Cedars-Sinai Medical Center : Erectile dysfunction drugs allowed more chemotherapy to reach brain tumors in laboratory study

The drugs blocked an enzyme and opened blood vessels to tumors but not normal brain

LOS ANGELES (July 28, 2008) – In a study using laboratory animals, researchers found that medications commonly prescribed for erectile dysfunction opened a mechanism called the blood-brain tumor barrier and increased delivery of cancer-fighting drugs to malignant brain tumors.

The experiments were conducted at Cedars-Sinai Medical Center's Maxine Dunitz Neurosurgical Institute and published in Brain Research.

Viagra (sildenafil) and Levitra (vardenafil) are known as PDE5 inhibitors because they block an enzyme, phosphodiesterase5, which interrupts a series of biochemical events that cause the decreased blood flow of erectile dysfunction. This laboratory rat study, published online ahead of print in the journal, found that similar biochemical interactions in the small vessels of the brain play a major role in the blood-brain tumor barrier, which impedes delivery of anti-tumor drugs into brain tumors. PDE5 inhibitors were found to open the barrier and increase drug transport in this early animal study.

Although the normal blood-brain barrier, which regulates access to the brain from the bloodstream, shares many characteristics with the blood-brain tumor barrier, the signaling mechanism blocked by PDE5 inhibitors is unique to the blood-brain tumor barrier. This allows the PDE5 inhibitors to selectively increase drug transport to malignant brain tumors without affecting normal brain tissue.

According to the researchers, these findings may have significant implications in improving drug delivery to brain tumors in patients.

"This is the first study to show that oral administration of PDE5 inhibitors increases the rate of transport of compounds across the blood-brain tumor barrier and improves the effectiveness of the anti-tumor drug adriamycin in the treatment of brain tumors in a rat model. We chose adriamycin for this study because it is one of the most effective drugs against brain tumor cell lines in the laboratory but it has very little effect in animals and humans because it is unable to cross the blood-brain tumor barrier. The combination of vardenafil and adriamycin resulted in longer survival and smaller tumor size," said neurosurgeon Keith L. Black, M.D., chairman of the Department of Neurosurgery at Cedars-Sinai Medical Center and director of the Maxine Dunitz Neurosurgical Institute.

Black, the article's first and corresponding author, has been recognized for his earlier groundbreaking work to break through the blood-brain tumor barrier with natural and synthetic bradykinin, a peptide that temporarily opens the barrier and increases anti-cancer drug delivery into certain tumors by more than 1,000 percent. In 2000, he received the Javits Neuroscience Investigator Award from the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, for his blood-brain barrier research.

In the current studies, the blood-brain tumor barrier-opening effects of PDE5 lasted considerably longer than those of bradykinin and allowed greater transport across the barrier into tumor tissues. Because vardenafil was found to be more effective than sildenafil in increasing blood-brain tumor barrier permeability and transport, vardenafil was used in a survival study of 29 tumor-bearing rats. Those treated with saline (control) survived 32 days on average while those treated with vardenafil alone survived about 35 days and those treated with adriamycin alone survived about 42 days. When vardenafil was combined with adriamycin, rats survived an average 53 days.

Although the researchers exposed the laboratory animals to doses of sildenafil and vardenafil that are comparable to the dose range approved for erectile dysfunction in humans, there were no detectable side effects in the rats, and neither drug increased transport of tracers into normal brain tissue.

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Funding for the studies was provided by the National Institute of Neurological Disorders and Stroke (the Javits Award), the Maxine Dunitz Neurosurgical Institute and the Ruth and Lawrence Harvey Chair in Neuroscience, held by Black.

Citation: Brain Research, "PDE5 Inhibitors Enhance Tumor Permeability and Efficacy of Chemotherapy in a Rat Brain Tumor Model," available online ahead of print.

Society for Experimental Biology and Medicine : Imiquimod, an immune response modifier, is dependent on the OGF-OGFr signaling pathway

Researchers at The Pennsylvania State University College of Medicine, Hershey, Pennsylvania have discovered that the efficacy of imiquimod, a clinically important immune response modifier with potent antiviral and antitumor activity, is dependent on the Opioid Growth Factor (OGF)-OGF receptor (OGFr) axis for its action. This discovery, reported in the August 08 issue of Experimental Biology and Medicine, provides new insights into a widely used drug that may lead to development of new agents that will enhance effectiveness and attenuate side-effects.

Imiquimod and resiquimod are imidazoquinoline compounds. Imiquimod (Aldara, R-837, S26308), the best characterized and most widely used, is highly efficacious in the treatment of external genital and anal warts, basal cell carcinoma, actinic keratoses, Kaposi's sarcoma, chronic hepatitis C infection, and intraepithelial carcinoma. Therefore, the underlying mechanism of imiquimod action is of clinical importance. Imiquimod has been reported to be a toll-like receptor-7 agonist, and its anti-tumor effect exerted by modification of the immune response and stimulation of apoptosis. The mechanism of imiquimod on cell proliferation is unclear.

The research team, led by Dr. Ian S. Zagon, Distinguished University Professor, and Dr. Patricia J. McLaughlin, Professor, along with a pre-doctoral student Renee N. Donahue, in the Department of Neural & Behavioral Sciences and collaborator Moshe Rogosnitzky of MedInsight explored mechanisms responsible for the remarkable clinical action of this class of drugs. Specifically, using tissue culture models, the investigators found that imidazoquinolines upregulate OGFr which in turn stimulates the interaction of the OGF-OGFr axis. This native, tonically active inhibitory pathway is known to regulate cell proliferation by modulating cyclin dependent kinase inhibitors, resulting in a retardation of cells at the G1-S interface of the cell cycle. Neutralization of OGF or knockdown of OGFr by siRNA technology eliminated the inhibitory effects of imidazoquinolines on cell replication. "Thus our data," Dr. Zagon said, "brings a paradigm shift to our thinking about a drug widely used in the clinics. Rather than imiquimod activity being mediated by induction of various cytokines, including interferon (IFN)-α, IFN-γ, tumor necrosis factor-α (TNFα) interleukin (IL)-1α, and IL-12 as currently thought, an entirely new pathway - native to body chemistry - has been discovered to regulate cell proliferation by imidazoquinolines." Co-author, Moshe Rogosnitzky adds: "The elucidation of imiquimod's immune-independent mechanism of action in cancer also creates exciting new therapeutic possibilities for a number of non-cancer conditions, and these are now being further explored. Such studies could lead to new off-label applications for imiquimod as well as development of imiquimod analogues and unique combination therapies." Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine stated "Through decades of elegant and ground-breaking work, Zagon and colleagues have identified the role of met-enkephalin (the opioid growth factor –OGF) and the OGF receptor in regulating cell proliferation. The current study demonstrates that the mechanism of imidazoquinoline activity is via OGF and OGFr which will have a profound impact on its use as a therapeutic for cancer and many other non-cancerous disorders."

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Experimental Biology and Medicine is a journal dedicated to the publication of multidisciplinary and interdisciplinary research in the biomedical sciences. The journal was first established in 1903.

Experimental Biology and Medicine is the journal of the Society of Experimental Biology and Medicine. To learn about the benefits of society membership visit www.sebm.org. If you are interested in publishing in the journal please visit www.ebmonline.org.

