson, these findings are helping to create research models for studying a broadly important pathway of pro-inflammatory programmed cell death. The findings also support the notion that diverse disease agents can use different mechanisms to elicit this pathway.

Examining this system provides insight into mechanisms of both beneficial and pathological cell death, and the strategies that infectious disease agents employ to manipulate the body's responses, Cookson said. His group's previous studies of Yersinia, the plague pathogen, revealed that cell death mechanisms can be re-directed from a passive, non-inflammatory pathway, to a more beneficial inflammatory pathway. This finding suggests the possibility of treating diseases by modulating cell death pathways.

In addition to its protective role in fighting infection, Cookson added, caspase-1 also plays a role in many medical conditions characterized by cell death and inflammation. These conditions include organ damage in the heart, brain, lungs, nerves, and kidneys. Understanding pro-inflammatory cell death pathways may lead to new therapies against fatal or disabling diseases, such as serious infections, heart attack, cancer and stroke.

Cookson is part of the National Institutes of Health-funded Microscale Life Sciences Center, a collaboration among scientists and engineers from the UW, the University of Arizona, the Fred Hutchinson Cancer Research Center, and Brandeis University. The scientists work to discover basic mechanisms in the formation, growth, and decline of human cells. Their aim is to develop biotechnology to combat widespread diseases and environmental threats to human health.

Allergic response tied to lipid molecules in cell membrane

Fri, 07 Mar 2008 04:59:37 PST

( from http://www.rxpgnews.com ) A team of Penn State University researchers is the first to demonstrate that lipid molecules in cell membranes participate in mammals' reactions to allergens in a living cell. The finding will help scientists better understand how allergy symptoms are triggered, and could contribute to the creation of improved drugs to treat them. The work will be reported in the 14 March issue of the Journal of Biological Chemistry.

The team studied clusters of cholesterol-rich lipid molecules that they believe serve as platforms for the receptors that receive antibodies, the proteins that protect the body from allergens. In this case, the team examined IgE antibodies, which upon binding to their receptors initiate a cell's release of histamine--the substance that causes the unpleasant, but beneficial, mucous production, congestion, and itchiness associated with allergies. This research is basically the molecular foundation for why many people sneeze in the spring, said Ahmed Heikal, an associate professor in the Department of Bioengineering and a leader of the project.

While the idea that lipid clusters--also known as lipid domains--are involved in the allergic response is not new, the Penn State team is the first to document this connection in a living cell under physiological conditions. No one has observed the domains in action because they are too small and too transient--held together by very weak molecular interactions--to be viewed with a light microscope, said Erin Sheets, a Penn State assistant professor of chemistry who also is a leader of the project. To overcome this challenge, added Heikal, we used a combination of imaging and spectroscopy techniques that we are developing in our laboratories.

In their experiment, the researchers first labeled the cell membrane and IgE antibodies with two different fluorescent tags. Next, they introduced an allergen and watched as it bound to receptors on the cell membrane, thus initiating an allergic response.

But to demonstrate that this activity was taking place within the lipid domain, the researchers had to take advantage of a property of fluorescence, called fluorescence lifetime, in which molecules are excited with very short laser pulses. The length of time a molecule remains in its excited state before emitting a photon--the fluorescence lifetime--provides unique information about the fluorescently-labeled molecule's environment and its chemical structure. For example, a particular molecule might relax to its lowest-energy state quickly or slowly depending on whether it is exposed to a solvent.

We previously showed that our fluorescently-labeled membrane probe has a longer lifetime within a cholesterol-rich lipid domain, said Sheets. Here we show that changes in this lifetime follow the changes that occur during the first steps in the allergic response process. Our results also show that lipid domains in the cell membrane associate with IgE antibodies and their receptors in the initial stages of an allergic reaction.

In the future, Sheets and Heikal plan to apply the team's discoveries to a project involving aging. During the aging process, T cells, which protect the body from foreign substances like viruses and cancer cells, can lose their ability to signal effectively. Sheets and Heikal plan to use these fluorescence-lifetime imaging tools to examine the structure and integrity of T-cell membranes with a goal of determining why they lose their knack for signalling and how this problem can be corrected.

We want to compare the effectiveness of signaling in young T cells, which clear out debris quickly, to old T cells, which are not as efficient, said Sheets. I think it will be a pretty cool application of our technique.

Scientists successfully treat new mouse model of inflammatory bowel disease

Thu, 06 Mar 2008 04:59:37 PST

( from http://www.rxpgnews.com ) March 6, 2008 -- Researchers trying to improve cancer immune therapy have made an unexpected find: They've produced the most accurate mouse model to date of inflammatory bowel disease (IBD), a cluster of conditions that afflict approximately 1.4 million Americans with abdominal pain, constipation and diarrhea.

The two most common forms of IBD are Crohn's disease and ulcerative colitis (UC); in extreme cases, they can be fatal. The mouse model closely resembles the most serious form of human UC and is uniformly fatal. But scientists successfully treated the mice with a pair of broad-spectrum antibiotics, easing gut inflammation and increasing survival. The results, reported this week in Public Library of Science-Medicine, have researchers eager to follow up both in the clinic and the lab.

The antibiotics we gave the mice were used individually in unsuccessful clinical trials as ulcerative colitis treatments, but now we have colleagues who are thinking of giving combined therapy an informal try, says co-senior author Thaddeus S. Stappenbeck, M.D., Ph.D., assistant professor of pathology and immunology and of developmental biology. The antibiotics probably won't be a cure by themselves, but they may provide us with a potent new approach to combine with other therapies.

The mice may also allow scientists to learn which species of gut microorganisms are becoming embroiled in battles with host immune systems, triggering the symptoms of UC. That information could allow the development of stronger and more specific treatments.

Silvia Kang, a former graduate student in the laboratory of co-senior author Paul Allen, Ph.D., the Robert L. Kroc Professor of Pathology and Immunology, created the mouse model by crossbreeding two mouse lines they had developed for cancer immune therapy research. Each mouse line had one protein knocked out that restrained immune T cells from shifting into attack mode.

The idea was to see if we could create super killer T cells we could use to attack tumors, says Allen. But all the mice became sick early on, started to lose weight and we soon realized that they all had serious gastrointestinal issues.

Allen decided to consult with Stappenbeck, an expert in IBD.

I've looked at quite a few proposed mouse models of IBD, and I recognized right away that this had the potential to be outstanding, says Stappenbeck. The colons of the mice were incredible. They were filled with inflammatory T cells. We found the mice almost exactly replicated the most acute types of ulcerative colitis.

Unlike prior models of IBD, the mice consistently develop gastrointestinal problems within a short time period and at a predictable point in their lifespan. When researchers treated the mice at three weeks with the antibiotics ciprofloxacin and metronidazole, colon inflammation was reduced and the mice were able to gain weight and survive longer.

Scientists believe IBD results from the host immune system damaging the tissues of the gut while erroneously attacking food and gut microorganisms that aid food digestion. There are an estimated 500 different species of microbes living in the gut, so sorting out which species are being attacked by the immune system has been an imposing challenge.

The new model may significantly ease that challenge. Although the dual antibiotics used to treat the mice are broad-spectrum, they didn't sterilize the guts of the mice, suggesting that the treatment happened to eliminate the microorganisms causing IBD.

We'd like to treat the mice and then reintroduce candidate microorganisms into their guts to see if this restarts the inflammatory reaction, says Stappenbeck.

Stappenbeck and Allen plan continued collaborative study of the model.

Immune deficiency and balance disorder result from single gene defect

Thu, 21 Feb 2008 04:59:37 PST

( from http://www.rxpgnews.com ) A genetic defect that causes a severe immune deficiency in humans may also produce balance disorders, according to a new study by researchers at the University of Iowa, The Jackson Laboratory and East Carolina University.

The study, published online Feb. 21 in the Journal of Clinical Investigation, examined a specialized strain of Jackson Laboratory mice with a mutation that eliminates the production a protein called p22phox. Disruption of this protein causes a form of chronic granulomatous disease (CGD) -- a severe immune deficiency -- in humans.

The researchers found that mice without p22phox develop an immune deficiency that mimics human CGD. They also discovered that the gene defect produces a severe balance disorder in the mice caused by loss of gravity-sensing crystals in the inner ear.

The implication is that human patients with CGD caused by defects in this gene may also have balance disorders, said Botond Banfi, M.D., Ph.D., UI assistant professor of anatomy and cell biology and senior author of the study. If that is the case, this would be the first patient population where we could study the consequences of losing the sensation of gravity.

We hope that clinicians will test the balance capacity of those patients with this rare form of CGD Banfi added. Although it is hard to say what the consequences might be of not sensing gravity, these patients may be more prone to accidents like falling.

In addition to Banfi, the research team included Yoko Nakano, Ph.D., a UI postdoctoral fellow in Banfi's laboratory and lead author of the study; David Bergstrom, Ph.D., research scientist, and Chantal Longo-Guess, research assistant, both at The Jackson Laboratory; Sherri Jones, Ph.D., associate professor of communication sciences and disorders at East Carolina University; and William Nauseef, M.D., UI professor of internal medicine.

P22phox is emerging as a critical subunit of a family of enzymes that produce reactive oxygen species (ROS). For many years, ROS were simply thought of as destructive molecules that can kill infecting bacteria but also damage human cells. More recently, however, ROS have been shown to play an important role in many normal cell processes, including development and blood pressure regulation. The family of enzymes that produce ROS are called NADPH oxidases (Nox), and disruption of these enzymes has been implicated in a range of diseases, including cardiovascular and neurodegenerative diseases as well as immune deficiencies like CGD.

There are several forms of CGD caused by different genetic defects affecting the Nox complex of pathogen-fighting cells called phagocytes. CGD caused by lack of p22phox is one of the least common forms of the disease in humans. The mutant mouse, which was produced by The Jackson Laboratory's Neuromutagenesis Facility, represents the first animal model for this version of CGD and will be helpful in understanding the disease and developing potential treatments.

The study found that the mice without the p22phox protein were unable to produce ROS in phagocytes and were particularly susceptible to infection. For mice without the protein, infection with bacterial pneumonia was universally fatal. In contrast, normal mice had a 100 percent recovery rate from the same infection.

The mutant mice also had a severe balance disorder. Unlike normal mice that quickly learned how to walk on a rotating rod without falling off, the mutant mice always fell off within a few seconds. Additionally, the study showed that activity of nerve cells in the inner ear responsible for sending gravity signals to the brain was absent in the mutant mice.

Loss of p22phox affects two enzyme complexes: one in phagocytes that is responsible for the immune defect, and one in the inner ear, Banfi said. Since this is the first mouse model for defects in the p22phox subunit, this is the first time that its role in balance has been revealed.

Although inner ear cells looked normal in the mutant mice, the researchers discovered that otoconia -- tiny calcium carbonate crystals that are essential for sensing gravity -- do not form in the inner ears of these mice. Restoring the normal gene to the mutant mice rescued otoconial production and prevented the balance disorder. However, although the treatment did improve the mice's immune response, the partial restoration of gene expression was not sufficient to cure the immune deficiency completely.

This may mean that gene therapy, which would only partially restore expression of p22phox, would not completely cure CGD in humans, cautioned Banfi. We may have to look for alternatives and these mice will be ideal models to test new ideas for therapy.

The team was also able to track the location of the Nox complex during embryonic development of the inner ear by visualizing the location of p22phox. Interestingly, the complex does not reside in the same place that the otoconia form leading the researchers to propose a new mechanism by which the Nox complex controls production of the crystals.

Gene newly linked to inherited ALS may also play role in common dementia

Wed, 20 Feb 2008 04:59:37 PST

( from http://www.rxpgnews.com ) Scientists at Washington University School of Medicine in St. Louis have linked a mutation in a gene known as TDP-43 to an inherited form of amyotrophic lateral sclerosis (ALS), the neurodegenerative condition often called Lou Gehrig's disease.

Researchers found the connection intriguing because studies by other groups have revealed abnormalities in the TDP-43 protein in both sporadic and inherited ALS, as well as in several other neurodegenerative disorders.

The potential link to sporadic ALS is particularly interesting. If we can confirm TDP-43's association with inherited ALS, mutating this gene may give us a way to model sporadic ALS in laboratory animals for the first time, says senior author Nigel Cairns, Ph.D., research associate professor of neurology and pathology and immunology. That could give us a potent tool for better understanding ALS and developing new treatments.

The study appears February 20 in Annals of Neurology. It was conducted at the Hope Center for Neurological Disorders, a partnership between the University and Hope Happens, a St. Louis-based non-profit organization dedicated to raising funds for neurological research.

Approximately 30,000 U.S. citizens have ALS, a condition that kills motor neurons, the nerve cells that control muscles. This causes gradually increasing paralysis and typically leads to death over a course of several years. Approximately five to 10 percent of all ALS cases are inherited; the rest are sporadic.

Hope Happens was founded by Christopher Hobler, a St. Louisan who developed ALS and died from the disorder in 2005. Hobler's grandfather and cousin had previously died from the disorder, and Hobler and his family founded Hope Happens to promote awareness of ALS and other neurodegenerative conditions and to raise money for research to develop new treatments and cures.

In 1993, scientists linked an inherited form of ALS to mutations in the gene for a protein called superoxide dismutase-1 (SOD1). Since then, many had thought altering the SOD1 gene's function was the most promising way to model and understand sporadic ALS.

That has all been turned upside down in the last two years, though, says Cairns. In that time, abnormal TDP-43 deposits have been identified in sporadic ALS cases and in some inherited forms of ALS that don't involve a SOD1 mutation.

TDP-43 is an influential regulator of messenger RNA splicing, the process that edits protein-building instructions from DNA to allow the proteins to be built properly. TDP-43 abnormalities in ALS patients have included altered folding and a chemical change known as phosphorylation, both of which can radically alter the protein's function.

As a result, several research groups have been looking for a case where a mutation in the TDP-43 gene was linked to inherited disease. The new study is the first to tentatively establish such a link. Michael Gitcho, Ph.D., a postdoctoral research associate in Dr. Cairns' lab, and colleagues found that every member of a family affected by an inherited form of ALS had a particular mutation in TDP-43. Next, they looked at 1,505 people not related to the family and unaffected by ALS. This second search found no examples of the same mutation.

Because the family they studied is small, scientists need further evidence to confirm that the mutation is causing ALS. Researchers are working to introduce the mutated human TDP-43 gene they identified in the family into a transgenic mouse model. They hope the mouse will generate a model for ALS-like pathology.

If this affirms the link, they will begin tracing the effects of the mutation on genes whose splicing is regulated by TDP-43, working to identify key links in the chain reaction that leads to motor neuron death. These links may become new targets for pharmaceutical treatments.

What they learn may also shed light on other neurodegenerative disorders. Co-author Alison M. Goate, D. Phil., the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry, notes that abnormal TDP-43 has been found in patients with frontotemporal dementia, the second most common cause of early-onset dementia after Alzheimer's disease.

As our understanding of these diseases progresses, we're starting to see common elements, says Goate. This protein may allow us to link together a number of important disease entities and pinpoint new targets for therapeutic intervention.

Vaccine/antibody therapy effective, milder side effects in melanoma and ovarian cancer

Mon, 18 Feb 2008 04:59:37 PST

( from http://www.rxpgnews.com ) BOSTON--One of the shortcomings of a therapy that uses millions of identical antibodies to boost the immune system's attack on cancer cells is that many patients whose tumors recede in response to the treatment also experience serious inflammatory problems, such as severe diarrhea and rashes. In a new study, a team led by Dana-Farber Cancer Institute researchers shows that giving periodic infusions of such monoclonal antibodies to patients who have received a widely used cancer vaccine unleashes a strong immune response to tumors, with less-harsh side effects.