Infectious Diseases Society of America : Booster vaccination may help with possible future avian influenza pandemic

New evidence suggests that a booster vaccination against H5N1 avian influenza given years after initial vaccination with a different strain may prove useful in controlling a potential future pandemic. The study is published in the August 1 issue of The Journal of Infectious Diseases, now available online.
H5N1 continues to pose a major health risk to birds and humans. As of mid-June, more than 60 percent of the more than 380 human cases have been fatal, and hundreds of millions of birds have died or been culled to prevent the spread of the disease. Should the virus evolve making human-to-human transmission more likely, a destructive global influenza pandemic could result.
The cornerstone of planning for such a possible pandemic is the development and distribution of effective vaccines. Several vaccines have been developed, but as the virus continues to mutate into genetically distinct lineages, or clades, the problem arises as to whether vaccines based on an older clade will be effective against newer versions. The new study is the first to report that giving one dose of a newer-clade vaccine to those who were vaccinated previously with older versions is more effective than giving only doses of the newer vaccine to unvaccinated subjects.
The study, conducted by Nega Ali Goji, MD, and colleagues from New York, Maryland, and Alabama, gave a single booster dose of a vaccine based on a clade 1 H5N1 virus circulating in Vietnam in 2004 to subjects who eight years earlier had received two doses of a vaccine based on the original, clade 0 virus that appeared in Hong Kong in 1997. Sixty-four percent had a positive immune response, which compares favorably to the results of a previous study using two doses of the clade 1 Vietnam virus, in which only 43 percent of those vaccinated had a positive immune response.
The results not only support the booster technique, but also show that even though the virus had mutated since the initial vaccination, using it to boost an earlier vaccine is more effective than simply vaccinating subjects with the most current vaccine. These findings are important given the fact that influenza viruses are mutating constantly.
"These results suggest that one strategy for pandemic control could involve prevaccination of some segments of the population prior to the emergence of a pandemic so that effective protection could be achieved with a single dose schedule if and when a pandemic emerges," the authors wrote. "If the finding that priming can result in enhanced responses to single-dose vaccination schedules were confirmed, then pre-pandemic vaccination programs could be considered, especially in populations of first responders, health care workers, or the military. Such populations might then be able to be effectively and rapidly vaccinated with a single dose of a vaccine specific for an emerging pandemic if it were to occur."
In an accompanying editorial, Gregory A. Poland, MD, of the Mayo Clinic College of Medicine, noted that some are already looking to begin such prevaccination primers against H5N1 influenza. For example, Japan is planning to immunize health care workers starting in 2009, and the U.S. Department of Defense is offering a vaccine to those in high risk specialties.
Dr. Poland pointed out that new studies are needed to investigate different types of vaccine administration, deal with vaccinations that prevent death but not infection and illness, search for more broadly cross-protective influenza vaccines, and collect data on the vaccination of those who are not healthy adults. Although, he said, "determining who should receive these vaccines, when, and in what order and under what circumstances deserves widespread debate," he agrees that the findings of the study are novel, as they "suggest that such a prime-boost strategy using vaccines derived from different H5 clades, separated by years, may be worthwhile, immunologically feasible, and safe."
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Fast Facts
1) Experts are concerned about a possible pandemic of H5N1 influenza. As of mid-June, 60 percent of the more than 380 human cases have been fatal, and half a billion birds have died or been culled to prevent the spread of the disease. Should the virus evolve making human-to-human transmission more likely, a destructive global influenza pandemic could result.
2) Giving a "booster" vaccine using a recent strain of virus to those previously vaccinated with an older strain was more effective than only vaccinating with the recent strain. Especially relevant is the fact that the primer and booster vaccines were derived from different strains of the virus and still were effective.
Founded in 1904, The Journal of Infectious Diseases is the premier publication in the Western Hemisphere for original research on the pathogenesis, diagnosis, and treatment of infectious diseases; on the microbes that cause them; and on disorders of host immune mechanisms. Articles in JID include research results from microbiology, immunology, epidemiology, and related disciplines. JID is published under the auspices of the Infectious Diseases Society of America (IDSA). Based in Arlington, Va., IDSA is a professional society representing more than 8,000 physicians and scientists who specialize in infectious diseases. For more information, visit www.idsociety.org.

Medical College of Georgia : Nuclear stress test can detect more than blockages

A less invasive test commonly used to diagnose coronary disease also may be used to detect one of the leading causes of heart failure, say researchers at the Medical College of Georgia.

By using a nuclear stress test to look at how fast blood flows into the heart’s pumping chamber – the left ventricle – they can determine if a patient’s left ventricle is having trouble.

When the ventricle fails to properly fill with blood because it’s stiff and unable to relax, it’s called diastolic dysfunction, accounting for 40 to 60 percent of patients with heart failure, according to the American Heart Association. When it occurs, the left side of the heart pumps too little blood while the right side continues to pump normally, and the lungs fill up with blood.

"If someone has a slow fill rate, that means the left ventricle is not relaxed enough to get enough blood," says Dr. Dineshkumar Patel, internal medicine resident. "And if the left ventricle cannot receive enough blood, then it cannot collect enough blood to be pumped out to the rest of the body. There is a four-fold increase in morbidity and mortality when diastolic dysfunction is present in patients with coronary disease."

It is easier for physicians to test how well the heart pumps, called systolic function, using an echocardiogram and cardiac catheterization, says Dr. Patel.

An echocardiogram utilizes an ultrasound beam that travels through the front of the chest wall and lungs to the heart, and cardiac catheterization is a very invasive procedure using a thin plastic tube which is inserted into an artery or vein in the arm or leg and advanced into the chambers of the heart.

"But not all patients can undergo this test because it is so invasive," Dr. Patel adds. "And it's difficult to diagnose diastolic dysfunction with these [tests] when the systolic function is normal because you can have a perfectly normal pumping heart and still have this condition."

Dr. Patel collaborated with Dr. Vincent J.B. Robinson and looked at 52 consecutive patients who underwent cardiac catheterization within 15 days of a nuclear stress test to test the efficacy in diagnosing diastolic dysfunction.

During a nuclear stress test, radioactive thallium is injected into the bloodstream to show how well blood flows to the heart muscle. Scans are taken shortly after an exercise test to show blood flow when the heart is stressed and two or three hours later to show blood flow during rest.

"This test is usually used to identify blockages in the heart," Dr. Patel explains. "But in addition to the blockages, we have demonstrated that it also shows the left ventricle filling pressure, thus giving us an excellent prognostic value in predicting diastolic dysfunction because when the filling pressure is too high, the left ventricle has a hard time receiving blood."

Dr. Patel and the MCG nuclear cardiology research team compared the diastolic filling pressure from the catheterization and from the nuclear stress test and found that the latter had a 94 percent specificity in detecting diastolic dysfunction.

The nuclear stress test plots out a heartbeat in 16 frames, and that represents the diastolic filling curve at 16 points, like taking a melon and slicing it into 16 even pieces, says Dr. Robinson, nuclear cardiologist at MCG and the Charlie Norwood Veterans Affairs Medical Center of Augusta and faculty adviser on the study. The slope of the filling portion of the curve is a representation of the left ventricle filling pressure used as a marker of diastolic dysfunction.

"We have discovered that just looking at these markers can tell us whether a patient has diastolic dysfunction or not,” says Dr. Robinson. "Diastolic function is a major prognostic factor in these patients with coronary disease. Previously, the nuclear stress test was only detecting diastolic dysfunction in patients who were already sick, whose hearts were weak and barely pumping.

"In other words, the test only picked up patients who had diastolic and systolic dysfunction," he says. "But now, we can use the diastolic filling curve on a nuclear stress test to diagnose patients with diastolic dysfunction who have normally squeezing hearts."

You can be in great physical shape and still have diastolic dysfunction, says Dr. Patel. "We can prevent heart failure before you start complaining of chest pain and shortness of breath."

Dr. Patel's study was published in the May issue of the Journal of Nuclear Medicine. He is one of five finalists worldwide of the prestigious American Heart Association's Melvin Judkins Young Clinical Investigator Award, which recognizes meritorious research from early career investigators and promotes careers in cardiovascular radiology.

MCG news categories related to this story:

Cardiovascular Disease
Faculty
Students
School of Medicine

University of Cincinnati : Farming at young age may lead to bone disease in adulthood

Although farm chores are likely to keep young boys in shape and out of trouble, University of Cincinnati (UC) environmental health experts caution that it could be harmful to overall bone health if done too often at a young age.

A UC research team recently reported data suggesting that excessive weight-bearing activities—such as squatting, kneeling or lifting—can affect the mechanical properties of developing bone. They say this could leave junior farmers more susceptible to degenerative skeletal disorders later in life.

"Research has clearly shown that healthy adults who engage in excessive weight-bearing activities often develop bone disorders," explains Amit Bhattacharya, PhD, a UC professor of environmental health and principal investigator of the study. "These excessive, repetitive weight-bearing activities could cause irreparable trauma and impair growth in young children whose bones are still developing."

The UC-led team's findings were published in June 2008 issue of Journal of Agromedicine.

For this pilot study, Bhattacharya's team wanted to know if high levels of load-bearing activity done repetitively, such as shoveling chicken feed, would cause changes in the mechanical properties of bone—specifically, mass and structural strength.

The team recruited 36 boys, age 12 to 19, from Butler County, Ohio, to study the biomechanical properties of developing bone. Eighteen boys had a history of regular work on family farms and the remainder were not involved in farm-related activities.