The study, to be published online by the Proceedings of the National Academy of Sciences on the week of Feb. 18, reflects efforts to untangle the benefits of monoclonal antibody therapy from its drawbacks, which result from a too-aggressive immune system assault on normal, healthy tissue. Besides demonstrating the potential usefulness of a vaccine-and-antibody approach, the new study suggests a way of refining treatment strategies even further, based on the biological events that antibody treatment sets in motion.

We now have a better understanding of how the treatment works -- by increasing the ratio of tumor-killing to immune system-suppressing cells, says the study's lead author, Stephen Hodi, MD, of Dana-Farber. This suggests techniques for further focusing the immune system to attack the cancer with less 'fallout' for normal tissue.

The study focused on a molecular socket, or receptor, on the surface of the immune system's CD4+ T cells, which guide an attack on infected or cancerous cells. The receptor, known as CTLA-4 (for cytotoxic T lymphocyte-associated antigen), functions as a kind of shut-off valve for CD4+ T cells: When the receptor is stimulated, it causes the T cells to become inactive, quieting the immune response. Blocking CTLA-4 with a monoclonal antibody -- a protein uniquely fit for the job -- offers a way to keep the immune response at full force.

Studies and clinical experience have shown that CTLA-4-targeting monoclonal antibodies do increase the immune system's tumor-destroying activities in some patients. But many of these patients also develop serious inflammatory conditions, raising the possibility that the therapeutic and harmful effects of the treatment are linked.

The current study involved a cancer vaccine made from patients' own tumor cells. The vaccine is created by removing tumor cells from the body, irradiating them so they stop growing, and inserting a gene that causes them to produce a protein called GVAX. When the cells are then re-infused into patients, GVAX acts like a siren to the immune system, prompting a more energetic attack on cancer cells throughout the body.

Unfortunately, these results are rarely lasting. Most patients treated with the vaccine eventually die as their disease resumes its progress.

For that reason, researchers have begun studying whether combining GVAX vaccines with monoclonal antibody therapy could lengthen remissions, since blocking CTLA-4 could bolster the immune response spurred by the vaccine. And there was reason to think the combination could tamp down the inflammatory problems associated with antibody therapy alone.

Using a vaccine to provoke a stronger immune response to cancer may enable us to use lower levels of CTLA-4 blockers, which could reduce the severity of their side effects, Hodi explains.

In an earlier study, he and his colleagues demonstrated that a single infusion of anti-CTLA-4 antibodies caused extensive tumor destruction in all five metastatic melanoma and ovarian cancer patients who had previously been immunized with a GVAX vaccine.

The new study, a joint effort of Dana-Farber's melanoma program and Cancer Vaccine Center, tested the combination in a larger number of participants. Eleven melanoma patients were infused with a CTLA-4-blocking antibody (Ipilumimab (R)) one to four months after receiving GVAX, and every two to three months thereafter, as needed.

In contrast to previous, more intensive antibody doses, none of the patients had severe side effects, although they all developed mild, low-level inflammatory conditions (usually a rash that went away in a few days). Moreover, in eight of the participants, tumors throughout the body either receded or became stable. The three other patients experienced less dramatic improvements that became apparent after several months of therapy.

Similarly encouraging results were obtained in nine patients with advanced ovarian cancer, although two of them did develop severe inflammatory problems. Although large die-offs of tumor tissue were less common than in the melanoma group, some of the ovarian cancer patients did experience such results.

To understand what was happening at a basic cellular level, researchers studied tumor samples from six patients following antibody treatment. They found that tumor death was greatest in samples with high ratios of CD8+ T cells -- the foot soldiers of immune system attack -- to FoxP3+ regulatory T cells, which can reduce the immune response.

Our results suggest that combination therapies of GVAX vaccine and CTLA-4-blocking antibodies could be enhanced by agents that target regulatory T cells such as FoxP3+, remarks Hodi, who is also an assistant professor of medicine at Harvard Medical School. Future work will focus in that direction.

Moving an active gene from the interior of the nucleus can silence genes , preventing their transcription . scientists report .

Thu, 14 Feb 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Moving an active gene from the interior of the nucleus to its periphery can inactivate that gene report scientists from the University of Chicago Medical Center .

Attachment to the inner nuclear membrane, they show, can silence genes, preventing their transcription--a novel form of gene regulation.

Several years ago, we and others described the correlation between nuclear positioning and gene activation, said study author Harinder Singh, Louis Block Professor of Molecular Genetics and Cell Biology and an Investigator in the Howard Hughes Medical Institute at the University of Chicago.

With that in mind, we wanted to take the next step, to design an experiment that could test causality. Could we move a gene from the center of the nucleus to the periphery, we asked, and then measure the consequences of such repositioning?

In mammalian nuclei, chromatin--a complex of DNA and associated proteins--is organized into structural domains through interactions with distinct nuclear compartments. In this study, the authors developed the molecular tools to take specific genes from these interior compartments, move them to the periphery and attach them to the nuclear membrane--which turned those genes off.

Not only were selected test genes that served as markers turned off after being attached to the inner nuclear membrane, but also nearby real genes the scientists quoted.

Transparent fish to make human biology clearer

Wed, 06 Feb 2008 04:59:37 PST

( from http://www.rxpgnews.com ) Zebrafish are genetically similar to humans and are good models for human biology and disease. Now, researchers at Children's Hospital Boston have created a zebrafish that is transparent throughout its life. The new fish allows scientists to directly view its internal organs, and observe processes like tumor metastasis and blood production after bone-marrow transplant in a living organism.

The fish, described in the February 7 issue of Cell Stem Cell, was created by Richard White, MD, PhD, a clinical fellow in the Stem Cell Program at Children's, with others in the laboratory of Leonard Zon, PhD.

The classic method for studying human diseases in animals is to allow the animal to get the disease, kill and dissect the animal, then ask, what happened? But in cancer and other fast-changing processes that traverse the body, this method is bound to miss something. It's like taking a photograph when you need a video, says White, also an instructor of medicine at the Dana-Farber Cancer Institute.

Zebrafish embryos have enabled researchers to study disease in live organisms, since they are transparent. But zebrafish adults are opaque. Everything after four weeks has been invisible to us, says White.

White's first experiment on the zebrafish examined how a cancer spreads. The process by which a tumor goes from being localized to widespread and ultimately fatal is the most vexing problem that oncologists face, says White. We don't know why cancer cells decide to move away from their primary site to other parts in the body.

White created a fluorescent melanoma tumor in the transparent fish's abdominal cavity. Viewing the fish under a microscope, White saw the cancer cells begin to spread within five days. He even saw individual cells metastasize, something that has not been observed, so readily and in real-time, in a living organism.

The spreading melanoma cells appeared to home to the skin after leaving the abdominal cavity. This told us that when tumor cells spread to other parts in the body, they don't do it randomly, says White. They know where to go.

White plans to study tumor cell homing, then look for ways to modify the tumor cells or cells of the host so that the spreading cells never find their new location.

The fish may also answer questions about stem cell transplants. While transplants of blood-forming stem cells help cancer patients rebuild healthy blood, some transplants don't take, for reasons that are unknown. Scientists have lacked a full understanding what steps blood stem cells must take to do their job, says White.

White showed the process is observable in the fish. He first irradiated a transparent fish's bone marrow, then transplanted fluorescent blood-forming stem cells from another zebrafish. By four weeks, the fluorescent stem cells had visibly migrated and grown in the fish's bone marrow, which is in the kidney. Even individual stem cells were visible, something researchers haven't easily observed in a living organism, White says.

By studying how the stem cells embed and build blood in the fish, scientists can look for ways to help patients rebuild their blood faster. Drugs and genes could be tested in the living fish, with direct observation of results, White says.

T cell immunity enhanced by timing of interleukin-7 therapy

Tue, 05 Feb 2008 08:24:37 PST

( from http://www.rxpgnews.com ) MADISON -- That the cell nurturing growth factor interleukin-7 can help ramp up the ability of the immune system to remember the pathogenic villains it encounters is well known.

But precisely how this natural protein works its magic on the cells of the immune system is not well understood. Now, however, in research that may have implications for developing vaccines against HIV and cancer, a team of scientists from the University of Wisconsin-Madison has found that the timing of interleuin-7 therapy is critical for increasing the number of killer cells that zero in on and destroy virus-infected cells.

Writing in the current online issue (Feb. 1, 2008) of the Journal of Clinical Investigation, a team led by UW-Madison School of Veterinary Medicine Professor of pathobiological sciences Marulasiddappa Suresh reports that therapeutic administration of interleukin-7 can be linked to a stage of early infection to effectively increase the number of a type of killer cell that recognizes and selectively assassinates virus-infected cells.

These cells need to get interleukin-7 for their survival, explains Suresh, of the killer immune cell known as CD8 T cells, a type of white blood cell that attacks virus-infected cells, foreign cells and cancer cells. Interleukin-7 is produced in very small amounts in bone marrow, spleen, and the thymus, but scientists have been able to isolate and synthesize the agent, which is now in pre-clinical testing for a variety of conditions.

This is one of the most exciting cytokines in pre-clinical human trials, says Suresh. The idea is that it might be used as an immune restorative agent. It is absolutely essential for normal development and functioning of the immune system.

Effectively stimulating the immune system -- the complex of organs and cells that defends the body against infection and disease -- is a grail of biomedical science in the fight against infectious diseases.

Suresh explains that upon infection, the body unleashes an army of T cells to fight infected or rogue cells. But when the body perceives an infection may be contained, the number of T cells it deploys is dramatically reduced. However, a certain number of T cells, known as memory cells and that are capable of recognizing a recently vanquished foe, remain. Stimulating memory T and B cells is the basis of vaccination, but vaccines often do not induce a sufficient number of memory CD8 T cells.

Despite the promise of interleukin-7 as a means to bolster immunity, an optimal treatment regimen has yet to be determined.

In studies in mice, Suresh and his colleagues found that T cell memory is best enhanced when interleukin-7 is administered during a phase of infection when the number of T cells is ramping down.

In the new Wisconsin study, Suresh's group gave interleukin-7 to mice during different stages of a viral infection. They found that by administering interleukin-7 when the number of T cells is in decline, it is possible to increase the number of memory CD8 T cells that remain to stand guard and protect against re-infection.

"The purpose of the immune response is to expand these cells," says Suresh, explaining that T cells act like serial killers, snuffing one infected cell after another until the viral infection is controlled.

During the expansion phase of infection, when the body is generating the most T cells, administration of interleukin-7 seems to have no effect, according to Suresh. But during the contraction phase, memory is increased.

"We tried this in a DNA vaccine and it works," says Suresh. "Even with the weakest vaccine, we could increase the memory cells and improve protection against infection. What this shows is that the number of memory cells are not predetermined. You can increase them and interleukin-7 drives their proliferation."

Breakdown of kidney's ability to clean its own filters likely causes disease

Tue, 29 Jan 2008 04:59:37 PST

( from http://www.rxpgnews.com ) Jan. 29, 2008 -- The kidney actively cleans its most selective filter to keep it from clogging with blood proteins, scientists from Washington University School of Medicine in St. Louis reveal in a new study.

Researchers showed that breakdown of this self-cleaning feature can make kidneys more vulnerable to dysfunction and disease.

We speculate that defects of this clearance mechanism can leave things on the filter that can damage it, says senior author Andrey Shaw, M.D., Emil R. Unanue Professor of Immunobiology in Pathology and Immunology. This could include autoimmune antibodies that mistakenly target the body's own tissues like those that occur in the disease lupus.

The study appears in the Jan. 22 Proceedings of the National Academy of Sciences.

Despite extensive knowledge of the structure of the kidney, several scientific controversies linger over how the organ does its complicated and essential job of filtering wastes from the blood for disposal without simultaneously discarding too much water or key blood proteins in the urine. Understanding how these tricky tasks are accomplished is essential to developing new treatments for kidney disease and renal failure, which are among the top ten causes of death in the United States.

Like many mechanical filtering systems, the kidney passes the blood through a series of progressively finer screens. After passing through a structure known as the glomerular basement membrane (GBM), fluid and serum proteins must finally pass through the most selective filter of the kidney, which is comprised of specialized epithelial cells called podocytes. These cells form a web-like barrier to the passage of large serum proteins into the urine.

The kidney screens 150 to 200 liters of blood daily, and we were curious as to how the kidney keeps the filter from clogging up, says first author Shreeram Akilesh, an M.D./Ph.D. student. The two most common blood serum and plasma proteins are albumin, which helps regulate blood volume and convey a number of different substances around the body, and immunoglobin G (IgG), a type of immune system antibody. Because they're so common, we figured they would be among the most likely to get stuck on the filter, and set out to look for proteins that help clear them.

Researchers looked for proteins made in podocytes that could bind to albumin and IgG, reasoning that such proteins likely provide the handles the podocytes need to grab proteins and clear them from the filter.

A protein known as FcRn was high on the list of likely suspects. Akilesh had studied FcRn previously in the laboratory of coauthor Derry C. Roopenian, Ph.D., professor at the Jackson Laboratory in Bar Harbor, Maine. Prior research there and in other laboratories had revealed that FcRn binds to both IgG and albumin and is present in human podocytes.

After confirming that the FcRn protein also is made in mouse podocytes, scientists then asked if FcRn was responsible for clearing IgG antibody from the filter. To do this, they measured the retention of a radioactive tracer in the kidneys of normal mice and in mice where the gene for FcRn had been disabled. Mice lacking FcRn had difficulty clearing antibody from the kidney.

When researchers studied the mice lacking FcRn for longer periods of time, they saw evidence that antibodies were accumulating in the kidney.

In another experiment, researchers gave the mice injections of large quantities of protein to saturate the clearance system. They followed those injections with what would normally have been a harmlessly small dose of an antibody potentially toxic to the kidney. The mice developed kidney damage as a result. Researchers believe this was because they couldn't clear the toxic antibody from the GBM quickly enough.

This is the first clear demonstration that the filter system in the kidney isn't just a passive mechanical filter, it's actually involved in its own maintenance, says Akilesh. It also provides us with a nice mechanism for explaining how the normal function of this filter may be breaking down in ways that leads to kidney disease and damage.

To follow up, Shaw plans to look for other podocyte proteins involved in filter clearance.

Eczema still on the increase in developing countries

Mon, 07 Jan 2008 04:59:37 PST

( from http://www.rxpgnews.com ) Experts are warning policy makers that allergic disease might replace infectious disease as a major cause of ill health in cities undergoing rapid demographic changes in developing countries.

New research tracking the number of cases of childhood eczema across the globe has revealed big changes in the prevalence of the condition over the last five to ten years and suggests that environmental factors could be having a significant impact.

Research, by a team of allergy experts across the world, has shown a levelling off in the number of cases of eczema in children aged between 13 to 14 years and a decrease in some countries like the UK and New Zealand where childhood eczema was once highly prevalent. But a continuing rise in younger children aged between six and seven and in the number of cases reported in developing countries is of growing concern.

Their paper, published in the Journal of Allergy and Clinical Immunology, suggests environmental factors are key for eczema expression because it is highly unlikely that genetic factors would change in such a short time.

Hywel Williams, Professor of Dermato-Epidemiology in the Centre of Evidence-Based Dermatology at The University of Nottingham, who led the eczema research, says eczema needs to be tackled at a public health level in many countries.