Researchers developed a list of 22 tasks children of this age might be asked to do. Each boy was surveyed about the tasks he performed to split participants into farm and non-farm groups.

In order to gauge overall bone health, the team took two measurements: bone mass, which is a measure of how much bone exists, and dynamic bone quality, the bone's ability to sustain incoming force during physical activity. A person's bone mass continues to accumulate up through their mid 20s.

"If bone is unable to adequately absorb incoming shockwaves, it can cause microdamage and eventually crack," explains Bhattacharya. "When it happens at a lower level, the body can recover. But if happens too much and more frequently in developing bone, it may predispose these children to degenerative skeletal disorders later in life."

The UC study showed that young boys who participated in regular farming activities had significantly lower bone-damping ability compared to the non-farming group. "Damping" refers to the bone's ability to absorb shock when the heel strikes the ground.

"We've detected signs that high levels of cumulative weight-bearing activity during a time of rapid bone growth could cause chronic trauma to bone growth plates," says Bhattacharya. "Larger studies are needed to determine the extent of damage, but our initial findings support taking a closer look at how much physical activity farming children are doing and make sure their bone is developing normally for their age."

Bhattacharya points out that weight-bearing activities are not bad—it's excessive activity in this age group that causes concern.

Increased stress concentrations cause maladaptations in bone modeling, which can lead to osteoarthritis conditions that make the bones very stiff and cause damage to the cartilage between the bones.

"It's a very sensitive balance of what is acceptable and at what point it becomes dangerous," he adds.

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UC's Nelson Watts, MD, Jessica Gordon, and Rakesh Shukla, PhD; Thomas Waters, PhD, of the National Institute for Occupational Safety and Health; Steve Bartels, of the Ohio State University Butler County extension office; and Robert Colman of SignaLysis, Inc. also participated in this National Institute for Occupational Safety and Health-funded research.

University of Washington Researchers link Huntington's disease to overactive immune response in the brain

The damage to brain tissue seen in Huntington's disease may be caused by an overactive immune response in the bloodstream and the brain, according to new findings from two teams of researchers at the University of Washington in Seattle and University College London. The findings will be published online July 14 in the Journal of Experimental Medicine.

Working separately, the two teams found evidence in both brain cells and the bloodstream suggesting an important link between the immune system's response and Huntington's disease. Together, the findings may help scientists find biological markers for monitoring the disease progression earlier and with more accuracy, and could help them develop new treatments for the disease. Huntington's is a fatal inherited neurodegenerative disorder for which there is currently no effective treatment.

The UW team, lead by Dr. Thomas Moeller, research associate professor of neurology, had previously studied the role of inflammation and immune response in neurodegenerative diseases like Huntington's and ALS, also known as Lou Gehrig's disease. In this study, they found that patients with Huntington's had higher levels of immune-system signaling molecules, called cytokines, in their brain tissue.

The UW researchers then looked at a mouse-based model of the disease, studying the response of microglia, the immune cells of the nervous system. When the microglia were treated with a molecule triggering an immune response, the microglia from Huntington's mice produced much higher levels of cytokines, the immune system molecules. That finding suggests that the protein produced by the Huntington's disease genetic mutation, a protein called huntingtin, is causing the immune cells to be overactive. The researchers think that overly strong immune response may be the mechanism through which the disease causes damage to neurons in the brain.

"When we found increased levels of cytokines in the brains of Huntington's disease patients, we were very excited," Moeller said. "Inflammation in the brain has been increasingly recognized as an important component in other neurodegenerative diseases such as Alzheimer's or Parkinson's disease. These findings might open the door to novel therapeutic approaches for Huntington's disease that target inflammation."

The team at University College London focused their work on immune cells in the bloodstream, and found similar results linking the disease to the body's immune response.

"The similar effect in the blood of Huntington's patients suggests that we have discovered a new pathway in the disease by which the mutant protein could cause damage," Moeller explained. "The protein could be causing damage through an abnormally overactive immune system in both the blood and the brain. While damage from Huntington's is typically seen in the brain, this new pathway is quite easy to detect in the blood of patients, so we may have found a unique window from the blood into what the disease is doing in the brain."

The immune response in the blood may also help researchers use immune-system molecules as biological markers for the disease, which can be difficult to diagnose in early stages. Better tracking of Huntington's disease progression may help researchers to fine-tune interventions aimed at slowing the disease before it has affected as much brain tissue.

Huntington's affects an estimated 30,000 people in the United States. It is characterized by loss of motor control and cognitive functions, as well as by depression or other psychiatric problems.

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Both the UW and University College London research projects were supported by CHDI, Inc., a nonprofit organization that provides funding for Huntington's disease research.

JAMA and Archives Journals : Joint replacement may improve osteoarthritis symptoms in older adults

Older adults who have hip or knee replacement surgery for severe osteoarthritis may take several weeks to recover but appear to have excellent long-term outcomes, according to a report in the July 14 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

As the U.S. population ages, the number of older adults with osteoarthritis is increasing, according to background information in the article. The disease causes debilitating pain and often restricts older adults' mobility. Non-invasive treatments such as medications and physical therapy appear to be of limited value for the advanced stages of osteoarthritis. However, surgery may be associated with risks and discomfort.

Mary Beth Hamel, M.D., M.P.H., and colleagues at Beth Israel Deaconess Medical Center, Boston, studied medical decision-making and treatment outcomes in 174 patients age 65 and older (average age 75.2) who had severe osteoarthritis of the hip or knee. Participants' arthritis symptoms and functional status were assessed at the beginning of the study, between 2001 and 2004, and again 12 months later. Patients who chose to have joint replacement surgery were assessed six weeks, six months and 12 months after the procedure.

During 12 months of follow-up, 51 patients (29 percent) had joint replacement surgery, including 30 knee and 21 hip replacements. None of these patients died, 17 percent had postoperative complications and 38 percent had pain lasting more than four weeks following surgery. Patients age 75 and older took about the same amount of time to return to regular activities as those age 65 to 74, with most patients requiring assistance with activities such as shopping and household chores for more than a month.

At the 12-month mark, scores on scales measuring osteoarthritis symptoms improved more significantly in patients who had surgery than in patients who did not have surgery. Close to half (45 percent) of patients who did not have surgery reported that surgery was not offered to them as a potential treatment. Participants who did not have surgery tended to be older, have lower incomes and be more worried about surgical complications and a long recovery than those who did have surgery.

"Our findings of excellent outcomes from joint replacement surgery in elderly patients with severe hip or knee osteoarthritis corroborate and extend the findings of previous studies," the authors conclude. "These data should help inform discussion about joint replacement surgery and allow patients to consider the risks and benefits of surgery as well as the expected postoperative recovery experience."

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(Arch Intern Med. 2008;168[13]:1430-1440. Available pre-embargo to the media at www.jamamedia.org.)

Editor's Note: This study was supported by the Paul Beeson Physician Faculty Scholars in Aging Research Program. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Journal of Experimental Medicine : Exhausted B cells fail to fight HIV

Antibodies stick to HIV particles, preventing them from infecting other cells and triggering their destruction by immune cells. This antibody response starts out strong in HIV-infected individuals but eventually peters out. To find out why, scientists from the National Institute of Allergy and Infectious Diseases examined the cells that make the antibodies, known as B cells.

The group now finds that HIV gradually depletes the numbers of healthy, functional B cells. Individuals who had high levels of HIV in their blood had lots of B cells, but they failed to replicate normally or to produce high-quality antibodies. The fatigued B cells sported a protein called FCRL4, which dampens B cells' ability to respond to infection. How HIV turns on FCRL4 remains to be seen.

HIV is already known to knock out the defensive cells that directly attack and destroy infected cells. This new study reveals yet another way the virus dismantles the immune system.

American Chemical Society's Weekly PressPac

-- July 9, 2008

Scientists are reporting a new method that uses sugar molecules instead of antibodies to detect influenza.

ARTICLE #1 FOR IMMEDIATE RELEASE

Detecting flu viruses in remote areas of the world
Journal of the American Chemical Society

Researchers in Ohio and New Mexico are reporting an advance in the quest for a fast, sensitive test to detect flu viruses — one that requires no refrigeration and can be used in remote areas of the world where new flu viruses often emerge. Their new method, the first to use sugar molecules rather than antibodies, is in the July 2 issue of the Journal of the American Chemical Society, a weekly publication.