He says that moderate or severe cases of eczema have a significant impact on family life and carry an economic burden comparable with that of asthma. Constant scratching often leads to sleep deprivation which also affects carers as well as incurring significant financial costs.

Professor Williams and his international team analysed information from two worldwide surveys of asthma and allergy symptoms in children which was carried out by the International Study of Asthma and Allergies in childhood (ISAAC) between 1991 and 2001. ISAAC was formed in 1991 to facilitate research into asthma, allergic rhinitis and eczema by promoting a standardised methodology, and currently holds a Guinness World record for the largest epidemiological study in children.

Professor Williams and his team analysed over 300,000 children aged 13 to 14 years from 105 centres in 55 countries and nearly 190,000 children aged six to seven years from 64 centres in 35 countries.

The largest decreases in children aged between 13 to 14 years were seen in developed countries in northwest Europe, such as the United Kingdom, Ireland, Sweden, Germany and also New Zealand. Professor Williams says this provides some reassurance that an allergic disease epidemic is not increasing inexorably throughout the world, and that a threshold effect may be in operation.

Most of the biggest increases in the 13 to 14 age group were seen in developing countries such as Mexico, Chile, Kenya and Algeria and in seven countries in Southeast Asia.

However, in six to seven year olds most countries showed significant increases over the five to ten year period.

More sun exposure may be good for some people

Mon, 07 Jan 2008 04:59:37 PST

( from http://www.rxpgnews.com ) UPTON, NY - A new study by scientists at the U.S. Department of Energy's Brookhaven National Laboratory and colleagues in Norway suggests that the benefits of moderately increased exposure to sunlight - namely the production of vitamin D, which protects against the lethal effects of many forms of cancer and other diseases - may outweigh the risk of developing skin cancer in populations deficient in vitamin D. The study will be published online in the Proceedings of the National Academy of Sciences the week of January 7, 2008.

We know that solar radiation is the leading cause of skin cancer, said communicating author Richard Setlow, a Senior Biophysicist Emeritus at Brookhaven and a well-known expert on the link between solar radiation and skin cancer. Setlow's group was the first to establish that ultraviolet A (UVA) radiation and visible light are the primary causes of malignant melanoma, the deadliest form of skin cancer. He and his colleagues emphasize that people need to protect themselves from the harmful effects of sun exposure.

But solar radiation is also a major, if not the main, source of vitamin D in humans. In the presence of sunlight, the body converts certain precursor chemicals to active vitamin D.

Since vitamin D has been shown to play a protective role in a number of internal cancers and possibly a range of other diseases, it is important to study the relative risks to determine whether advice to avoid sun exposure may be causing more harm than good in some populations. The concern, he says, is particularly great in populations from northern latitudes, such as Scandinavia, where sun exposure is extremely limited.

In the current study, Setlow and his colleagues used a model incorporating information on solar radiation intensity and a vertical cylinder shape to represent the human body's skin surface to calculate the relative production of vitamin D via sunlight as a function of latitude, or distance from the equator. The cylindrical model more realistically represents human body sun exposure than flat surface exposure measurements used in previous models. The scientists also examined the incidence of and survival rates for various forms of cancer by latitude.

According to the calculations, people residing in Australia (just below the equator) produce 3.4 times more vitamin D as a result of sun exposure than people in the United Kingdom, and 4.8 times more than people in Scandinavia.

There is a clear north-south gradient in vitamin D production, Setlow says, with people in the northern latitudes producing significantly less than people nearer the equator.

In populations with similar skin types, there is also a clear increase in the incidence of all forms of skin cancer from north to south. This gradient in skin cancer rates indicates that there is a true north-south gradient in real sun exposure, Setlow says.

The scientists also found that the incidence rates of major internal cancers such as colon cancer, lung cancer, and cancers of the breast and prostate also increased from north to south. However, when the scientists examined the survival rates for these cancers, they found that people from the southern latitudes were significantly less likely to die from these internal cancers than people in the north.

In previous work, we have shown that survival rates for these cancers improve when the diagnosis coincides with the season of maximum sun exposure, indicating a positive role for sun-induced vitamin D in prognosis - or at least that a good vitamin-D status is advantageous when combined with standard cancer therapies, Setlow says. The current data provide a further indication of the beneficial role of sun-induced vitamin D for cancer prognosis.

So, how can people get the benefits of vitamin D without running the risk of deadly skin cancer

As far as skin cancer goes, we need to be most worried about melanoma, a serious disease with significant mortality, Setlow says.

Melanoma is triggered by UVA (the long UV wavelengths) and visible light. Vitamin-D production in the body, on the other hand, is triggered by UVB (the short UV wavelengths at the earth's surface). So perhaps we should redesign sunscreens so they don't screen out as much UVB while still protecting us from the melanoma-inducing UVA and visible light, Setlow says.

Increased UVB exposure may result in an increase in non-melanoma skin cancers. But these are relatively easy to cure and have very low mortality rates compared with the internal cancers vitamin D appears to protect against, Setlow adds.

Another option would be to increase vitamin D consumption while continuing to wear sunscreen. Vitamin D is easily accessible in many foods and liquids, such as cod liver oil and milk, and in dietary supplements.

2 genes are important key to regulating immune response

Fri, 28 Dec 2007 04:59:37 PST

( from http://www.rxpgnews.com ) NEW YORK (Dec. 28, 2007) -- A research team at Weill Cornell Medical College in New York City has identified two genes that may be crucial to the production of an immune system cytokine called interleukin-10 (IL-10).

The discovery fills in an important missing link in a biochemical pathway that's long been tied to disorders ranging from lupus and Type 1 diabetes, to cancer and AIDS.

IL-10 production has to be kept in a delicate balance for health, explains study senior researcher Dr. Xiaojing Ma, Professor of Immunology and Microbiology in the Departments of Microbiology and Immunology and Pediatrics at Weill Cornell. Too much IL-10 can leave the body more vulnerable to killers such as viruses and cancer, and to certain antibody-driven autoimmune diseases such as lupus, while too little can lead to run-away inflammatory pathology. Therefore, a better understanding of IL-10 regulation moves us closer to understanding these illnesses and -- potentially -- how to better treat them, he says.

The findings are reported in this month's issue of Immunity (vol. 27).

Dr. Jianguo Liu, of Weill Cornell, and Dr. Elaine Y. Chung, formerly of Weill Cornell and now a post-doc at the University of Pennsylvania, were co-lead researchers on the study.

Every second, millions of the body's cells undergo naturally programmed cell death -- a process called apoptosis. In healthy individuals, these dying or dead cells are spotted and then quickly ingested and removed by immune system scavenger cells such as macrophages.

However, to prevent this type of clean-up from triggering a wider immune response, macrophages express the IL-10 cytokine in the presence of apoptotic cells.

IL-10 suppresses the activity of immune system T-cells that might otherwise run amuck, Dr. Ma explains.

That can be a good thing, of course, he says. But on the other hand, when immune system T-cell activity is weakened too much, that can help encourage AIDS in those infected with HIV. Also, excessive T-cell suppression can keep the immune system from destroying rogue cancer cells in people battling malignancy.

All of this means that anything that we can learn about IL-10 production -- and related T-cell suppression -- is a boon to medical research, Dr. Ma explains.

Prior studies had already shown that CD36 -- a protein receptor lying on the surface of the macrophage -- was important for the recognition of apoptotic cells by macrophages. In this work, the researchers observed that CD36 also helped to trigger IL-10 production whenever apoptotic cells were around.

The team then asked a deeper question: What signals lead to IL-10 production from CD36 present at the cell surface

To find out, the Weill Cornell group first exposed macrophages to apoptotic (dying) cells. They then used sensitive assays to look for key biochemical changes occurring downstream of CD36 activation.

We found proteins in the cell nucleus that were binding to a site we knew was critical for the production of IL-10 as macrophages encountered apoptotic cells, Dr. Ma says. In subsequent biochemical experiments, the team identified the two genes responsible for the transcription (gene-directed production) of these proteins.

These genes -- pre-B transcription factor 1(Pbx-1) and Pbx-regulating protein 1 (Prep-1) -- are best known to scientists as partners for their role in embryonic development and several forms of leukemia, with Pbx playing a major part in hematopoeisis, the production of new and myriad blood cell types.

In that sense, their presence as immune system transcription factors came as a big surprise to us, Dr. Ma says. In fact, we still haven't figured out exactly how Pbx-1 and Prep-1 are involved in regulating IL-10 transcription. I really hope this study opens up new avenues for immunologists to find out whether there's a brand new biochemical pathway to be discovered.

The findings could also reveal exciting new information as to how aberrant IL-10 expression contributes to disease.

Because IL-10 expression (and related T-cell suppression) are so important to the etiology of so many illnesses, discoveries like ours could point to molecular pathways that may become important new targets for drug discovery going forward, Dr. Ma explains. It's these types of breakthroughs in the lab that -- step by step -- will end up bringing real hope to patients down the line.

Drug aimed at 2 bioterror agents blocks live viral infection, Weill Cornell team reports

Wed, 19 Dec 2007 04:59:37 PST

( from http://www.rxpgnews.com ) NEW YORK (Dec. 19, 2007) -- Two deadly and highly infectious viruses -- both potential bioterror threats -- may have met their match in a new drug developed by scientists at Weill Cornell Medical College in New York City.

Hendra and Nipah viruses are related, newly recognized zoonotic viruses that can spread from their natural reservoir in fruit bats to larger animals -- including pigs, horses and humans.

The mode of transmission isn't clear, but is thought to be relatively easy -- either by close contact with an infected host or by breathing in the microscopic pathogens. Infection often leads to a fatal encephalitis, and there is currently no effective treatment against these illnesses.

However, in breakthrough research conducted last year, researchers at Weill Cornell manipulated a peptide (protein) related to a third pathogen, parainfluenza virus, that appeared to block pseudo Hendra and Nipah viruses from entering and infecting human cells.

Now, this entry inhibitor approach has proven effective in blocking the infection of live virus in animal cells, pointing the way to a drug that could be stockpiled to help stop an outbreak in humans.

Those findings appeared recently in the Journal of Virology.

We have now tested the peptide-based entry inhibitor in monkey cells to show that it does effectively block infection with both live Hendra and Nipah, explains study senior researcher Dr. Anne Moscona, a professor of pediatrics and of microbiology and immunology at Weill Cornell Medical College, and an attending physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

Public health officials have sounded alarm bells ever since Nipah virus first emerged in pigs and then humans living in Southeast Asia. More recently, cases of Hendra virus began to show up in horses and their human handlers in Australia.

Experts who drew up the U.S. National Institute of Allergy and Infectious Diseases' Biodefense Research Agenda have included both viruses as potential bioterror agents.

Theoretically, it's possible to go out into the field and collect Hendra virus from bats, for example, Dr. Moscona says. We've been urgently working on this because right now there's absolutely nothing that can be done to stop this fatal, transmissible illness.

Luckily, prior research at Weill Cornell had laid out some important groundwork. The study's lead author, Dr. Matteo Porotto, has worked for years studying these types of microorganisms, using the parainfluenza virus as his model.

We were able to develop the strategy that we describe in this paper because our work on parainfluenza had already helped us understand how these viruses fuse with host cells, says Dr. Porotto, assistant professor of microbiology in the Department of Pediatrics at Weill Cornell Medical College.

Based on that work, Drs. Porotto and Moscona knew that when the receptor-binding molecule on the virus -- simply called G -- binds to the surface of the cell, it activates a special fusion protein. This fusion molecule has to then undergo some shape changes to turn itself into a six-helix bundle. Once that's done, it helps the virus fuse with, and enter, the cell, Dr. Porotto explains.

However, the Weill Cornell team discovered that a peptide specific to the parainfluenza virus fusion protein (F) can inhibit this shape-changing step -- stopping fusion cold.

Surprisingly, this parainfluenza F-peptide turned out to be even more effective at inhibiting Hendra virus fusion than peptides derived from the Hendra virus itself, Dr. Moscona says. It also appears to do much the same thing with the Nipah virus, inhibiting fusion there, too.

The team discovered just why the F peptide works so well in a collaboration with Dr. Min Lu, associate professor of biochemistry at Weill Cornell. These peptides act like door jambs -- their particular shapes prevent 'doors' in the viral 'fusion protein' from closing as they should. The parainfluenza peptide's shape simply makes it a better door jamb, Dr. Porotto said.

Much of this research is modeled on insights gained from two decades of investigation into another lethal virus, HIV. In fact, T-20, or Fuzeon -- one of the earliest effective HIV-suppressing drugs -- acts on a similar principle to block that virus' entry into cells.

The next step, according to the researchers, is to use what they've learned to design even more effective peptides that should work even better.

However, one issue with peptides is that you have to be concerned about how long they are going to last in the bloodstream, Dr. Moscona says. So, we are also developing methods of sustained-release -- for example, encasing the peptide in a polymer pellet that would be injected under the skin. The pellet would then release the drug slowly over the course of a week. That could form a viable method suitable for stockpiling, she says.

Dr. Lewis Drusin receives American College of Physicians James D. Bruce Memorial Award

Wed, 19 Dec 2007 04:59:37 PST

( from http://www.rxpgnews.com ) NEW YORK (Dec. 19, 2007) -- In recognition of his distinguished contributions in preventive medicine, epidemiologist Dr. Lewis Drusin of NewYork-Presbyterian Hospital/Weill Cornell Medical Center has been selected by the American College of Physicians to receive the prestigious James D. Bruce Memorial Award, one of 17 awards in internal medicine for 2008.

The convocation ceremony will take place on May 15, 2008, at the annual meeting of the American College of Physicians in Washington, D.C.

Past recipients include such notables as Nobel Prize winner Dr. Jonas Salk (polio vaccine), Dr. Donald Henderson (smallpox) and NewYork-Presbyterian/Weill Cornell's Dr. Walsh McDermott, who served as a mentor to Dr. Drusin.

Dr. Drusin is professor of clinical medicine and professor of clinical public health at Weill Cornell Medical College, and attending physician at NewYork-Presbyterian/Weill Cornell, where he was formerly director of the Division of Epidemiology.

We want to extend our congratulations to Dr. Drusin, whose career-long contributions to preventive medicine make him very deserving of this special honor, say Dr. Antonio M. Gotto, Jr., the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College, and Dr. Herbert Pardes, president and CEO of NewYork-Presbyterian Hospital.

Dr. Drusin has made outstanding contributions to the prevention and study of nosocomial infections and sexually transmitted diseases, publishing more than 50 papers and book chapters. At Weill Cornell, he directs a program placing Public Health and Community Medicine clerkship students in field locations, and has helped establish an endowment that offers international rotations to medical students. He served as president of the American Venereal Disease Association (now the American STD Association), and he has held prominent roles in many international scientific congresses and study groups relating to sexually transmitted diseases. Since 1995, he has served as the main representative of the International Union Against Sexually Transmitted Infections to the Economic and Social Council of the United Nations. He is a fellow of the American College of Physicians, a fellow of the Royal College of Physicians of London and one of only two American honorary life members of the British Association for Sexual Health and HIV.

He earned his undergraduate degree at Union College (Schenectady, N.Y.) and received his medical degree from Cornell University Medical College (now Weill Cornell Medical College). Dr. Drusin also holds an M.P.H. from the Columbia University School of Public Health.

I am deeply honored to be considered among such esteemed company, says Dr. Drusin. It is exiting when you make your career choices according to what's fun to do, and then you find out later that other people have appreciated what you've done.