In the new study, Jurgen Schmidt, Suri Iyer, and colleagues point out that conventional tests for flu viruses — including bird flu — rely on antibodies, proteins produced by the immune system, to recognize viruses. But antibody-based tests can be expensive and require refrigeration to remain stable.

Their solution involved development of artificial forms of sialic acid, a sugar molecule found on the surface of cells that flu viruses attach to when they attack humans. In laboratory tests, the researchers showed that their highly-selective artificial sugars could be used to quickly capture and recognize two common strains of influenza viruses, H1N1, which infects birds, and H3N2, which infects pigs and humans. They used the molecules to differentiate between 2 strains (Sydney and Beijing) commonly found in human infections without isolating the viral RNA or surface glycoproteins. The sugars remain stable for several months, can be produced in large quantities, and exhibit extended shelf life. — MTS

ARTICLE #1 FOR IMMEDIATE RELEASE
"Detection of Intact Influenza Viruses using Biotinylated Biantennary /S-/Sialosides"

DOWNLOAD FULL TEXT ARTICLE
http://dx.doi.org/10.1021/ja800842v

CONTACT:
Jurgen Schmidt, Ph.D.
Los Alamos National Laboratory
Los Alamos, New Mexico 87545
Email: jschmidt@lanl.gov

Suri S. Iyer, Ph.D.
University of Cincinnati
Cincinnati, OH 45221-0172
Phone: 513-556-9273
Fax: 513-556-9239
Email: suri.iyer@uc.edu

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Researchers are reporting the protein composition of the fang-like jaws of Nereis virens, a common marine worm. The finding could be used in construction and aerospace.

ARTICLE #2 FOR IMMEDIATE RELEASE

Marine worm's jaws say "cutting-edge new aerospace materials"
Biomacromolecules

Researchers in California and New Hampshire report the first detailed characterization of the protein composition of the hard, fang-like jaws of a common marine worm. Their work could lead to the design of a new class of super-strong, lightweight materials for use as construction and repair materials for spacecraft, airplanes, and other applications. Their study is scheduled for the July 14 issue of ACS' Biomacromolecules, a monthly journal.

In the new study, Chris C. Broomell and colleagues note that Nereis virens, also known as the sandworm or ragworm, is a burrowing marine worm found in shallow waters in the North Atlantic region. Researchers remain intrigued by the remarkable hardness of its jaws and long pincers, which rivals that of human teeth and exceed the hardness of many synthetic plastics. But little is known about the exact chemical composition of these structures.

Broomell and colleagues collected the jaws of 1,000 worms and analyzed their protein content using high-tech instrumentation. They found that the primary chemical in the jaws and pincers of the worm is a unique protein, named Nereis virens jaw protein-1 (Nvjp-1), which is rich in the amino acid histidine. The researchers also characterized the chemical conditions needed for its formation, such as the presence of zinc, which could allow researchers to create synthetic versions of this super-hard, lightweight material. — MTS

ARTICLE #2 FOR IMMEDIATE RELEASE
"Cutting Edge Structural Protein from the Jaws of Nereis virens"

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http://dx.doi.org/10.1021/bm800200a

CONTACT:
Chris C. Broomell, Ph.D.
University of California at Santa Barbara
Santa Barbara, California 93106
Phone: 406-599-6678
Email: broomell@lifesci.ucsb.edu

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ARTICLE #3 FOR IMMEDIATE RELEASE

New "scrubber" speeds removal of powerful anthrax clean-up agent
Organic Process Research & Development

Researchers in New Jersey report discovery of a fast, efficient method for removing a powerful pesticide used to sterilize buildings and equipment following anthrax attacks. Their chemical "scrubber" removes 99 percent of the pesticide following fumigation and could pave the way for its broader use in anthrax clean-up efforts, the scientists say. Their study is scheduled for the July 18 issue of ACS' Organic Process Research & Development, a bi-monthly journal.

In the new study, Roman Bielski and Peter J. Joyce note that the commonly used pesticide, methyl bromide, is superior to chlorine dioxide for destroying anthrax-causing bacteria and their spores. However, it is highly toxic to humans and may harm the environment by destroying the ozone layer. Researchers thus have sought an efficient method for removing this promising anthrax decontamination agent.

Bielski and Joyce documented the effectiveness of their removal method in experiments with an empty office trailer filled with air containing methyl bromide. They treated air exhausted from the trailer with a solution of sodium sulfide combined with a powerful catalyst. This chemical "scrubber" removed more than 99 percent of the methyl bromide from the air. — MTS

ARTICLE #3 FOR IMMEDIATE RELEASE
"The Use of Methyltricaprylylammonium Chloride as a Phase Transfer Catalyst for the Destruction of methyl Bromide in Air Streams"

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http://dx.doi.org/10.1021/op800016j

CONTACT:
Roman Bielski, Ph.D., and Peter J. Joyce, Ph.D.
Value Recovery, Inc.
Bridgeport, New Jersey 08014
Phone: 856-467-6316
Fax: 856-467-6317
Email: bielski@ptcvalue.com

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Scientists are reporting that venom of snakes, such as the Bothrops asper from Costa Rica, could differ based on geographical regions, an important finding in the production of antivenom.

ARTICLE #4 FOR IMMEDIATE RELEASE

Snake venom tells tales about geography
Journal of Proteome Research

Just as people give away their origins by that southern drawl or New England twang, poisonous snakes produce venom that differs distinctly from one geographic area to another, the first study of the "snake venomics" of one of the most common pit vipers in Latin America has found. The study is scheduled for the August 1 issue of ACS' monthly Journal of Proteome Research.

In the new study, Juan J. Calvete and colleagues point out that researchers have known for decades that venom collected from snakes of the same species from different geographic locations can differ in terms of their biological effects and symptoms on snakebite victims. However, scientists know little about the chemical differences behind these geographically different venoms.

To find out, the scientists collected venom samples from adult and newborn specimens of the lancehead pitviper from two geographically isolated populations from the Caribbean and Pacific regions of Costa Rica. After a detailed laboratory analysis of the proteins found in the venom — so-called "snake venomics" — the researchers found major differences in the venoms collected from the two regions. They also found distinct differences in proteins collected from newborns and adult snakes. The study "highlights the necessity of using pooled venoms as a statistically representative venom for antivenom production" for human snakebite victims, the report states. — MTS

ARTICLE #4 FOR IMMEDIATE RELEASE
"Snake Venomics of the Lancehead Pitviper Bothrops asper: Geographic, Individual, and Ontogenetic Variations"

DOWNLOAD FULL TEXT ARTICLE
http://dx.doi.org/10.1021/pr800332p

CONTACT:
Juan J. Calvete, Ph.D.
Instituto de Biomedicina de Valencia
Valencia, Spain
Phone: 34 96 339 1778
Fax: 34 96 369 0800
Email: jcalvete@ibv.csic.es

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ARTICLE #5 EMBARGOED FOR 9 A.M., EASTERN TIME, July 14, 2008

'Electronic chemicals' pave the way for brighter, more energy-efficient future
Chemical & Engineering News

From solar power to computer chips to advanced lighting, new materials developed by chemists are helping consumers reap the benefits of advanced electronics, according to an article scheduled for the July 15 issue of Chemical & Engineering News. Some of these electronics will soon appear on store shelves and offices near you.

In the C&EN cover story, writers Michael McCoy, Alexander Tullo, and Jean-Francois Tremblay point out that so-called 'electronic chemicals' play key roles in today's advanced electronics but go largely unnoticed by consumers. These unsung materials, part of a multibillion dollar electronic materials market, provide improved solar panels that crank out more fossil fuel-free electricity and new computer chips that are smaller and more energy efficient than ever. These materials also fuel the development of organic light emitting diodes (OLEDs) that promise energy savings and could render today's incandescent light bulbs and fluorescent bulbs obsolete, according to the article.

But making advanced electronics comes with a steep price. Chemical companies now invest billions of dollars to build new manufacturing plants to produce raw materials for advanced electronics. Manufacturers are also spending heavily on research and development, as new electronic advances demand innovative new chemicals, the article states.

ARTICLE #5 EMBARGOED FOR 9 A.M., EASTERN TIME, July 14, 2008
"Electronic chemicals"

This story will be available on July 14 at
http://pubs.acs.org/cen/coverstory/86/8628cover.html

FOR ADVANCE INFORMATION, CONTACT:
Michael Bernstein
ACS News Service
Phone: 202-872-6042
Fax: 202-872-4370
Email: m_bernstein@acs.org

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Journalists' Resources

ACS's 236th National Meeting, August 17-21, Philadelphia
One of 2008's largest and most important scientific conferences — the 236th National Meeting and Exposition of the American Chemical Society-- will be held Aug. 17-21, 2008, in Philadelphia, Pa. At least 12,000 scientists and others are expected for the event, which will include more than 8,000 reports on new discoveries in chemistry. The multi-disciplinary theme is Chemistry for Health: Catalyzing Transitional Research. Stay tuned for information on registration, housing, press releases, and onsite press briefings that will be available via the Internet.

New ACS Annual Report
The 2007 ACS annual report, Our Science, Our Lives, Our Stories, can be a valuable resource for journalists trying to keep pace with chemistry and the multiple fields of science that involve chemistry. The report features ACS members describing in their own words why they became chemists, what they find rewarding about their work and how the transforming power of chemistry helps address mounting global problems and improves people's lives. Some are humorous, some are poignant. All of them are compelling. The newly published report is at: http://www.acsannualreport.org/acsannualreport/2007.

Pfizer's work on penicillin becomes National Historic Chemical Landmark
Pfizer's deep-tank fermentation — a revolutionary process that enabled mass production of penicillin for use in World War II — was designated a National Historic Chemical Landmark by the American Chemical Society (ACS) in a special ceremony in Brooklyn, N.Y., on June 12. The process ushered in the era of antibiotics and represented a turning point in modern medicine. After World War II, Pfizer applied its deep-tank fermentation to manufacture the antibiotics streptomycin and Terramycin,® which proved effective against a wide range of deadly bacteria. For more information, the press release can be found at: http://portal.acs.org/portal/acs/corg/content?_nfpb=true&_pageLabel=PP_ARTICLEMAIN&node_id=222&content_id=WPCP_010032&use_sec=true&sec_url_var=region1

ChemMatters Matters for Journalists
This quarterly ACS magazine for high school chemistry students, teachers, and others explains the chemistry that underpins everyday life in a lively, understandable fashion. ChemMatters is available at www.acs.org/chemmatters. You can also receive the most recent issues by contacting the editor, Pat Pages, at: 202-872-6164 or chemmatters@acs.org.

ACS Press Releases
General science press releases on a variety of chemistry-related topics.
http://portal.acs.org/portal/acs/corg/content?_nfpb=true&_pageLabel=PP_ARTICLEMAIN&node_id=222&content_id=CTP_006740&use_sec=true&sec_url_var=region1

General Chemistry Glossary
http://antoine.frostburg.edu/chem/senese/101/glossary.shtml

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Global Challenges/Chemistry Solutions
Don't miss this special series of ACS podcasts on some of the 21st Century's most daunting challenges, and how cutting-edge research in chemistry matters in the quest for solutions. This sweeping panorama of challenges includes topics such as providing a hungry, thirsty world with ample supplies of safe food and clean water; developing alternatives to petroleum to fuel the global economy; preserving the environment and assuring a sustainable future for our children; and improving human health. An ongoing saga of chemistry for life — chemistry that truly matters— Global Challenges debuts June 25 with new episodes through December. Subscribe at iTunes [itpc://feeds.feedburner.com/GlobalChallenges] or listen and access other resources at the ACS web site www.acs.org/GlobalChallenges.

Bytesize Science, a new podcast for young listeners
Bytesize Science is a science podcast for kids of all ages that aims to entertain as much as it educates. Subscribe to Bytesize Science using iTunes [http://ax.phobos.apple.com.edgesuite.net/WebObjects/MZStore.woa/wa/browserRedirect?url=itms%253A%252F%252Fax.phobos.apple.com.edgesuite.net%252FWebObjects%252FMZStore.woa%252Fwa%252FviewPodcast%253Fid%253D266670954]
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Science Elements: ACS Science News Podcast
http://portal.acs.org/portal/acs/corg/content?_nfpb=true&_pageLabel=PP_SUPERARTICLE&node_id=1355&use_sec=false&sec_url_var=region1 The ACS Office of Communications is podcasting PressPac contents in order to make cutting-edge scientific discoveries from ACS journals available to a broad public audience at no charge.

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American Orthopaedic Society for Sports Medicine : Dramatic increase in 'Tommy John' surgery in young patients cause for concern

Upside to 'epidemic' surgery: 83 percent successful in return to play, new research finds

ORLANDO, Florida – Eighty-three percent of athletes who had "Tommy John" elbow reconstruction surgery were able to return to the same or better level of play, according to a study released today at the 2008 American Orthopaedic Society for Sports Medicine Annual Meeting at JW Marriott Orlando Grande Lakes. While reassuring to athletes, the study authors find the trend of more and more young athletes requiring the surgery, alarming.

"Before 1997 this surgery was performed on only 12 of 97 patients who were 18 or younger (12 percent)," said co-author E. Lyle Cain, MD, fellowship director for the American Sports Medicine Institute, Andrews Sports Medicine and Orthopaedic Center in Birmingham, Alabama. "In 2005 alone, 62 of the 188 operations performed, were on high school athletes, a third of the surgical group. The reality is that this surgery is successful and that's good. But a disturbing trend of younger kids needing the surgery is troubling. This should be a wake-up call to parents and coaches that specialization in baseball where kids don't get adequate time off is very dangerous."

"Tommy John" surgery is a procedure where a damaged elbow ligament (Ulnar Collateral Ligament or UCL) is replaced with a tendon from elsewhere in the body. The surgery is named for Hall of Fame pitcher Tommy John, who was the first person to have the surgery in 1974. John returned to the major leagues and went on to win 164 games after the surgery. Prior to this historic surgery, a UCL injury was a career-ending injury.

In the study, 743 patients who had the Tommy John surgery were contacted for follow-up evaluations and completed a questionnaire about their recovery. The majority of the patients were baseball players (94.5 percent), the remaining 5.5 percent were involved in track, football or other sports. The study found that 622 patients (83 percent) returned to the previous level of competition or higher. Of the major league players, 75.5 percent returned to the same level of play. For minor league players 56 percent returned to the same level or higher. The average time from surgery to full competition was 11.6 months after reconstruction, according to study results. Additionally about 10 percent of the patients had complications, mostly minor.

"The increase in the number of UCL reconstructions being done now can be attributed to many things: improved diagnostic techniques, heightened awareness, increased chance of positive outcome with current surgical techniques, but most importantly, the overuse of young throwing arms," said Dr. Cain. "In the past 10 years, year-round baseball leagues have proliferated. So the best young pitchers are throwing many more pitches and learning to throw more difficult pitches. It's great that the surgery is successful, but prevention of the injury should be the goal. Kids should be urged to rest and be careful about saving their arms, rather than leading to long-term problems at a young age."

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The American Orthopaedic Society for Sports Medicine (AOSSM) is a world leader in sports medicine education, research, communication and fellowship, and includes national and international orthopaedic sports medicine leaders. The Society works closely with many other sports medicine specialists, including athletic trainers, physical therapists, family physicians, and others to improve the identification, prevention, treatment, and rehabilitation of sports injuries.

For more information, please contact AOSSM Director of Communications, Lisa Weisenberger at 847/292-4900, or e-mail her at lisa@sportsmed.org. You can also visit the AOSSM Web site at http://www.sportsmed.org/.

University of Illinois at Urbana-Champaign :

CHAMPAIGN, Ill. — With more new mothers in the workplace than ever before, there has been a corresponding increase in the number of child-care facilities in the United States.

At the same time, data from a variety of sources point to a growing prevalence of overweight infants and toddlers.

Is there a connection?

According to a new study co-written by University of Illinois community health professor Juhee Kim and Karen Peterson, a professor of nutrition and society at Harvard University’s School of Public Health, child-care factors and feeding practices may indeed play a role.

“Our study is the first to report, to our knowledge ... the potential importance of infant child care on infant nutrition and growth,” the researchers said in an article published in the July issue of the Archives of Pediatrics & Adolescent Medicine, a publication affiliated with the Journal of the American Medical Association. “The results of this study indicate that structural characteristics of child care, such as age at initiation, type and intensity, were all related to infant feeding practices and weight gain among a representative sample of U.S. infants.”