Immune system may target some brain synapses, Stanford researchers find

Thu, 13 Dec 2007 04:59:37 PST

( from http://www.rxpgnews.com ) STANFORD, Calif. - A baby's brain has a lot of work to do, growing more neurons and connections. Later, a growing child's brain begins to pare down these connections until it develops into the streamlined brain of an adult.

Now researchers at the Stanford University School of Medicine have discovered the sculptor behind that paring process: the immune system.

The value of this discovery goes beyond understanding how connections are weeded out in a normal, developing brain. The finding could also help explain some neurodegenerative disorders - such as glaucoma, Alzheimer's disease and multiple sclerosis - that result from the loss of too many neuronal connections, which are known as synapses.

The advance, which has implications for drugs that could halt or reverse such conditions, will be published in the Dec. 14 issue of the journal Cell.

It was widely known that synapse elimination occurs during normal development of a child's brain, but until now, no one knew how certain synapses were flagged for removal. We have identified the long-mysterious mechanism by which excess synapses are sculpted away in the developing brain, said the study's senior author, Ben Barres, MD, PhD, professor of neurobiology.

Barres' team found that the brain-sculpting process was controlled by a component of the immune system known as the classical complement cascade.

The complement cascade is one part of the multipronged attack the immune system launches throughout the body when it detects a foreign invader. Consisting of more than 20 small proteins that normally circulate in the blood in their inactive forms, the complement system is triggered into action by an invading parasite. The first activated protein activates a second one, which in turn activates a third, continuing down the line in a domino effect, ultimately yielding a membrane-attack response that kills cells.

Barres' team produced the first proof that the complement system also plays a role in the brain by showing that complement proteins bind to unwanted synapses, targeting them for elimination. Future studies will determine how the synapses are marked for death.

When children reach the age of 10, synapse elimination normally shuts down. But the researchers found that this elimination process becomes reactivated very early in glaucoma, a neurodegenerative disease that is a major cause of blindness. They found that the earliest known sign in glaucoma was the complement cascade becoming active at synapses, followed by massive synapse loss. Only much later did the neurons die, which is the hallmark of neurodegenerative diseases.

This is interesting, as these complement proteins are known to be drastically up-regulated in nearly every neurodegenerative disease process that has been examined, said Barres. Up-regulation is the process by which a cell increases the amount of a molecule, such as a protein, in response to a change in its environment. Alzheimer's disease, which involves massive synapse loss, has a hundredfold up-regulation of complement proteins, he said.

First author Beth Stevens, PhD, a postdoctoral scholar in Barres' lab, said these findings in glaucoma made the team wonder if the same synapse-elimination process is restarted in other neurodegenerative diseases. It's an exciting thought, as this would be the earliest sign of disease so far, she said.

The Barres laboratory has long been interested in the development and function of glial cells, which constitute around 90 percent of the cells in the human brain. These cells - specifically oligodendrocytes and astrocytes - provide support and protection for neurons, but the main role of the glia is a mystery, said Barres. His lab has been systematically identifying proteins and chemical factors that glial cells produce to modulate the activity of neurons.

The current finding of the complement cascade's involvement in the synapse-paring process was a bit of serendipity, said Stevens. The team knew the process coincided with the appearance of astrocytes in the developing brain, so they decided to run a microarray - the lab tools that can screen thousands of genes at a time - to see which neuronal genes were most active when neurons are exposed to astrocytes.

Unexpectedly, they found that the first protein in the complement cascade, called C1q, was the most up-regulated of all proteins.

The role of the complement system was known in the rest of the body, but this opened up the question of what was going on in the brain, said Stevens. It was surprising that C1q was the most changed protein; we didn't even think it was expressed in the brain.

Stevens went on to painstakingly characterize the role of the complement cascade. She ultimately showed that astrocytes make complement proteins that tag brain synapses during development. Complement protein C1q, and another one called C3, were required for synapse elimination.

Based on their finding that synapse elimination was reactivated in glaucoma, Stevens and Barres have a number of collaborations under way looking at the complement cascade's role in other neurodegenerative disorders, including Alzheimer's, autism, Lou Gehrig's disease (known as ALS), multiple sclerosis and Parkinson's.

As synapse loss and C1q up-regulation are prominent features of all these diseases, our findings imply that drugs that blockade the complement cascade may provide a new treatment for many different neurodegenerative diseases, Barres said.

Lymphatic vessel and lymph node function are restored with growth factor treatment

Sun, 02 Dec 2007 04:59:37 PST

( from http://www.rxpgnews.com ) The frequent spread of certain cancers to lymph nodes often necessitates surgery or radiation therapy that damages the lymphatic system and can cause lymphedema, a condition of localized fluid retention that often increases susceptibility to infections.

The researchers of the University of Helsinki, Finland, and the Ludwig Institute of Cancer Research show that application of vascular endothelial growth factor-C (VEGF-C) to replace excised mouse lymph nodes and lymph vessels ensures formation of mature lymphatic vessels and incorporation of lymph node transplants into existing lymphatic vasculature. An improved outcome of lymph node transplantation is evidenced by improved lymphatic drainage and restoration of normal lymphatic vascular anatomy in VEGF-C-treated mice.

The ability to transfer lymph nodes that reconstitute a functional network of lymphatic vessels in adult tissues is of particular importance in cancer follow-up therapy, as lymph nodes can prevent systemic dissemination of metastases. Accordingly, VEGF-C-treated lymph nodes were more effective in trapping metastatic tumor cells than control transplants.

It has been estimated that approximately 20-30% of patients that have undergone irradiation or surgery of the armpit in response to lymph node metastases develop lymphedema later on. Damage to the large collecting lymphatic vessels, which resemble smaller veins, causes the vast majority of all lymphedemas. It has been estimated that several million patients suffer from such acquired lymphedema worldwide. The treatment of lymphedema is currently based on physiotherapy, compression garments and occasionally surgery, but means to reconstitute the collecting lymphatic vessels and cure the condition are limited.

The Finnish researchers applied vascular endothelial growth factor-C (VEGF-C) gene therapy in mice after surgery removal of axillary lymph nodes, a procedure that mimicked removal of axillary lymph nodes in patients in response to metastatic breast cancer. They found that treatment of lymph node-excised mice with adenoviral VEGF-C gene transfer vectors induced robust growth of the lymphatic capillaries, which gradually underwent an intrinsic remodeling, differentiation and maturation program into functional collecting lymphatic vessels, including formation of uniform endothelial cell-cell junctions and intraluminal valves.

As VEGF-C quite potently increases the rate of lymph node metastasis, the researchers sought to develop a mode of therapy that could be safely applied also in patients that had been treated for cancer. They established that the VEGF-C therapy greatly improved the outcome of lymph node transplantation. As a result, they were able to reconstruct the normal gross anatomy of the lymphatic network in the axilla, including both the lymphatic vessels and the nodes, suggesting that VEGF-C therapy combined to autologous lymph node transfer is feasible in the clinical setting.

The advantage of this rationale is increased patient safety in instances of recurrent malignancies, as the transplanted lymph nodes provide an immunological barrier against systemic dissemination of cancer cells, as well as other pathogens.

The findings demonstrate for the first time that growth factor therapy can be used to generate functional and mature collecting lymphatic vessels. This, combined with lymph node transplantation, allows for complete restoration of the lymphatic system in damaged tissues, and provides a working model for future treatment of lymphedema in patients. Effective lymph node transplantation holds tremendous potential for immunotherapy applications in the treatment of diseases such as cancer and chronic infections. Furthermore, the findings encourage the use of growth factor therapy to enhance the vascular integration and viability of transplanted tissues.

The group is currently pursuing this form of therapy in larger animal models in order to eventually treat lymphedema patients. Further the group aims to discover methods that would accelerate lymphatic vessel maturation.

Poxvirus ability to hide from the immune system may aid vaccine design

Thu, 15 Nov 2007 04:59:37 PST

( from http://www.rxpgnews.com ) The cowpox virus, a much milder cousin of the deadly smallpox virus, can keep infected host cells from warning the immune system that they have been compromised, researchers at Washington University School of Medicine in St. Louis have found. The scientists also showed that more virulent poxviruses, such as the strains of monkeypox prevalent in Central Africa, likely have the same ability.

The study's authors say the finding will help efforts to design new vaccines for use against cowpox, monkeypox and, if it ever became a concern again, smallpox. Researchers working on the next generation of poxvirus vaccines are hoping to minimize the risk of vaccination and to make the vaccines protective against a broader range of viruses.

Poxvirus vaccines are cross-protective, meaning that immunization from one poxvirus appears to confer protection from other poxviruses, but there are significant risks associated with adult administration of the current vaccine, says senior author Wayne Yokoyama, M.D., professor of pathology and immunology and of medicine and a Howard Hughes Medical Institute investigator. There are also efforts underway to see if recombinant poxvirus vaccines can convey protection against a broader range of viruses, including HIV and cytomegalovirus.

In addition, the finding is likely to help scientists understand why one strain of poxvirus is more dangerous than another. The results appear Nov. 15 in Cell Host and Microbe.

Three decades ago, doctors eliminated the deadliest poxvirus, smallpox, using another poxvirus, vaccinia, as a vaccine. But a few smallpox samples remain in government facilities in the United States and Russia, and those samples have led to concern that terrorists might try to obtain smallpox and use it in a bioterror attack.

Additionally, other species of poxvirus continue to be sources of human disease and, occasionally, deaths. Outbreaks of cowpox, which Edward Jenner used to demonstrate the concept of vaccination in the late 1700s, still occur. In addition, multiple outbreaks of the monkeypox virus, which can cause smallpox-like disease in humans, have occurred in Africa and the United States in the past decade.

To help clinicians better prepare for the possibility of a new natural poxvirus outbreak or a bioterror attack using a poxvirus, Minji Byun, a graduate student in Yokoyama's laboratory, led a laboratory study of interactions between the cowpox virus and the immune systems of mice. Byun collaborated with Xiaoli Wang, M.D., Ph.D., instructor in the laboratory of Ted Hansen, Ph.D., professor in the Department of Pathology and Immunology. The research was supported in part by the Midwest Regional Center of Excellence in Biodefense and Emerging Infectious Diseases Research (MRCE), a multi-institutional research center anchored at Washington University School of Medicine.

Normally the immune system in mice and humans can learn of a viral invasion through a group of molecules known as the major histocompatibility complex (MHC) class I. Because these molecules sit on the surfaces of cells and display samples of proteins from inside the cells, they act as identification badges, in effect telling immune system sentinels, here's what I'm made of. When immune T cells see virus-derived protein fragments in a cell's MHC class I display, they assume it's been infected and initiate an immune system attack.

But Byun and her colleagues found that cowpox was preventing MHC class I from ever getting to the surface of infected cells. They linked the suppression to a cowpox virus protein, CPXV203, showing that it binds to MHC class I. This binding yanks MHC class I off course by targeting it to the cellular recycling machinery. Once in the recycling loop, MHC class I cannot escape to the cell surface.

Other viruses have similar strategies for immune system evasion, but this is the first study showing that the poxviruses that are most closely related to smallpox virus can use this approach, says Byun.

A search of the genomes of monkeypox virus revealed a similar protein in the more virulent family of virus strains found in Central Africa. But the less virulent strains active in Western Africa tend to have truncated versions of the proteins similar to CPXV203, leaving them unable to act on MHC class I.

When researchers eliminated the CPXV203 gene and infected mouse cells with the modified cowpox virus, they found it still was able to suppress the appearance of MHC class I on infected cell surfaces, but not as thoroughly.

There's likely another viral mechanism that produces the same result, Byun speculates. But it has to be acting on MHC class I in a different way because a search through the cowpox genome failed to reveal any other viral proteins with the same key module as CPXV203.

Pharmaceutically blocking CPXV203 and other similar immune evasion proteins may be tough, according to Yokoyama, because that would disrupt an important natural protein recycling process, potentially causing significant side effects. He believes the finding is more likely to be useful to vaccine scientists. Many vaccines are composed of weakened forms of the microbes they protect against, and the modified cowpox lacking CPXV203 is likely less virulent.

Yokoyama plans additional studies of poxvirus-immune system interaction in live mice.

Abnormal immune cells may cause unprovoked anaphylaxis

Fri, 09 Nov 2007 04:59:37 PST

( from http://www.rxpgnews.com ) Two new clinical reports shed light on why some people suffer from recurrent episodes of idiopathic anaphylaxis--a potentially life-threatening condition of unknown cause characterized by a drop in blood pressure, fainting episodes, difficulty in breathing, and wheezing.

In some of these individuals, researchers have found mast cells (a type of immune cell involved in allergic reactions) that have a mutated cell surface receptor that disturbs normal processes within the cell. Scientists supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), say the association of this mutation with unprovoked anaphylaxis is striking. The hope is that these individuals may respond to inhibitors targeting the mutated cell surface receptor.

While some people suffer anaphylaxis as part of a serious allergic reaction, in two out of three people, anaphylaxis has no known cause and thus the anaphylactic reaction is called idiopathic.

Anaphylaxis occurs when mast cells release large quantities of chemicals (histamines, prostaglandins and leukotrienes) that cause blood vessels to leak, bronchial tissues to swell and blood pressure to drop. Resulting conditions such as shock and unconsciousness usually resolve in most people treated with epinephrine (adrenaline) and first aid measures. In rare cases, however, death may occur.

Abnormally low blood pressure and fainting episodes are also features of mastocytosis--a disease in which people have an excessive number of mast cells. Several years ago, Dean Metcalfe, M.D., chief of the Laboratory of Allergic Diseases at NIAID, Cem Akin, M.D., Ph.D., and their NIAID colleagues decided to find out whether idiopathic anaphylaxis might have a genetic trigger related to that seen in mastocytosis. It is known that systemic mastocytosis in adults often results from a mutation in the Kit receptor found on the surface of mast cells, a discovery first made by Dr. Metcalfe's team in 1995.

The mutation causes an abnormal growth of mast cells, as is observed in bone marrow biopsies of patients with mastocytosis. So the NIAID team asked, if the Kit mutation could make mast cells grow and cause mastocytosis, and this was associated with anaphylactic reactions, could the same mutation predispose mast cells to release chemicals responsible for idiopathic anaphylaxis?

In a two-year study conducted at the NIH Clinical Center, the researchers examined 48 patients diagnosed with mastocytosis with or without associated anaphylaxis, 12 patients with idiopathic anaphylaxis, and 12 patients with neither disease. Within the group of 12 patients who had idiopathic anaphylaxis, five were found with evidence of a disorder in a line of mast cells (clonal mast cell disorder). The researchers looked for evidence of a Kit mutation in three patients by analyzing bone marrow samples, and all three samples yielded a positive result. The findings demonstrate that some patients with idiopathic anaphylaxis have an aberrant population of mast cells with mutated Kit.

We believe the mutation may be predisposing people to idiopathic anaphylaxis, says Dr. Metcalfe. Our findings suggest that in patients with idiopathic anaphylaxis as well as in people with severe allergies, we should look for critical genetic mutations that may change the way a mast cell reacts.

Dr. Metcalfe and his NIAID colleagues report their findings in two journals. The study that appears in an early online edition in Blood describes the presence of an abnormal mast cell population in a subset of patients with idiopathic anaphylaxis. The findings about the mechanism leading to mass cell activation by Kit and the IgE receptor responsible for allergic reactions appear online in Cellular Signalling.

According to the NIAID team, both Kit and the IgE receptor responsible for allergic reactions activate mast cells via a common interior protein of mast cells. They also found that the mutated Kit markedly elevates the activity of that protein, which results in increased cell signaling.