Specifically, Kim and Peterson found that 9-month-old infants who routinely receive non-parental care – provided by relatives, licensed day-care centers or more informal child-care providers – may experience higher rates of unfavorable feeding practices. The babies also weigh more than those whose primary caregivers are their parents.

The researchers’ findings could have significant public-health ramifications, as weight gain in infancy can ultimately be a predictor of obesity later in life.

Obesity, in turn, is linked to a number of chronic illnesses, such as diabetes and hypertension, as well as adulthood morbidity and mortality.

In their study, Kim and Peterson analyzed baseline data from a nationally representative sample of 8,150 9-month-old infants to determine whether infant-feeding practices and non-parental care might be a factor in the rise in weight of the infants. They used data collected for children enrolled in the Early Childhood Longitudinal Study, Birth Cohort, conducted by the U.S. Department of Education’s National Center for Education Statistics.

Kim and Peterson found that 55.3 percent of the infants had received regular, non-parental child care, with half of those infants receiving full-time child care. Among babies in child care, 40 percent began receiving such care at age 3 months; 39 percent, between 3 and 5.9 months, and 21 percent at 6 months or older.

“Weight gain and the prevalence of overweight were lowest among infants who received care by parents,” the researchers noted in the published article.

The researchers also examined data regarding breastfeeding initation for babies receiving parental and non-parental care, along with the stage at which solid foods were introduced to the infants. Only starting solid foods before 4 months of age was associated with increased overweight among infants.

“Infants who initiated child care before 3 months of age had lower rates of ever having been breastfed and higher rates of early introduction of solid foods,” they wrote. “Infants in parental care were more likely to have breastfeeding initiated and solid foods introduced after 4 months of age compared with those in child-care settings.”

Further, infants in part-time child care gained more weight – 175 grams – by 9 months of age, compared with those receiving only parental care. Those being cared for by relatives also showed a weight gain – 162 grams.

“A strength of our findings,” the researchers noted, “is that the observed effects of child-care factors remained significant after controlling for maternal pre-pregnancy BMI (body mass index) and a child’s birth weight.”

“Although both factors are known to be strong predictors of childhood overweight status, in our study, only birth weight was a significant factor in weight gain.”

Kim said there are a couple of important take-home messages from their research results for parents and child-care providers.

“Parents may want to have enough communication with child-care providers about when, what and how to feed their babies during their stay in day care, which is important to avoid potential risk of overfeeding or underfeeding at home,” she said.

“Child-care professionals can encourage parents’ active involvement in the decision process of what, when and how to feed infants. Child-care providers also need to participate in nutrition-education/training programs to understand the importance of starting solid foods, transition from breast milk or formula to foods, and how to implement recommended practices to ensure a healthy eating environment.”

Kim hopes to be able investigate relationships among child care, feeding practices and weight gain in children in other parts of the world.

“It would be interesting to conduct a cross-cultural study,” she said. “Considering eating is a socio-economical and cultural event, the impact of child care on infant feeding practices – food consumption – might be different among different countries.”

The current research was supported in part by the Berkowitz Fellowship of the department of nutrition, Harvard School of Public Health; an Early Childhood Longitudinal Study, Birth Cohort training grant from the National Center for Education Statistics; and training grants on statistical analysis for education policy from the American Educational Research Association.

European Molecular Biology Laboratory : Teaching old drugs new tricks

Scientists predict new uses for existing drugs from their side effects

Researchers from the European Molecular Biology Laboratory (EMBL) discovered a new way to make use of drugs' unwanted side effects. They developed a computational method that compares how similar the side effects of different drugs are and predicts how likely the drugs act on the same target molecule. The study, published in Science this week, hints at new uses of marketed drugs.

Similar drugs often share target proteins, modes of action and unpleasant side effects. In reverse this means that drugs that evoke similar side effects likely act on the same molecular targets. A team of EMBL researchers now developed a computational tool that compares side effects to test if they can predict common targets of drugs.

"Such a correlation not only reveals the molecular basis of many side effects, but also bears a powerful therapeutic potential. It hints at new uses of marketed drugs in the treatment of diseases they were not specifically developed for," says Peer Bork, Joint Coordinator of EMBL's Structural and Computational Biology Unit.

The approach would prove particularly useful for chemically dissimilar drugs used in different therapeutic areas that nevertheless have an overlapping, so far unknown protein target profile. Similar strategies have proven successful in the past. For example, the drug marketed as Viagra was initially developed to treat angina, but its side effects of prolonged penile erection led to a change in its therapeutic area.

Applying the new method to 746 marketed drugs, the scientists found 261 dissimilar drugs that in addition to their known action also likely bind to other unexpected molecular targets. 20 of these drugs were then tested experimentally and 13 showed binding to the targets that were predicted by side effect similarity. Testing 9 of these drugs further in cellular assays they all showed activity and thus a desired effect on the cell through their interaction with the newly discovered target proteins.

The results reveal that side effects can help find new, relevant drug-target interactions that might form the basis of new therapies. The brain enhancer Donepezil, for example, proved to share a target with the anti-depressant Venlafaxine, supporting that Donepezil could be also used to treat depression.

The big advantage of marketed drugs is that they have already been tested and approved for safe use in patients. This means they can move a lot faster from bench to bedside than newly discovered drugs that often take up to 15 years before they can be applied in patients.

"With some more tests and refinement our method could in future be applied on a bigger scale. New drugs could routinely be checked in the computer for additional hidden targets and potential use in different therapeutic areas. This will save a lot of money and would speed up drug development tremendously," concludes Bork.

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American Orthopaedic Society for Sports Medicine : Cadaver tissue fails nearly 25 percent of the time in young ACL reconstructions

Graft type and patient activity level may contribute to failure rate, authors say

ORLANDO, Florida – With an estimated 80,000 Anterior Cruciate Ligament (ACL) tears happening each year in the United States (Source: American Journal of Sports Medicine 2006 ; 9:1512-1532), including recently to famed golfer, Tiger Woods, choosing the best replacement ligament for surgery is one key to success. A study released today at the 2008 American Orthopaedic Society for Sports Medicine's Annual Meeting at the JW Marriott Orlando Grande Lakes, found that with a failure rate of almost 24 percent, the use of cadaver replacement ligaments may not be the best choice for young, athletic patients.

"Choosing a replacement ligament, whether it comes from a cadaver or the patient's own tissue is a decision that must be made by the surgeon and patient," said co-author Kurre Luber, MD, orthopedic surgery fellow at Mississippi Sports Medicine and Orthopaedic Center. "This study found a very high failure rate in patients 40 years and younger with high activity levels in ACL-dependent sports like tennis, basketball, soccer and downhill skiing. Certainly, it would be naïve to think that only the graft selection led to these failures, we also need to look at surgical technique (single versus double bundle). Better outcome measures also need to be developed. However, this study definitely raises questions about the validity of using cadaver tissue in this patient subgroup."

The ACL is one of the major stabilizing ligaments of the knee. Located in the center of the knee joint, it runs from the thigh bone to the shin bone through the center of the knee. Typically, tearing the ACL occurs with a sudden direction change. To repair a torn ACL, a surgeon replaces the damaged ligament with a new one, either from a cadaver or the patient's own body. Typically, either the patellar-tendon bone or the hamstring tendons is used.

In the study, 64 patients, 40 years old or younger with high activity levels who had ACL reconstruction with a cadaver replacement ligament, were followed for a minimum of two years. ACL reconstruction failure was defined as requiring a second reconstruction due to injury or graft failure or poor scores on a combination of orthopaedic outcome measure tests. The study found that 15 (23.4 percent) of the 64 patients' ACL reconstructions failed as defined by the study.

"This failure rate in this young, active population is exceedingly high when compared to a previous study that looked at failure rates of cadaver replacement ligament in patients older than 40," said corresponding author Dr. Gene Barrett. "The older group's failure rate was 2.4 percent. So while there are obvious benefits of using the cadaver ligament, like avoiding a second surgical site on the patient, a quicker return to work and less postoperative pain, for a young patient who is very active, it may not be the right choice."

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The American Orthopaedic Society for Sports Medicine (AOSSM) is a world leader in sports medicine education, research, communication and fellowship, and includes national and international orthopaedic sports medicine leaders. The Society works closely with many other sports medicine specialists, including athletic trainers, physical therapists, family physicians, and others to improve the identification, prevention, treatment, and rehabilitation of sports injuries.

For more information, please contact AOSSM Director of Communications Lisa Weisenberger at 847/292-4900, or e-mail her at lisa@aossm.org

American Orthopaedic Society for Sports Medicine research finds Cool, air blown under football shoulder pads reduces body temperature and heart rate

New possibility to reduce potential for heat illness, study suggests

ORLANDO, Florida – Cool, dry air flowing between the athlete and their football pads reduces core body temperature and heart rate dramatically, thereby reducing the likelihood of heat-related illness, a study released today at the 2008 American Orthopaedic Society for Sports Medicine Annual Meeting at JW Marriott Orlando Grande Lakes shows. The study found that air forced under the uniform, rather than misted, cool air blown on to the uniform, could be a helpful measure to avoid heat-related illness in football players. This study, funded by a grant from NFL Charities, represents a novel advancement in the pursuit of methods to decrease the incidence of heat related illness.

"Heat stroke in football players has unfortunately been brought to national attention following the deaths of five football players between 2001 and 2004," said lead author Mary Beth Horodyski, EdD, Associate Professor and Director of Research for the Department of Orthopedics and Rehabilitation at the College of Medicine at the University of Florida. "We wanted to look at this new technology for cooling the athlete by blowing cool, dry air underneath their uniform to see how it would affect body temperature and heart rate."

Heat-related illness happens when the systems used by the body to regulate heat become overwhelmed and cannot compensate. Under these conditions, heat and body temperature climbs uncontrollably. Since 1995, 31 football players have died from heat stroke (23 high school, 5 college, and 2 professional, and one sandlot*).

This study monitored 15 athletes wearing shoulder pads, shorts and football helmets who participated in two testing sessions: on one day no air was blown under their shoulder pads and on another day cool, dry air was blown under the shoulder pads during rest periods and the recovery session. Three, 15-minute exercise cycles, separated by 10-minute rest periods were followed by a 20-minute recovery session. The exercise cycles consisted of jogging and sprinting on a treadmill in a room with a heat index of approximately 92 degrees Fahrenheit.

The study found that on the testing session day when the athletes had the cool, dry air blown under their shoulder pads, there was as much as 1 degree Fahrenheit reduction in core body temperature. The most dramatic difference in core body temperature was during the third recovery period. The athletes' average core body temperature was 100.3 degrees Fahrenheit for the cool dry air testing sessions, but for the same time period the average core body temperature was 101.7 degrees Fahrenheit without the cool dry air.

Additionally, with the cool, dry air the athletes had a significantly lower heart rate of about 8 to 10 beats per minute than without the cool, dry air.

"Obviously when the air was blown underneath the uniforms, the athletes benefited," said Dr. Horodyski. "Any small amount of reduction in core body temperature and decrease in heart rate could be the difference between an athlete suffering a heat-related illness or not. We need to continue investigating new technology such as this to prevent heat illness."

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The American Orthopaedic Society for Sports Medicine (AOSSM) is a world leader in sports medicine education, research, communication and fellowship, and includes national and international orthopaedic sports medicine leaders. The Society works closely with many other sports medicine specialists, including athletic trainers, physical therapists, family physicians, and others to improve the identification, prevention, treatment, and rehabilitation of sports injuries.

For more information, please contact AOSSM Director of Communications, Lisa Weisenberger at 847/292-4900, or e-mail her at lisa@sportsmed.org. You can also visit the AOSSM Web site at www.sportsmed.org.

Baylor College of Medicine :Enzyme key to 'sister act' that maintains genome stability

Keeping the genome stable is a "sister act" of matched chromatids – the pairs of the double helix DNA molecule that exist during the chromosome duplication in the S phase of the cell cycle.

Maintaining the chromatids in their sister pairs rests with Eco1, a kind of enzyme known as an acetyltransferase. Now researchers at Baylor College of Medicine, in a collaboration of two laboratories, have shown that Eco1 and its human homologue maintain sister chromatid cohesion and thus genome stability through a chemical process called acetylation that affects Smc3, one of the key components of the cohesion protein complex. A report on their work appears in the current online issue of the journal Molecular Cell.

This activity is critical to maintaining the stability of the cell's genome and its survival, said Dr. Jun Qin, associate professor of biochemistry and molecular biology and molecular and cellular biology at BCM and a senior author of the report.

"If a cell lacks this acetyltransferase activity, it's dead," said Dr. Xuewen Pan, assistant professor of biochemistry and molecular biology and molecular and human genetics at BCM and also a senior author.

"This is critical for genome stability, cell growth and organism survival," said Qin.

"The collaboration in this work was important," he said. His laboratory carried out the work in human cells, and Pan's did the work in yeast.

"We pooled the resources of our two laboratories and took advantage of the power of the genetics in yeast and the power of proteomics and cell biology in the human. If a single labor had worked on this project, we would not have as complete a story," Qin said.

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Others who took part in this work include Jinglan Zhang, Xiaomin Shi, Yehua Li, , Junlin Jia, Zhiwei Huang, Tao Yang, Xiaoyong Fu, Sung Yun Jung, Yi Wang and Pumin Zhang , all of BCM and Beom-Jun Kim and Seon-Tae Kim of Sungkyunkwan University School of Medicine in Korea.

Funding for this work came from the National Institutes of Health and the Korea Research Foundation Grant from the Korean Government.

When the embargo lifts, this report will be available at www.molecule.org.

For more information on basic science research at BCM, please go to http://www.bcm.edu/fromthelab/.

University of Pennsylvania School of Medicine : Molecular motor works by detecting minute changes in force

Understanding its inner-workings applies to range of processes, from hearing to insulin signaling

PHILADELPHIA - Researchers at the University of Pennsylvania School of Medicine discovered that the activity of a specific family of nanometer-sized molecular motors called myosin-I is regulated by force. The motor puts tension on cellular springs that allow vibrations to be detected within the body. This finely tuned regulation has important implications for understanding a wide variety of basic cellular processes, including hearing and balance and glucose uptake in response to insulin. The findings appear in the most recent issue of Science.

"This is the first demonstration that myosin-I shows such dramatic sensitivity to tension," says senior author E. Michael Ostap, Ph.D., Associate Director, Pennsylvania Muscle Institute and Associate Professor of Physiology. "It is surprising that a molecular motor can sense such small changes in force."

Myosin-I is a biological motor that uses the chemical energy made by cells to ferry proteins within cells and to generate force, powering the movement of molecular cargos in nearly all cells.

In two specific cases, myosin I puts tension on the specialized spring-like structures in human ears that enable hearing and maintenance of balance, and also has a role in delivering the proteins that pump glucose into cells in response to insulin. "However, why a tension-sensing molecular motor is needed for this function is unknown," says Ostap.

In collaboration with Henry Shuman, PhD, Associate Professor of Physiology, the research team used optical tweezers -- a combination focused laser beam and microscope, of sorts -- to measure incredibly small forces and movements (on the piconewton and nanometer level) to discover that myosin I motors are regulated by force. The motors pull on their cellular cargos until a certain tension is attained, after which they stop moving, but will hold the tension. If something happens in the cell to decrease this tension, the motor will restart its activity and will restore the lost tension.

Myosins use the energy from ATP to generate force and motion. Humans have 40 myosin genes that sort into 12 myosin families. Members of the myosin family have been found in every type of cell researchers have examined. The Ostap lab is investigating the biochemical properties of several members of the myosin family to better understand movement in cells, which is important in development, wound healing, the immune response, and the spread of cancer, among other functions. These new findings shed light on the role of myosin I in cells, supporting the notion that this molecular motor is more important in generating and sustaining tension rather than transporting protein cargo.

The research team will now apply these results to better understand how cells use these tension sensors to carry out their physiological functions.

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This research was supported by the National Institute of General Medical Sciences and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals — its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation's "Honor Roll" hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center — a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

Scripps Research Institute research scientists reveal key structure from ebola virus

Breakthrough findings point to targets for drugs and vaccines

Described in the July 10, 2008 issue of the journal Nature, the research reveals the shape of the Ebola virus spike protein, which is necessary for viral entry into human cells, bound to an immune system antibody acting to neutralize the virus. The structure provides a major step forward in understanding how the deadly virus works, and may be useful in the development of potential Ebola virus vaccines, or treatments for those infected.