The scientists are now looking to see if artificial mast cells with mutated Kit behave or release chemicals in a manner different from normal mast cells, and also if they respond to inhibitors targeting Kit.

Mice help researchers understand chlamydia

Mon, 29 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Genetically engineered mice may hold the key to helping scientists from Queensland University of Technology and Harvard hasten the development of a vaccine to protect adolescent girls against the most common sexually transmitted disease, Chlamydia.

Dr Michael Starnbach from Harvard Medical School is in Australia to work with QUT on a joint research project using a mouse model to study how the immune system responds to infections such as Chlamydia.

Ultimately the idea is to understand enough about how Chlamydia interacts with cells and how the immune system responds to those infected cells, to be able to understand which components of the immune system need to be stimulated to fight the Chlamydia infection, Dr Starnbach said.

At Harvard we have been working on the basic biology of how the immune fighter cells known as T-cells respond to infection.

When a person is infected with Chlamydia, the organism enters into the outermost cells of the genital tract and stays there and replicates within those cells.

Once they're hidden within the cells, only the T-cells can recognise that the cells are infected.

T-cells are able to recognise cells that are infected and destroy those cells, ultimately eliminating the organism from the body.

Dr Starnbach said the mouse model being developed by QUT and Harvard would see mice genetically engineered with T-cells that were specifically directed to protect against the mouse strain of Chlamydia.

In doing this we will be able to learn things about what is involved in protecting mice against Chlamydia infection and then mimic those responses with vaccines, he said.

Professor Peter Timms along with Professor Ken Beagley, from QUT's Institute of Health and Biomedical Innovation, are heading a QUT research team working with Dr Starnbach.

QUT has already identified certain proteins that may be able to be incorporated into vaccines to protect against Chlamydia infection, Professor Timms said.

We've been testing these proteins and, by working with Harvard, we hope to build on this research.

Professor Timms said, with rates of Chlamydia infection in some Australian communities as high as 12 per cent of the female population, there was a real need to develop a vaccine.

Chlamydia is the most common sexually transmitted disease in the world and results in infertility in women and long-term chronic pelvic pain, he said.

There are antibiotics to treat Chlamydia, but there's no vaccine to prevent it. In many cases women don't know they are infected because there are not really any physical signs or symptoms, so by and large they don't get treatment.

Study proposes new theory of how viruses may contribute to cancer

Tue, 23 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) PITTSBURGH, Oct. 23 � A new study suggests that viruses may contribute to cancer by causing excessive death to normal cells while promoting the growth of surviving cells with cancerous traits. Viruses may act as forces of natural selection by wiping out normal cells that support the replication of viruses and leaving behind those cells that have acquired defects in their circuitry. When this process is repeated over and over, cancer can develop say study authors, led by Preet M. Chaudhary, M.D., Ph.D., professor of medicine at the University of Pittsburgh School of Medicine. Their findings are published by Public Library of Science in the Oct. 24 issue of PLoS ONE.

Infection with viruses has been linked to many human cancers, including some forms of Hodgkin�s and non-Hodgkin�s lymphomas, sarcomas and cancers of the throat and liver. Over the years, scientists have proposed a number of mechanisms to explain this link. One commonly held belief is that when a virus infects a cell, its genetic material alters the cell, making it grow uncontrollably, eventually leading to cancer. Some viruses also are thought to promote cancer by causing chronic inflammation. In his study, Dr. Chaudhary proposes that viruses also can lead to cancer in a less direct manner.

�We believe a separate mechanism may be at play in which a cellular insult, such as infection with a virus, selects a few pre-existing mutated clones of cells, promotes their further growth and multiplication, eventually leading to the emergence of fully cancerous cells. Consequently, similar to the role played by natural selection during evolution, excessive cell death, rather than its absence, may be a defining force that drives the initial emergence of cancer,� said Dr. Chaudhary. He named this model the Phoenix Paradigm in which cancer theoretically arises out of the ashes of dead cells.

The paradigm was developed based on a study of cells infected with the Kaposi�s sarcoma associated herpesvirus, or KSHV, also known as human herpesvirus 8 (HHV-8). The researchers examined a gene called K13 that activates a pathway previously implicated in cancer development. Cells with low K13 expression allowed KSHV to replicate, and these cells subsequently died off, the researchers noted. Cells with higher expression of K13 emerged after KSHV replication and showed defective expression of two key proteins that are known to promote cancer.

�This paradigm, if validated by further studies, has implications not only for an improved understanding of the processes involved in cancer, but also for the development of effective strategies for its prevention and treatment,� said Dr. Chaudhary.

Hand hygiene initiative aims to decrease healthcare-associated infection in developing countries

Mon, 22 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) An open-access commentary in the December 2007 issue of Infection Control and Hospital Epidemiology examines a recently launched a global initiative by the World Health Organization (WHO) to combat healthcare-associated infection by improving hand hygiene in health care. The commentary is part of the Global Theme Issue on Poverty and Human Development. An international collaboration organized by the Council of Science Editors of simultaneously published research from more than 200 medical and scientific journals , the Global Theme Issue aims to raise awareness of the relationship between poverty and human development.

Authors Benedetta Allegranzi, MD (World Alliance for Patient Safety, World Health Organization), and Didier Pittet, MD, MS (Infection Control Program, University of Geneva Hospitals, Geneva), note that healthcare-associated infection is a major patient safety problem found in every hospital, healthcare system, and country.

The risk of healthcare-associated infection is 2 to 20 times higher for patients in developing countries than for patients in industrialized countries. A complex array of factors contribute to that increased risk, including lack of resources, inappropriate use of antibiotics, use of counterfeit drugs, understaffing and lack of training of health care professionals, and governments that are overwhelmed with larger health issues and cannot commit to infection control procedures and standards.

The WHO recently launched the First Global Patient Safety Challenge, �Clean Care is Safer Care,� to reduce healthcare-associated infection worldwide. �The First Global Patient Safety Challenge represents an unprecedented initiative to improve infection control practices and procedures in any healthcare setting, regardless of the level of economic development,� explains Dr. Pittet. �Never before in the history of infection control has there been such an opportunity to improve the health of so many millions of individuals by promoting basic but essential practices through the powerful channels of the WHO, which allow the involvement of governments and influence their healthcare systems.� The ministries of health from 43 countries have already signed the pledge to reduce healthcare-associated infection and another 20 are expected to join by the end of 2007.

The WHO developed guidelines on hand hygiene in health care based on scientific evidence and international expertise. A multimodel implementation strategy will turn the guidelines into practice and will suggest feasible ways to induce changes that will result in increased hand hygiene compliance and reduced morbidity and mortality due to healthcare-associated infection. Part of the effort is to make the indications for hand hygiene universally understandable and not open to interpretation. It focuses on only five points when hand hygiene is required when providing health care.

A worldwide pilot test of the strategy and tools is under way to evaluate the feasibility, sustainability, cost-effectiveness and cultural adaptation of a multimodel strategy for hand hygiene improvement.

�Results obtained from the worldwide testing will be invaluable in helping to shape scale-up and sustainability worldwide and will go a long way to ensuring that infection control practices continuously improve and contribute to enhanced patient safety,� conclude the authors.

Zinc may reduce pneumonia risk in nursing home elderly

Mon, 22 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) BOSTON � When elderly nursing home residents contract pneumonia, it is a blow to their already fragile health. Simin Nikbin Meydani, DVM, PhD of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University and colleagues report that maintaining normal serum zinc concentration in the blood may help reduce the risk of pneumonia development in that population.

�Based on our data, it appears that daily zinc intake can help nursing home residents who are susceptible to pneumonia, especially those with low serum zinc concentrations in their blood,� says Meydani, corresponding author and director of the Nutritional Immunology Laboratory at the USDA HNRCA . �The study participants with normal serum zinc concentrations in their blood reduced their risk of developing pneumonia by about 50 percent. Additionally, deaths from all causes were 39 percent lower in this group.�

Meydani and colleagues analyzed blood samples from a previous study that investigated the role of Vitamin E in preventing respiratory infections in nursing home residents ages 65 and older. The study enrolled 617 men and women from 33 nursing homes in the Boston area. All of the participants received daily supplements containing 50 percent of the recommended dietary allowance of several vitamins and minerals, including zinc, for one year. Foods that provide zinc include oysters, red meat, poultry, whole grains, beans and dairy products.

In the present study, published in the October issue of the American Journal of Clinical Nutrition, the authors compared blood samples collected at the beginning and the conclusion of the one-year study. The participants whose serum zinc concentrations remained low throughout that 12-month period had more difficulty battling pneumonia. �Not only did those participants have a higher risk of developing pneumonia when they did become sick, they did not recover as quickly and required a longer course of antibiotics,� says Meydani, who is also a professor at the Friedman School of Nutrition Science and Policy and the Sackler School of Graduate Biomedical Sciences, both at Tufts University. �We also noted a higher rate of death from all causes.�

Maintaining normal serum zinc concentration in the blood throughout the 12-month study period benefited the participants even if they did develop pneumonia. Meydani adds, �Those participants with normal serum zinc concentrations in their blood were more likely to spend fewer days on antibiotics and recover more quickly.�

Meydani and colleagues conclude that zinc may reduce the risk of pneumonia, and its associated complications in nursing home residents. �Zinc is already known to strengthen the immune system; however, there needs to be further investigation of zinc and its effect on pneumonia development and prevention in nursing homes,� Meydani says. �The next step would likely be a clinical trial.�

Scientists discover how gold eases pain of arthritis

Mon, 22 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) DURHAM, N.C. � Scientists at Duke University Medical Center may have solved the mystery surrounding the healing properties of gold � a discovery they say may renew interest in gold salts as a treatment for rheumatoid arthritis and other inflammatory diseases.

Physicians first used injections of gold salts in the early 1900s to ease the pain and swelling associated with arthritis. But treatment came at a high cost: The shots took months to take effect and side effects included rashes, mouth sores, kidney damage and occasionally, problems with the bone marrow�s ability to make new blood cells. Recently, new treatments like methotrexate and biologically engineered drugs have replaced gold as a preferred treatment, and gold salts, while remaining effective, are usually administered as a last resort.

But Dr. David Pisetsky, chief of the division of rheumatology and immunology in the department of medicine at Duke, says �we shouldn�t dismiss gold salts so quickly. We scientists have really never understood why gold works. Now that we have a better handle on its action, we may be able to use that mechanism to create new and better gold-like drugs to treat arthritis.�

Pisetsky had long been interested in a particular molecule, HMBG1, which provokes inflammation, the key process underlying the development of rheumatoid arthritis. HMBG1 is a dual-function molecule, which means that it behaves one way when it�s inside the nucleus of a cell, and quite another way when it�s released from the cell.

Pisetsky says that inside the nucleus, HMGB1 is a key player in transcription, the process that converts genetic information in DNA to its RNA equivalent. But when HMGB1 is released from the cell � either through normal processes or cell death � it becomes a stimulus to the immune system and enhances inflammation.

�Interestingly, HMGB1 is not produced evenly throughout the body,� says Pisetsky.

�There is an unusually high amount of it in the synovial tissue and fluid around the joints � where arthritis occurs.�

Pisetsky, working with colleagues at the University of Pittsburgh and the Karolinska Institute in Sweden, stimulated mouse and human immune system cells to secrete HMGB1, then treated them with gold salts. They found that the gold blocked the release of HMGB1 from the nucleus. That, in turn, should lessen the amount available to provoke the body�s immune system, weakening the inflammatory response.

�Basically, keeping HMGB1 corralled inside the nucleus is a good thing, when it comes to arthritis,� says Pisetsky.

Pisetsky says gold inhibits the release of HMGB1 by interfering with the activity of two helper molecules that ease HMGB1�s release from the cell, interferon beta and nitric oxide.

The study will appear in the January, 2008 issue of the Journal of Leukocyte Biology, but a preprint is already online at the journal�s website at:

Study reveals 2 genes linked to disabling arthritis

Sun, 21 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) SEATTLE � An international team of researchers led by a Fred Hutchinson Cancer Research Center geneticist has discovered two genes linked to a disabling form of arthritis called ankylosing spondylitis, a painful and progressive disease in which some or all of the spine�s vertebrae fuse together. The researchers also validated the association of two genes implicated in Graves� disease, an autoimmune condition that causes overactivity of the thyroid gland.

Principal investigator and corresponding author Lon Cardon, Ph.D., and colleagues in the U.K.-based Wellcome Trust Case Control Consortium and The Australo-Anglo-American Spondylitis Consortium reported their findings online Oct. 21 in Nature Genetics.

The study revealed two genes linked to ankylosing spondylitis: ARTS1 and IL23R, both of which influence immune function. Together with the previously known gene HLA-B27, the new findings increase to three the number of genes known to be involved in the disease. A person who carries all three genetic variants would be expected to have a one-in-four chance of developing the disease.

The discovery of both genes, as well as the validation of two prime genetic suspects in Graves� disease � genes known as TSHR and FCRL3 � arose from a comprehensive scan of the human genome in which dozens of researchers used genotyping technology to analyze DNA samples from thousands of patients suffering from a variety of common diseases and compared them to DNA from a similar number of healthy control subjects.

In addition to Graves� disease and ankylosing spondylitis, the study mined for common genetic variations associated with multiple sclerosis and breast cancer. The most significant findings, however, were in ankylosing spondylitis, a type of arthritis that not only affects the spine but also can attack other joints and organs, including the heart, lungs and eyes. The condition afflicts an estimated one in 200 males and one in 500 females and typically strikes during adolescence and young adulthood.

Previous research also has linked IL23R with inflammatory-bowel disease (Crohn�s disease) and psoriasis. �Clinically these diseases tend to occur together � people with inflammatory-bowel disease also tend to have a higher probability of having ankylosing spondylitis and psoriasis. The IL23R gene provides a genetic link that sheds new light on their co-occurrence,� said Cardon, a member of the Hutchinson Center�s Human Biology Division.

With these new clues in hand, researchers next will study the genes in model organisms to work out the pathways by which they cause disease. The ultimate goal is improved diagnostics and drug discovery. For example, knowing that genetic variation in IL23R is a risk factor for both Crohn�s disease and ankylosing spondylitis suggests that drugs being tested for one also may be effective against the other.

�We already knew that IL23R is involved in inflammation, but no one had ever thought it was involved in ankylosing spondylitis,� said Matthew Brown, M.D., a clinical researcher from the Wellcome Trust Centre for Human Genetics at the University of Oxford, who co-led the study with Cardon. A treatment for Crohn�s disease that inhibits the activity of this gene already is undergoing human trials, Brown said, and the drug also looks very promising as a potential treatment for ankylosing spondylitis.

�This is an exciting time for genetics. The Wellcome Trust Case Consortium has yielded more genetic discoveries for common diseases in 2007 than have been made in the entire history of the field,� said Cardon, a statistical methodologist who last year came to the Hutchinson Center�s Human Biology Division from the University of Oxford, where he conducted the research and retains an academic post.

�Seattle is very, very strong in epidemiology and genetics and has a worldwide reputation in biostatistics � that�s what brought me here,� said Cardon, also a professor of biostatistics at the University of Washington.

Major genetic breakthrough for ankylosing spondylitis brings treatment hope

Sun, 21 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Research funded by the Wellcome Trust and the Arthritis Research Campaign has identified two genes implicated in the disease ankylosing spondylitis, a common disease primarily causing back pain and progressive stiffness. The research, published online today in Nature Genetics, suggests that a treatment currently being trialled for Crohn's disease may also be applied to this disease.

Ankylosing spondylitis affects as many as 1 in 200 men and 1 in 500 women in the UK, typically striking people in their late teens and twenties. Whilst it mainly affects the spine, it can also affect other joints, tendons and ligaments. More rarely, it can affect other areas, such as the eyes, lungs, bowel and heart.� High-profile sufferers of the condition include former England cricket captain Mike Atherton.

Now, using a technique known as genome-wide association scanning, researchers led by Professors Lon Cardon, Matthew Brown and Paul Wordsworth, from the Wellcome Trust Centre for Human Genetics at the University of Oxford have analysed DNA samples from 1,000 patients with ankylosing spondylitis and a further 1,500 people unaffected by the disease in search of genetic mutations which, if present, increase a person's risk of developing the disease. The findings from this study were then confirmed by a team at University of Texas (Houston) led by Professor John Reveille.

Ankylosing spondylitis is a painful and often very disabling disease, says Professor Brown. Yet, our understanding of the causes of the disease, and hence our ability to treat it effectively, is relatively poor.

The researchers have identified two genes, ARTS1 and IL23R, which increase the risk of developing the disease. Together with the genetic variant HLA-B27, this takes the number of genes definitely known to be involved in the disease to three. A person carrying all three variants would be expected to have a one in four chance of developing the disease.

The IL23R gene plays a role in the immune response to infection, providing instructions for making a receptor present on the surface of several types of immune system cells. The receptor is involved in triggering certain chemical signals inside the cell that promote inflammation and help coordinate the immune system's response to infection. It is already recognised as playing a role in a number of autoimmune diseases, such as Crohn's disease (a type of inflammatory bowel disease) and psoriasis (a skin disease). Ankylosing spondylitis, Crohn�s disease and psoriasis are known to often occur together, and this genetic finding goes a long way to explain why.

Professor Brown believes that the unexpected involvement of IL23R in ankylosing spondylitis provides a major step towards being able to treat the disease.

We already know that IL23R is involved in inflammation, but no one had ever thought it was involved in ankylosing spondylitis, says Professor Brown. A treatment for Crohn's disease that inhibits the activity of this gene is already undergoing human trials. This looks very promising as a potential treatment for ankylosing spondylitis.

Scientists have known that there is a genetic component to ankylosing spondylitis for 37 years, since the discovery of the gene HLA-B27. However, how this gene led to disease is not known. Professor Brown believes that the gene ARTS1 may hold the answer.

A protein created by the HLA-B27 gene takes fragments of pathogens and displays them on the outside of immune cells. These fragments then trigger the immune system to fight against the pathogen. ARTS1 is involved in breaking up the pathogen into bite-size chunks that can be displayed by HLA-B27.

This strongly suggests that in ankylosing spondylitis, there are problems with the information that the HLA-B27 protein receives, thereby causing the disease, says Professor Brown.

Scientists believe that ankylosing spondylitis may be triggered in genetically-susceptible people by bacteria commonly found in the gut. Why this should be the case is unclear, but it is hoped that the new genetic discoveries will help answer this question.

These findings are very exciting and show the value of exploring the genetics of disease, says Dr Mark Walport, Director of the Wellcome Trust. It usually takes many years between genetic discoveries and new treatments for disease. In this case the two genes discovered to be associated with ankylosing spondylitis provide striking insights into the mechanisms of the disease and offer a possible new pathway for treatment.

The study is a collaboration between the Wellcome Trust Case Control Consortium and the Australo-Anglo-American Spondylitis Consortium funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

�These genetic studies involve large patient samples and require expertise over a wide range of scientific specialities�, says Professor Cardon. �Bringing together these two consortia was the final key that enabled these exciting discoveries.�

Immune cells fighting chronic infections become progressively 'exhausted,' ineffective

Thu, 18 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) (PHILADELPHIA) � A new study of immune cells battling a chronic viral infection shows that the cells, called T cells, become exhausted by the fight in specific ways, undergoing profound changes that make them progressively less effective over time.

The findings also point to interventions that would reverse the changes, suggesting that novel therapies could be developed to reinvigorate T cells that become depleted in their struggle against a virus. Alternatively, strategies that would intentionally trigger the immune-dampening mechanisms explored in the study could prove useful in countering autoimmune disorders in which the immune system is inappropriately activated.

Although the experiments were conducted in mice, the problem of T-cell exhaustion has also been identified in HIV, hepatitis B, and hepatitis C infections in humans, as well as some cancers, such as melanoma. A report on the study results appears in the current issue of Immunity, published online October 18.

�We knew that T cells responding to chronic infections become progressively compromised in many of their functional properties,� says E. John Wherry, Ph.D., an assistant professor in the Immunology Program at The Wistar Institute and lead author on the Immunity study. �Put simply, the T cells become exhausted as time passes. What we wanted to learn in our study was what the specific problems were with these cells and whether their depleted state could be reversed.�

Using a technique called gene-expression profiling, Wherry and his colleagues identified 490 genes whose activity in T cells is altered during a chronic viral infection. Closer study at different time points using a 22-gene subset of the larger group of genes provided molecular signatures of progressive T-cell exhaustion. Only a few changes in the activity of the 22 genes were seen at the end of the first week of infection, increasing to 9 differences at two weeks, 18 differences at one month, and 21 differences at two months. At the end of two months, T cells contending with a chronic infection were sluggish metabolically and immunologically unresponsive to stimulus.

One gene identified as playing a central role in this process is called PD-1, which codes for an inhibitory receptor on the surface of the T cells. By blocking PD-1 in vivo, the researchers found they could alleviate T-cell exhaustion, get more functional T cells, and control the infection better.

�Blocking this one pathway partially reverses T-cell exhaustion in some settings, suggesting that we may be able to intervene to reinvigorate depleted immune cells,� says Wherry. �The T cells undergo many changes during chronic infections, however, so that it will be important to learn how to treat them for multiple problems.�

Wherry notes that the mechanisms involved in T-cell exhaustion also have important upsides.

�The flip side of this process is that the immune system has developed an effective way to turn off its response to a stimulus � which is exactly what one wants to do in the case of autoimmunity,� he says.

He points out, too, that the energy outlay during the acute phase of the immune system�s response to an infection is enormous � and fundamentally unsustainable.

�In the first week of an immune response to a virus, T cells can divide every four to six hours, as fast as any other mammalian cell at any time during development,� Wherry says. �In terms of their rate of division, T cells are in the same category as cells in the earliest stages of embryonic development. The energy involved in doing this is extraordinary, and the body can�t keep that up for an extended period of time.�

Cross-species transplant in rhesus macaques is step toward diabetes cure for humans

Thu, 18 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) St. Louis, Oct. 18, 2007 � With an eye on curing diabetes, scientists at Washington University School of Medicine in St. Louis have successfully transplanted embryonic pig pancreatic cells destined to produce insulin into diabetic macaque monkeys � all without the need for risky immune suppression drugs that prevent rejection.

The transplanted cells, known as primordia, are in the earliest stages of developing into pancreatic tissues. Within several weeks of the transplants, the cells became engrafted, or established, within the three rhesus macaque monkeys that received them. The cells also released pig insulin in response to rising blood glucose levels, as would be expected in healthy animals and humans.

The approach reduced the animals' need for insulin injections and has promise for curing diabetes in humans, says senior investigator Marc Hammerman, M.D., the Chromalloy Professor of Renal Diseases in Medicine. The transplants worked without a need for immune suppression and that is a major obstacle we have overcome.

The researchers' results appear online and will be published in the journal Xenotransplantation in November.

Although the transplants fell short of producing sufficient insulin to cure the macaques' diabetes, Hammerman predicts that with additional research, including the transplantation of additional embryonic pig cells into the animals, he will be able to reduce their need for insulin injections entirely.

The new research follows on the heels of reports by Hammerman and his colleagues demonstrating that transplanted pig pancreatic primordia can cure both type 1 and type 2 diabetes in rats, without using immune suppression drugs. Other scientists have tried different types of pancreatic cell transplants � in animals and humans � as a stepping stone to curing diabetes, but they all require anti-rejection drugs. These drugs must be taken daily to stave off rejection and have adverse effects of their own that limit the success of the transplants.

As a treatment for diabetes in people, pig insulin typically works as well as the human form. Before recombinant DNA technology enabled pharmaceutical companies to manufacture human insulin in the 1980s, pig and cow insulin were routinely given to diabetic patients.

The primates in the current study had type 1 diabetes, the form that occurs when islet cells in the pancreas stop producing insulin all together. The Washington University researchers transplanted 19 embryonic pig pancreatic primordia into each diabetic monkey. Each primordium is smaller than the diameter of a period that ends a sentence and is transplanted into a membrane that envelops the intestines and other digestive organs.

The transplanted cells were retrieved from the pig embryos early in their development, which is believed to render them invisible to the primates' immune system or induce a state of tolerance, either of which eliminates the need for immune suppression.

The researchers determined by multiple methods that the transplanted cells became established within the primates. And as the cells matured, they began to release pig insulin. We found using every method that the cells engraft long-term and, thus, are not rejected by the animals' immune systems, Hammerman says. It's been more than two years since our first transplant was carried out. That particular primate doesn't produce any primate insulin, but has pig insulin circulating in its bloodstream that has reduced by more than 50 percent the amount of injected insulin the animal needs, compared to levels before the transplant. The animals have never received immune suppression drugs.

Two of the macaques remain healthy. One, however, became anemic about six weeks post-transplant and was euthanized a month later after developing acute respiratory distress. The researchers could not find a link between this animal's illness and the pancreatic cell transplants.

The two remaining macaques have each received two transplants of embryonic pancreatic cells. One of the animals has been followed for 23 months after his first transplant, and the amount of insulin he needs to have injected has declined by some 55 percent over baseline levels. The other macaque has been followed for 10 months after his initial transplant, and his need for injected insulin continues to decline over time.

Hammerman and his colleague Sharon Rogers, research instructor in medicine, are leaders in the emerging field of organogenesis, which focuses on growing organs from transplanted embryonic organ precursors known as primordia. Unlike embryonic stem cells, which can become virtually any cell type, primordia are locked into becoming cells of a particular organ.

We are encouraged by these results, Rogers says. The absence of a need for immune suppression in diabetic rats gave us hope that we were on the right track. But many findings in rats do not hold true for species that are more closely related to humans, such as non-human primates. This one did.

The team will now determine how best to eliminate the need for injected insulin in the diabetic macaques that receive transplants, thus demonstrating long-term effectiveness of the technique, and establish the absolute safety of pancreatic primordia transplants. If these experiments succeed, the researchers plan to conduct clinical trials in humans with diabetes.

We hope to find out how to apply our findings to human type 1 and type 2 diabetics because the embryonic pig primordia would represent an unlimited source of tissue for transplantation, Hammerman says.

West Nile virus' spread through nerve cells linked to serious complication

Thu, 18 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Oct. 18, 2007 -- Scientists believe they have found an explanation for a puzzling and serious complication of West Nile virus infection.

Researchers at Washington University School of Medicine in St. Louis and Utah State University showed that West Nile virus can enter a nerve cell, replicate and move on to infect other nearby nerve cells. Viruses traveling this infectious pathway can break into the central nervous system, triggering a condition known as acute flaccid paralysis that leaves one or more limbs limp and unresponsive. No treatment is currently available for this complication. Patients must undergo rehabilitation to relearn to use the affected limb.

Injection of a West Nile virus antibody, created by Washington University and a private biotechnology firm, blocked the complication in laboratory animals. The results appear online in the Proceedings of the National Academy of Sciences.

Preliminary data suggests there will be approximately 4,000 to 5,000 severe West Nile virus infections in the United States in 2007. First isolated in Africa in 1937, West Nile spread to the Middle East, Europe, and Asia before arriving in the United States in 1999. Most infections with the virus are mild or symptom-free, but infections in people with weakened immune systems and those over 50 sometimes lead to serious complications or death.

Senior author Michael Diamond, M.D., Ph.D., associate professor of molecular microbiology, of pathology and immunology and of medicine, began the new study because of a puzzling contrast in the ways West Nile virus infection affects the central nervous system.

One form of infection, encephalitis, causes inflammation of the brain and leads to fever, headaches, weakness and seizures. It is much more likely to occur in patients who are elderly or have weakened or suppressed immune systems. The other form of infection, acute flaccid paralysis, strikes patients with weakened immune systems but also affects a significant number of patients with healthy immune systems.

Based on our mouse model of West Nile virus infection, we already knew that the most likely cause of encephalitis was virus in the blood breaking through the blood-brain barrier to infect the brain, says Diamond. But the epidemiological contrast suggested to us that there might be a fundamentally different infectious mechanism behind paralysis.

In experiments led by Melanie Samuel, a graduate student in Diamond's lab, researchers found that West Nile virus could spread in either direction along the branches of neurons in culture. Samuel used an electron microscope to observe the virus traveling down nerve branches in small capsules known as vesicles. Researchers also found infected nerve cells released virus.

To test their results in an animal model, scientists used a suture to close off the sciatic nerve in hamsters. Then they injected West Nile virus directly into the nerve, either above the suture (i.e., closer to the spine) or below it. Animals who received an injection below the suture came down with encephalitis. But those whose injections were above the suture developed both encephalitis and paralysis because the virus was able to follow the sciatic nerve back to the central nervous system.

An untreated human patient's chances of developing flaccid paralysis from West Nile may come down to a roll of the dice, Diamond speculates. To break through the blood-brain barrier and cause encephalitis, high levels of the virus have to build up in the blood. In the elderly or patients with weakened immune systems, West Nile is able to replicate relatively freely in areas like the skin and lymph tissues, providing additional copies of the virus that build up in the blood.

Paralysis might not require such high levels of infection, he theorizes. What may happen instead is if a mosquito bites you and the virus is able to replicate in the vicinity of a nerve, by the time the immune system has cleared the infection in the skin, a small amount of virus may already be following the nerve back to the spinal cord. Unless you have a robust antibody response, you're probably not going to clear that fast enough, and you might get paralysis.

When scientists injected a therapeutic antibody the day after the viral injection, it blocked both encephalitis and paralysis. The antibody, developed by Washington University and Macrogenics Inc., has been licensed to Macrogenics for commercial development and is in early clinical trials in humans.

We already knew the antibody could block encephalitis, notes Diamond, in whose laboratory the antibody was originally developed. The levels of antibody in the central nervous system are relatively low compared to the rest of the body, but they're still high enough to block paralysis.

Diamond plans follow-up studies to see how long after infection the antibodies can be injected and still retain their protective effect against paralysis. He also plans to test whether the virus is sitting back and passively letting the nerve cell move it along or actively pushing itself forward by manipulating nerve cell physiology.

Diamond and co-author John D. Morrey have a financial interest in the antibody that is regulated in accordance with Washington University's conflict-of-interest policies.

Immune cells promote blood vessel formation in mouse endometriosis

Thu, 18 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A discovery in mice of immune cells that promote the formation of new blood vessels could lead to new treatments for endometriosis, a painful condition associated with infertility that affects up to 15 percent of women of reproductive age.

The formation of new blood vessels, or angiogenesis, is known to encourage the growth of tumors and endometriosis lesions. A team led by Ofer Fainaru, MD, PhD, a research associate in the Vascular Biology Program at Children's Hospital Boston and Harvard Medical School, found that dendritic cells�highly specialized immune cells�help trigger angiogenesis in a mouse model of endometriosis. Their findings were published online last month in the FASEB journal. Judah Folkman, MD, director of Children�s Vacular Biology Program, who helped found the field of angiogenesis, was the paper�s senior author.

Endometriosis occurs when endometrium, a tissue normally found in the inner lining of the uterus, grows elsewhere in the body�most commonly in the abdominal cavity. The misplaced endometrial tissue begins as small lesions, or masses, but once blood vessels are recruited, the lesions grow larger and respond to female hormones, resulting in inflammation, cyclic pelvic pain, and infertility.

In the mouse model, the researchers observed that dendritic cells infiltrate endometriosis lesions, and near the sites where they invade, new blood vessels form. Injecting mice with excess dendritic cells caused their lesions to gain more blood vessels and to grow larger.

The researchers also found that dendritic cells have a strikingly similar effect on intra-abdominal tumors.

When the researchers grew dendritic cells together with endothelial cells�the cells that line blood vessel walls�the endothelial cells migrated towards the dendritic cells. The team hypothesizes that dendritic cells, after embedding in a new lesion or tumor, act like foremen on a building team: they call in, direct and support endothelial cells that build the new blood vessels.

We believe that targeting dendritic cells may prove to be a promising strategy for treating conditions dependent on angiogenesis, such as endometriosis and cancer, says Fainaru. But first, the team must demonstrate that dendritic cells are essential�that without these cells in mice, new blood vessels do not form.

Our next step would be to look for specific dendritic cell inhibitors that could have the potential to block angiogenesis in these conditions, says Fainaru.

The team hopes to develop cell-specific therapy for angiogenesis-dependent diseases that will be more effective and less toxic than current treatments. Currently, the most effective treatment for endometriosis is surgically removing the lesions, but this does not prevent them from growing back�as large and symptomatic as before. If dendritic cells are indeed ringmasters and not sideliners in new blood vessel growth, locally knocking them out just after an initial surgery, or altering them in some way, could render the lesions tiny and harmless.

Similarly, potential dendritic-cell inhibitors, when added to other agents that stop new blood vessels from forming, could enhance doctors� ability to choke off growing tumors, Fainaru adds.

Reunion with patient inspires follow-up study on treatment for DiGeorge syndrome

Tue, 16 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) More than 20 years ago, doctors at Mattel Children's Hospital UCLA performed a successful bone marrow transplant on a baby girl who was born without a thymus gland and was suffering from severe immune deficiency. It marked the first time a bone marrow transplant, rather than a thymic transplant, had been used to treat the genetic condition known as DiGeorge Syndrome (DGS).

The doctors lost track of the young girl when her family moved away but were reunited with her when she returned to UCLA for heart treatment in 2005. Upon rechecking the young woman's immune system, they were pleased to learn that she continued to do well.

Inspired by her positive long-term outcome � along with a handful of other DGS bone marrow transplant patients worldwide � UCLA researchers embarked on a study to follow up on the benefits of bone marrow transplant treatment. Their findings are published in the October 2007 issue of the peer-reviewed Journal of Allergy and Clinical Immunology.

Overall, the researchers found that survival with bone marrow transplant was greater than 75 percent, similar to thymic transplantation.

We believe that this long-term follow-up study indicates that bone marrow transplant is a good procedure � and more readily available than thymic transplantation � for complete DiGeorge syndrome, said co-author Dr. E. Richard Stiehm, professor of pediatrics in the division of immunology, allergy and rheumatology at Mattel Children's Hospital UCLA. This also suggests that the thymus may not be necessary for immune development after birth, or that other tissues, such as the skin, may serve as a thymus equivalent.

DiGeorge syndrome is a common genetic immunodeficiency that occurs in one out of every 2,000 people. The syndrome includes thymic and parathyroid deficiency, chromosome abnormalities, low calcium levels and decreased immunity. Patients often have heart problems and developmental delay, which bone marrow or thymic transplants do not correct. Only a few patients have the severely deficient immune systems characteristic of complete DGS, which is similar to severe combined immunodeficiency (also known as bubble boy syndrome) and is fatal if untreated.

In this first report of extended survival in patients with complete DGS who were treated with bone marrow transplant with long-lasting immune reconstitution, researchers described the medical history and current immune function of two DGS patients who received transplants more than two decades ago. Now in their 20s, both patients lead normal lives free of serious infections and have preserved immune function.

The study also reviewed nine additional cases from other centers internationally and assessed the current status of all patients but one.

The thymus produces hormones that stimulate the production of certain infection-fighting cells. It is also of central importance in the maturation of T-cells (thymic cells), which help build immunity.

According to Stiehm, the thymus gland is the university of the immune system.

Stem cells must go there to be educated before entering the circulation to fight organisms, he said. The thymus continues to put out T-cells for a lifetime. It puts out naive T-cells that are then exposed to microbes to become memory T-cells. It was previously thought that the body needs a continuous supply of new naive cells to keep the immune system functioning, but now we think that maybe it's not necessary, since the memory cells from the donor may serve for a lifetime.

The significance is that adult memory cells from bone marrow, or peripheral blood, can persist in the circulation for several decades and keep the patient well, even though new naive T-cells from the thymus are not produced.

A bone marrow transplant works by replacing the patient's marrow with healthy marrow from a matched donor. Ultimately, the new marrow helps the patient produce normal blood cells.

A thymic transplant is an effective but complicated procedure that involves transferring the thymus tissue of another infant undergoing heart surgery, culturing it, and then surgically implanting it in the patient. It then takes several months for the thymus gland to grow and allow the patient to develop a functioning immune system.

Thymus transplantation is available in the U.S. only at Duke University's medical center. By contrast, bone marrow transplant is a standard procedure available at many large medical centers across the country and internationally.

Feline virus, antiviral drug studied to understand drug resistance

Wed, 10 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) COLUMBUS , Ohio �Researchers at Ohio State will spend the next two years testing their theories about just how an AIDS-like virus in cats is able to resist the powerful medicines that are thrown against it.

It's one of the latest efforts at understanding one of the leading problem areas in medicine today -- antimicrobial drug resistance. When bacteria or viruses become resistant to drugs, they become more difficult, or even impossible, to treat.

The project, funded by the National Institute on Drug Abuse, could reveal how some viral infections become able to withstand antiviral medications and even thrive in the presence of some drugs.

If successful, the research might pave the way to smarter, more effective treatments for a host of pathogens that have learned to resist most therapeutic efforts.

The project grew from important discoveries made five years ago as part of a controversial research program investigating the impact of methamphetamine on feline immunodeficiency virus (FIV) � one of only three animal viruses that can be used to mimick HIV (human immunodeficiency virus) infections in humans.

Surprisingly, that project showed that the virus was able reproduce itself 15 times faster when methamphetamine was present.

The work also showed that FIV mutated rapidly to adapt to grow in astrocytes, the dominant cell type within the brain, and that this phenomenon was accelerated by exposure to methamphetamine.

That observation led to an epiphany of sorts, explained Lawrence Mathes, professor of veterinary biosciences and associate dean for research and graduate studies in the College of Veterinary Medicine and principal investigator on the project.

�If the virus becomes drug-resistant as it routinely mutates into this new form, would that drug resistance occur earlier if methamphetamine were present� he asked.

After an initial phase five years ago that used cats as the animal model for the study, research shifted to more refined work with cell cultures of astrocytes grown in the laboratory, focusing on the changes taking place in individual cells. Mathes reasoned that the same mutated form of FIV would probably be present in the brains of infected cats.

He and his colleagues turned to tissue stored from another decade-old unrelated project that looked at how the virus suppressed the animals' immune systems.

�We went back to those tissues and, in fact, found that the same virus mutations we saw in the cultured cell experiments were present in that brain tissue but only after long-term infection,� he said.

The new research grant will use tissue culture methods to look specifically at how the presence of methamphetamine may increase the virus' ability to resist anitiviral drugs, in this case, a powerful AIDS drug called azidothymidine, or AZT.

�We know a lot about AZT, how it works and what mutations it causes in the virus,� he said. The researchers will treat FIV-infected cell cultures with low concentrations of AZT, forcing it to develop a resistance to the drug, repeating the procedure in the presence of methamphetamine.

�We know how long it normally takes the mutation to appear in the virus. We predict that it will appear earlier in cells exposed to both AZT and methamphetamine,� he said.

Mathes said that the first year of the project is focused on continued in vitro studies using both FIV and cat cell lines as well as parallel experiments with HIV in human cell lines.

If the results are promising, the researchers will test the drugs' interactions with the virus in a small study using two dozen cats in the second year.

Influenza: Insights into cell specificity of human vs. avian viruses

Tue, 09 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Rotterdam, The Netherlands � Researchers have identified which sites and cell types within the respiratory tract are targeted by human versus avian influenza viruses, providing valuable insights into the pathogenesis of these divergent diseases. The report by van Riel et al, �Human and avian influenza viruses target different cells in the lower respiratory tract of humans and other mammals,� appears in the October issue of The American Journal of Pathology and is accompanied by a commentary and highlighted on the cover.

Differences in cellular expression of target molecules correspond to host specificity of influenza viruses. They also define which organs or tissues are infected within the host. For example, highly pathogenic H5N1 avian influenza virus targets cells deep within the lower respiratory tract whereas human influenza virus is thought to target cells of the upper respiratory tract, including the trachea.

To better elucidate the differences between low and highly pathogenic avian influenza virus versus human influenza virus, researchers led by Dr. Thijs Kuiken of Erasmus MC, Rotterdam, The Netherlands, used a technique called virus histochemistry. This method examines the attachment pattern of influenza virus to isolated respiratory tissues, thus identifying the cells targeted by the virus.

When human viruses were tested, both attached strongly to the trachea and bronchi, but virus binding to the bronchioles and alveoli (deeper within the lung) was less abundant in comparison. In contrast, viral attachment of avian viruses was rare in the trachea but more abundant in the bronchioles and alveoli. Further, the cellular targets in the alveoli also differed: human virus preferred type I pneumocytes whereas avian virus bound type II pneumocytes and alveolar macrophages. Interestingly, low and highly pathogenic avian influenza viruses attached to the same cell types, demonstrating that factors other than binding ability must contribute to the pathogenicity.

These data are consistent with the differences in human disease presentation, with human influenza causing tracheobronchitis and highly pathogenic avian influenza causing severe pneumonia. But which animal models are the best for studying the disease in humans To answer this question, the authors next assessed the pattern of virus attachment in animal models used for influenza studies. Of several mammals tested, ferrets, cats, and pigs most closely resembled the human patterns of virus attachment for avian influenza viruses, thus demonstrating their usefulness as models of infection and disease.

These studies �improve our understanding of the pathogenesis of human respiratory tract disease from both human and avian influenza A virus infection,� state the authors. Combined with the results obtained with different animal models, they may lead to a better understanding of the factors that are critical for virus binding and infection, enabling the future development and testing of feasible control strategies.

Accentia announces investigational new drug application for Revimmune for refractory MS

Tue, 09 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) TAMPA, FL�(October 9, 2007)�Accentia Biopharmaceuticals announces that it met with the Food and Drug Administration (FDA) on September 26, 2007 for a scheduled pre-Investigational New Drug (pre-IND) meeting on Revimmune�. The FDA has indicated its support for Accentia to submit an IND for a pivotal Phase 3 randomized controlled, multi-center clinical trial of Revimmune, the company�s potential therapeutic for refractory, relapsing-remitting Multiple Sclerosis (MS). The FDA indicated that they support the proposed submission from Accentia and that they are in overall agreement with the proposed design of the Accentia clinical program.

The Revimmune MS study will enroll subjects in a one-year study comparing baseline disability to disability at month 12 with an interim data analysis. After consultation with the FDA on the design of the trial, it was agreed that the primary endpoint will be recovery of lost function and that this unique study will be done under a special protocol assessment (SPA). Accentia will proceed diligently with submission of the IND under a SPA and of an application for Fast Track status, and currently projects commencement of the Phase 3 study in the first half of 2008. A Special Protocol Assessment is a declaration from the Food and Drug Administration that a proposed Phase 3 trial 's design, clinical endpoints, and statistical analyses are acceptable for FDA approval. All prior approved therapeutics suppress rather than eliminate autoimmunity and they have used the more limited indication of a reduction in the rate of progression of disability as their primary endpoint, not a reduction in disability as for Revimmune.

Revimmune is the first drug to propose restoration of lost function in MS patients. Using a patent-pending, ultra-high intensity, short-course of an intravenous formulation of cyclophosphamide, Revimmune is intended to �reboot� a patient�s immune system, thereby eliminating autoimmunity, whereas current therapies, including oral cyclophosphamide, are used chronically to attempt to suppress the inflammation of autoimmunity. Based on long-term follow-up with patients that showed complete remissions in previous studies, there is substantial evidence that Revimmune has the potential to cure cases of severe refractory autoimmune diseases, including aplastic anemia and myasthenia gravis. Revimmune uses a drug approved for other indications at other doses.

Developed by Dr. Richard Jones, Dr. Robert Brodsky, and colleagues at the Johns Hopkins University School of Medicine, Revimmune temporarily eliminates peripheral immune cells, including the immune cells causing the autoimmunity, while selectively sparing hematopoeitic stem cells in the bone marrow. Investigators at Johns Hopkins discovered that stem cells are unique in having high levels of a particular protective enzyme that can be measured in advance of therapy, which makes them impervious to Revimmune, and allows the surviving stem cells to give rise to a new immune system over two to three weeks. The newly reconstituted peripheral immune system typically lacks the misdirected immunity to self-antigens, which is characteristic of autoimmune diseases.

Revimmune can be administered as an inpatient or outpatient infusion for four hours per day for four consecutive days. The treatment is intended to allow patients to recover at home while their immune system reconstitutes itself over a two to three week period. Revimmune includes a risk management program to enhance patient safety by ensuring appropriate patient selection, supportive care, and tracking of outcomes data.The principal investigator for the Phase 2 study with Revimmune at Johns Hopkins University School of Medicine is Dr. Douglas Kerr, associate professor of neurology. The co-principal investigators on this study are Dr. Daniel Drachman, Dr. Robert Brodsky, and Dr. Adam Kaplin. The National Multiple Sclerosis Society has supported the clinical protocol at Johns Hopkins University.

Stress contributes to range of chronic diseases, Carnegie Mellon psychologist says

Tue, 09 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) PITTSBURGH -- In a review of the scientific literature on the relationship between stress and disease, Carnegie Mellon University psychologist Sheldon Cohen has found that stress is a contributing factor in human disease, and in particular depression, cardiovascular disease and HIV/AIDS. Cohen�s findings will be published in the Oct. 10 issue of the Journal of the American Medical Association (JAMA). The article was co-authored by Denise Janicki-Deverts of Carnegie Mellon and Gregory E. Miller of the University of British Columbia.

Cohen�s JAMA article was based on a paper commissioned by the Institute of Medicine to examine the evidence that stress influences major diseases. In the JAMA article, the authors consider the behavioral and biological mechanisms through which stress contributes to disease and weigh the results of studies that have examined whether stress plays a role in depression, cardiovascular disease, HIV/AIDS and cancer. Those studies reveal that stress plays a role in triggering or worsening depression and cardiovascular disease and in speeding the progression of HIV/AIDS.

�The majority of people confronted with even traumatic events remain disease-free. Stress increases your risk of developing disease, but it doesn�t mean that just because you are exposed to stressful events, you are going to get sick,� said Cohen, the Robert E. Doherty Professor of Psychology at Carnegie Mellon.

According to the authors, the strongest evidence that stress contributes to disease comes from research on depression, which shows that stress is associated with the onset of depression as well as relapse in people who have recovered from it. Cohen said that particular types of stress are the biggest culprits in depression, namely �social stressors� such as divorce and the death of a loved one. Depression also is common among people who have been diagnosed with a serious illness, suggesting that physical disease itself is a stressful event that can lead to depression. On the other hand, chronic stress -- such as stress experienced daily in the workplace -- contributes to cardiovascular illnesses such as coronary heart disease, a relationship that medical studies have clearly demonstrated, Cohen said.

Results of research on the relationship between stress and HIV/AIDS have been less clear, but since 2000 studies have consistently demonstrated a link between stress and the progression of AIDS. Cohen said that the impact of stress may have become more pronounced in recent years because of the complex and demanding drug regimen that AIDS patients now undergo. He said stress may tax their ability to keep up with their treatment. In the JAMA paper, the authors also note that changes in the autonomic nervous system caused by stress may also contribute to disease progression by influencing the replication of the HIV virus.

�Individuals differ with regard to rate of progression through the successive phases of HIV infection. Some remain asymptomatic for extended periods and respond well to medical treatment, whereas others progress rapidly to AIDS onset, and suffer numerous complications and opportunistic infections. Stress may account for some of this variability in HIV progression,� the authors write.

Exactly how stress causes and contributes to disease is a question of particular interest to researchers. Cohen said there are two likely pathways. One is behavioral -- people under stress sleep poorly and are less likely to exercise; they adopt poor eating habits, smoke more and don�t comply with medical treatment. Stress also triggers a response by the body�s endocrine systems, which release hormones that influence multiple other biological systems, including the immune system.

�Effects of stress on regulation of immune and inflammatory processes have the potential to influence depression, infectious, autoimmune, and coronary artery disease, and at least some (e.g., viral) cancers,� the authors write.

Studies on the role of stress in cancer have not been consistent in their results. Researchers who study the influence of stress on the progression of cancer face many hurdles, according to Cohen and his colleagues. Cancer can go undiagnosed for a long time, and its progression is difficult to measure with much precision. There are many types of cancers, and it is possible that stress only influences those facilitated by sustained hormonal response and impairments in immunity.

�We will need additional studies across a broader range of cancers before we can fairly evaluate the role of stress in cancer,� Cohen said.

Patients with pneumonia who received pneumococcal vaccine have lower rate of death, ICU admission

Mon, 08 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Among patients hospitalized with community-acquired pneumonia, those who had previously received the pneumococcal vaccine had a lower risk of death and admission to the intensive care unit than patients who were not vaccinated, according to a report in the Oct. 8 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

Community-acquired pneumonia is a common condition resulting in considerable illness and death, according to background information in the article. A vaccine against Streptococcus pneumoniae, one of the causes of pneumonia�23-valent polysaccharide pneumococcal vaccine (PPV)�has been available since 1983. Most guidelines recommend PPV for those at high risk of developing pneumonia, including older adults and nursing home residents. However, some doubts have been raised about the effectiveness of PPV, and vaccination rates remain below the target 80 percent to 90 percent in these populations.

Jennie Johnstone, M.D., and colleagues at the University of Alberta, Edmonton, Canada, collected data on 3,415 patients with community-acquired pneumonia admitted to six hospitals between 2000 and 2002. The patients� vaccination status was determined through interviews, medical record reviews, contact with primary care physicians and records from the regional office of community health.

Of the patients, 22 percent had been vaccinated with PPV, and 624 died or were admitted to the intensive care unit (ICU). Those who had been vaccinated with PPV were less likely to die or be admitted to the ICU than those who had not been vaccinated (10 percent vs. 21 percent). This finding was mostly a result of lower ICU admissions�less than 1 percent of those vaccinated were admitted to the ICU, compared with 13 percent of those who were not vaccinated. Results were similar when the researchers looked only at patients older than 65 or those living in nursing homes�groups for whom universal PPV vaccination is recommended.

�In addition to improved clinical outcomes, our results suggest that there may also be an associated reduction in costs associated with pneumococcal vaccination, a health economic benefit that has not been captured in previous cost-effectiveness analyses of this vaccine,� the authors write. �Specifically, much of the benefit in our study was in terms of reduction in the need for costly ICU admissions; previous cost analyses have been restricted to examining the benefits of preventing pneumococcal disease but may have not adequately captured the possibility of attenuating the severity or mitigating the cost of disease in those for whom pneumonia is not prevented.�

Although 2,416 of the patients were eligible for vaccination upon being discharged from the hospital, only 215 (9 percent) received PPV at this time. �We believe that our results further the emphasize the importance of adopting current adult pneumococcal vaccination guidelines, particularly since only 22 percent of our population were vaccinated before their hospitalization and less than 10 percent of eligible patients were vaccinated before hospital discharge,� the authors conclude.

NIH grant supports UCSF research exploring early HIV infection

Mon, 08 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) A team led by researchers at the UCSF Positive Health Program has been named to receive $15 million over five years to expand understanding of the complex interactions between HIV and the immune systems of newly infected patients following HIV transmission.

The grant is being awarded by the National Institute of Allergy and Infectious Diseases, an arm of the National Institutes of Health.

�The program will provide an important platform for innovative research into HIV transmission and early infection in patients and aims to provide new clues for developing a vaccine and improving therapeutic outcomes,� said the grant�s primary investigator, Frederick Hecht, MD, professor of medicine at the UCSF Positive Health Program at San Francisco General Hospital Medical Center.

The research will be based on two clinical cohorts of recently infected patients: the

�The inclusion of the Brazil cohort allows us to look at two HIV subtypes simultaneously. Subtype C predominates in Sub-Saharan Africa and subtype B predominates in North America, though both are common in Southern Brazil. This provides us with a natural research study for understanding competing HIV subtypes,� said Hecht.

The overall grant aims to understand the viral and host factors that favor or block HIV transmission on a biological level and the factors that favor good control of early HIV infection by newly infected patients. The program is composed of four projects.

One project, led by Hecht, will focus on the transmission and persistence of two types of HIV resistance mutations. Some are caused by infection with HIV variants that have resistance mutations caused by exposure to antiretrovirals. Understanding how easily these mutations occur and how long they persist is important for long-term forecasting of the effectiveness of antiretroviral regimens in populations.

The other types of resistance mutations are those that allow the virus to escape an infected patient�s specific T-cell immune responses. HIV mutates constantly, thereby escaping attack from the body�s targeted T-cell defenses that are meant to kill the virus, and eventually eludes effective control in most individuals. Understanding this process could assist in vaccine development.

A second project, led by Steven Deeks, MD, of the Positive Health Program, examines properties of the outside of the HIV virus�the envelope�and how they influence HIV transmission and evolve in a newly infected individual after transmission. These envelope properties determine which cells most easily will succumb to infection with the virus. In addition, the envelope properties of HIV may affect the virus�s capacity to damage the immune system and determine how readily it is transmitted.

A third project, led by the UCSF-affiliated Gladstone Institute of Virology and Immunology�s Robert Grant, MD, MPH, is focused on superinfection, which is infection with a second HIV virus on top of a preexisting infection. The project will study how readily this occurs in early HIV infection�which appears to be the most vulnerable period for superinfection�and what factors may prevent it.

The fourth project, led by Douglas Nixon, MD, PhD, of the UCSF Division of Experimental Medicine, tests whether new immune responses, following HIV transmission to a newly infected patient, help to reverse some of the mutations that allowed the virus to escape immune responses in the HIV-individual who transmitted the virus.

How Candida albicans transforms from its normally benign form into life-threatening form

Thu, 04 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers at the Agency for Science, Technology and Research's (A*STAR) Institute of Molecular and Cell Biology (IMCB) have discovered new molecular mechanisms that provide a more detailed understanding of how the normally benign Dr. Jekyll-like fungus known as Candida albicans transforms into a serious and often life-threatening Mr. Hyde-like form.

C. albicans can cause serious and potentially life-threatening infections in the mouth, blood and other tissues of people who are undergoing cancer chemotherapy or radiation treatments, or who have developed AIDS or other diseases that damage the immunity of the individual.

In two separate papers published last month in Developmental Cell and in August in the EMBO journal, the team of scientists led by Wang Yue, principal investigator at IMCB, have managed to reveal previously unknown mechanisms which are responsible for causing the infectious phase of C. albicans.

The fungus starts its 'attack' on a patient by changing its oval shape into a filamentous form, which has thin, threadlike appendages emerging from the cell body. Wang's team, who has been studying C. albicans for more than seven years, was responsible for identifying the master controller protein called Hgc1 in 20041.

This controller functions like a regulator and tells the fungus when to start the transformation from the harmless oval shape to the infectious filamentous form.

One question remained, however - how does it activate the cellular machineries that determine the fungal cell shape? said Wang.

Wang's team found the answer to this question in two proteins called Rga2 and Cdc11. They discovered that they each function like a switch on two different cellular machineries that normally determines cell shape. The master regulator Hgc1 acts like the 'finger' that flips the switches to start the infection process, said Wang.

Our findings have uncovered detailed molecular mechanisms which define how these two proteins interact with the master 'controller' to cause infections. Thishas opened new opportunities for us to investigate further into a new range of therapeutic targets for fungal infections, explained Wang.

In the same issue of Developmental Cell, the team's work was given an expert mention by a leading C. albicans researcher, Dr. Peter Sudbery, stating its importance in bringing awareness of the cellular processes that is necessary for C. albicans to transform to its infectious state.

In addition, the new knowledge of the detailed interaction of these proteins with other cellular machineries has also revealed critical information on how cells in general determine their shape, a fundamental question in biology as Rga2 and Cdc11 are also found in nearly all eukaryotic organisms.

Largely due to the AIDS pandemic in the last 25 years, the once nearly harmless and commensal fungus Candida albicans has become one of the most prevalent microbial pathogens in AIDS patients, causing life-threatening infections with high death rate, especially in infected children.

Scripps research scientists develop innovative dual action anthrax vaccine-antitoxin combination

Thu, 04 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) The immune response generated in rats by the new agent protects against lethal toxin exposure after only one injection, and is faster and stronger than any currently available vaccine.

The new study, led by Scripps Research scientists Anette Schneemann and Marianne Manchester, and Salk Institute Professor John A.T. Young, was published in the October 5 issue of the journal PLoS Pathogens (Volume 3, Issue 10).

�The new anti-anthrax agent that we developed is an important and potentially critical development for anyone who works with the bacterium or those who might be exposed to it in a bioterrorism attack,� Schneemann said. �While other strategies are being pursued to develop improved anthrax vaccines, none of these offer the distinct advantage of combining the function of a vaccine with a potent antitoxin.�

Concerns about anthrax-a potentially fatal disease caused by the spore-forming, gram-positive bacterium Bacillus anthracis-as a weapon of bioterrorism has prompted increased efforts to develop better antitoxins and vaccines. The current vaccine, which was developed in the 1950s, is safe and effective, but requires multiple injections followed by annual boosters. Current anthrax treatment involves antibiotics such as ciprofloxacin and doxycycline that attack the bacteria but provide no protection against the dangerous toxins secreted by the bacteria.

The new study introduces a highly effective dual-action compound that leapfrogs current efforts to develop a second-generation anthrax vaccine. In the research, the scientists created a �multivalent display,� with several sites of attachment for recombinant protective antigen protein (PA), the primary component of the current anthrax vaccine, rather than only one. Virus-like particles coated with PA were found to produce a potent toxin-neutralizing antibody response that protected rats from the lethal anthrax toxin after only a single immunization.

The antitoxin strategy arose from the discovery of the anthrax toxin receptor, ANTXR2, in the Young lab. �The new anti-anthrax agent is based on a multivalent display of ANTXR2 on the surface of an insect virus,� explains Schneemann. �Our approach was based on the assumption that a multivalent display of recombinant protective antigen protein would induce a far more potent immune response. That turned out to be correct.�

Specifically, the new vaccine-antitoxin combination is based on the multivalent display (180 copies) of the PA-binding von Willebrand A (VWA) domain of the ANTXR2 cellular receptor on the Flock House virus. The chimeric virus-like particle platform, which produces protective immunity and has been shown to be safe, inhibited lethal toxin action in in vitro and in vivo models of anthrax infection.

In fact, rats survived exposure to the toxin four weeks after a single injection of the new double-acting agent. This result suggests an extremely rapid production of neutralizing antibodies without the use of an adjuvant, a secondary agent that helps stimulate the immune system and is often used to increase the vaccine response-key goals for the development of third-generation anthrax vaccines.

In addition to its use against anthrax, Schneemann notes that creating a multivalent platform may also have the potential to work against other infectious agents.

�One important reason for the success of this project is that it arose from the multidisciplinary and highly collaborative efforts of our team of microbiologists, structural biologists, and immunologists,� said Manchester, who headed a National Institutes of Health (NIH)-funded program project grant that supported the work.

Flu vaccine in painless skin patches under development at Emory, Georgia Tech with NIH grants

Wed, 03 Oct 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Flu vaccine delivered through painless microneedles in patches applied to the skin could soon be an alternative to delivery through hypodermic needles, according to researchers at Emory University and the Georgia Institute of Technology. Using new grants from the National Institutes of Health (NIH) totaling approximately $11.5 million over five years, researchers from the two institutions plan to develop a new vaccine product using the microscopic needles.

A vaccine administered through a skin patch would have a number of advantages, including less discomfort to the recipients, lower cost and reduced production time, says Richard Compans, PhD, professor of microbiology and immunology in the Emory School of Medicine. Potentially, individuals could administer the vaccine to themselves, perhaps after receiving it in the mail.

The Georgia Tech and Emory team plans to develop and assess the effectiveness of transdermal patches that include arrays of microscopic needles containing or coated with vaccine. They hope to design patches that could be stored for long periods of time at room temperature and that will increase the breadth and duration of immunity to influenza � perhaps with smaller amounts of vaccine.

We expect that this research will lead to a better way of delivering the flu vaccine, which will allow more people who need it to receive the immunization in a convenient and effective way, says Mark Prausnitz, PhD, a professor in the Georgia Tech School of Chemical and Biomolecular Engineering. Beyond that, the possibility of replacing a hypodermic needle with a microneedle patch should significantly impact the way that other vaccines are delivered.

The project team has extensive experience in microneedle development, influenza vaccines, vaccine delivery systems, product development and interdisciplinary collaboration. Beyond influenza, the research could have implications for immunization programs in developing countries, where eliminating the use of hypodermic needles could make vaccines more widely available and address the problem of disease transmission caused by the re-use of conventional hypodermic needles.

In April the NIH awarded a $32.8 million, seven-year contract to Emory, along with the University of Georgia, to establish the Emory/UGA Influenza Pathogenesis and Immunology Research Center, for which Dr. Compans is principal investigator. The center is working to improve the effectiveness of flu vaccines through a number of different projects studying how influenza viruses attack their hosts, how they are transmitted, and what new immune targets might be identified for antiviral medicines.

Dr. Prausnitz and his colleagues have been working since the mid 1990s to develop microneedle technology for painless drug and vaccine delivery through the skin. Much smaller than conventional hypodermic needles, the microneedles in the arrays are made of titanium, stainless steel or various polymers--including some that could dissolve into the skin, carrying vaccine with them. The Georgia Tech team has also developed manufacturing processes for microneedle patches and tested the ability of the needles to deliver proteins, vaccines, nanoparticles, and small and large molecules through the skin.

We expect microneedles to be less painful than conventional hypodermic needles because they are too small to significantly stimulate nerve endings, says Dr. Prausnitz. The NIH grants will allow us to move forward with perfecting the manufacturing process, refining the techniques for optimally inserting the microneedles into the skin and ensuring that vaccine delivered this way produces the necessary immune response.