"Much about Ebola virus is still a mystery," says Erica Ollmann Saphire, the Scripps Research scientist who led the five-year effort. "However, this structure now reveals how this critical piece of the virus is assembled and, importantly, identifies vulnerable sites that we can exploit."

There is currently no cure for Ebola hemorrhagic fever. The virus is spread when people come into contact with the bodily fluids of someone who is already infected. Most ultimately die from a combination of dehydration, massive bleeding, and shock. The best treatment consists of administering fluids and taking protective measures to ensure containment, like isolating the patient and washing sheets with bleach.

The breakthrough described in the Nature article, though, provides hope that one day modern medicine will have more to offer.

The structure of the antibody together with the viral glycoprotein helps reveal the mechanisms by which the molecules assemble on the viral surface and helps explain how the pathogen evades and exploits the human immune system. The structure also provides a guide for the design of drugs and vaccines to block this protein, potentially preventing disease and death.

The new research was made possible by an antibody isolated by Dennis Burton, a Scripps Research professor and one of the study's coauthors. The antibody—shown bound to the Ebola virus spike protein in the current research—was derived from bone marrow of one of the few survivors of the 1995 Ebola outbreak in Kikwit, a city in the southwestern part of the Democratic Republic of Congo. The Kikwit outbreak was particularly deadly, with a higher than 90 percent mortality rate for those infected.

In addition to its importance for Ebola, the new research has broader implications for the study of viruses in general.

"Structures of the native, oligomeric forms of viral glycoproteins as they exist on the viral surface are exceedingly difficult to achieve and thus exceedingly rare," notes Ollmann Saphire. "This structure now provides templates by which researchers studying other viruses could try to understand how their virus's surface protein is assembled and neutralized by an antibody."

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In addition to Ollmann Saphire, the article, "Structure of the trimeric, prefusion Ebola virus glycoprotein in complex with a neutralizing antibody from a human survivor," was authored by Jeffrey E. Lee, Marnie L. Fusco, Ann J. Hessell, Wendelien B. Oswald, and Dennis R. Burton at The Scripps Research Institute.

Support for the research was provided by grants from the National Institutes of Health, a Career Award from the Burroughs Wellcome Fund, and a fellowship from the Canadian Institutes of Health Research.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus by 2009.

University of North Carolina School of Medicine study ties ending moderate drinking to depression

Scientific evidence has long suggested that moderate drinking offers some protection against heart disease, certain types of stroke and some forms of cancer.

But new research shows that stopping drinking – including at moderate levels – may lead to health problems including depression and a reduced capacity of the brain to produce new neurons, a process called neurogenesis.

The findings from the Bowles Center for Alcohol Studies at the University of North Carolina at Chapel Hill appear online in the journal Neuropsychopharmacology.

"Our research in an animal model establishes a causal link between abstinence from alcohol drinking and depression," said study senior author Clyde W. Hodge, Ph.D., professor of psychiatry and pharmacology in the UNC School of Medicine. "In mice that voluntarily drank alcohol for 28 days, depression-like behavior was evident 14 days after termination of alcohol drinking. This suggests that people who stop drinking may experience negative mood states days or weeks after the alcohol has cleared their systems,"

The mice were tested for depression-like behavior using a widely recognized method called the Porsolt Swim Test. The mice are placed inside a beaker filled with water and allowed to swim for six minutes. Mice are good swimmers and have no problem completing this task. The amount of time they spend immobile (floating and not swimming) is measured as an index of despair or depression-like behavior. The more time a mouse spends immobile, the more "depressed" it is thought to be.

"This research provides the first evidence that long-term abstinence from moderate alcohol drinking – rather than drinking per se – leads to a negative mood state, depression," Hodge said.

The study also found that the emergence of depression was associated with a profound reduction in the number of neural stem cells (cells that will become neurons) and in the number of new neurons in a brain region known as the hippocampus. This brain region is critical for normal learning and memory, and recent studies show that the development of neurons in the hippocampus may regulate mood, Hodge said.

According to the researcher, the negative mood state in mice may represent depression in humans and appears to be linked to a diminished capacity of the brain to form new neurons. "Thus, people who drink moderate alcohol socially, or for potential health benefits, may experience negative mood or diminished cognitive abilities due to a loss of the brain's ability to form new neurons," he said.

But the study also found that treatment with an antidepressant drug during 14 days of abstinence prevented the development of depression and restored the capability of the brain to produce new cells.

"Treatment with antidepressant drugs may help people who suffer from both alcoholism and depression by restoring the brain's ability to form new neurons," Hodge said. "Moreover, this research provides an animal model of alcohol-related depression with which we can begin to fully understand the neurobiology underlying co-occurring alcoholism and depression, and thereby develop successful treatment options. At this point it appears that blunted neurogenesis may underlie the effects of abstinence from alcohol drinking on mood, but understanding the mechanisms by which this occurs is a key challenge for future research."

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Several co-authors, all from UNC, also contributed to the study: Jennie R. Stevenson, neurobiology graduate student; Jason P. Schroeder, Ph.D., and Kimberly Nixon, Ph.D., research associates with the Bowles Center; Joyce Besheer, Ph.D., assistant professor of psychiatry; and Fulton T Crews, Ph.D., director of the Bowles Center and professor of psychiatry and pharmacology.

The research was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (a component of the National Institutes of Health) and by the Bowles Center for Alcohol Studies.

Stevenson received a UNC Graduate School Impact award in 2006 and the Research Society on Alcoholism's Gordis Award in 2005 for aspects of this work.

Hodge can be reached at (919) 843-4823, (919) 966-5678 or chodge@med.unc.edu.

The study can be found at: http://www.nature.com/npp/journal/vaop/ncurrent/full/npp200890a.html.

School of Medicine contacts: Les Lang, (919) 966-9366, llang@med.unc.edu or Clinton Colmenares (919) 966-8757 or ccolmena@unch.unc.edu
UNC News Services contact: Patric Lane (919) 962-8596, patric_lane@unc.edu

Arizona State University : From foe to friend: Researchers use salmonella as a way to administer vaccines in the body

The plate on the left shows the minimal growth of Salmonella enterica. The plate on the right shows enhanced growth with the presence of arabinose, demonstrating an ability to effectively...

TEMPE, Ariz. – Researchers at the Biodesign Institute at Arizona State University have made a major step forward in their work to develop a biologically engineered organism that can effectively deliver an antigen in the body. The researchers report that they have been able to use live salmonella bacterium as the containment/delivery method for an antigen.

The work is a major step forward in development of a new means of biological containment that would be a key component to a new way to deliver vaccines in animals and humans. If fully developed, the new method could be used to administer vaccines to many of those who do not benefit from traditional vaccines because of their cost, because of drug resistance or because of limited effects on children.

Outlined in the paper, "Regulated programmed lysis of recombinant Salmonella in host tissues to release protective antigens and confer biological containment," published on the online version (July 7) of the Proceedings of the National Academy of Sciences, the researchers describe a new, novel and effective means of biological containment for antigen delivery. The method not only effectively delivers the antigen in the body, but does so in a way that does not infect the body with salmonella and does not leave any vaccine cells in the environment.

Wei Kong, a researcher in the Biodesign Institute at Arizona State University, holds plates demonstrating the enhanced growth of Salmonella enterica (on viewer's left) in the presence of arabinose.

The research team includes scientists formally at Washington University, St. Louis, and Megan Health Inc., St. Louis, who are now at ASU's Biodesign Institute and the School of Life Sciences.

"Our goal is to design, engineer and evaluate a live bacterial (using salmonella) antigen delivery system that would display regulated delayed lysis in vivo after invasion into and colonizing internal lymphoid tissues in an immunized individual," said Roy Curtiss, director of the Center for Infectious Diseases and Vaccinology at the Biodesign Institute and a professor in ASU's School of Life Sciences. Curtiss was part of the research team that made the discovery.

"We wanted to do this in a way so that no disease symptoms due to salmonella would arise, a protective immune response would be induced to the pathogen whose protective antigen was delivered by the vaccine construction (in this case against S. pneumoniae due to an immune response to PspA), and there would be no ability for live bacterial vaccine cells to either persist in vivo or to survive if shed into the environment," Curtiss added.

"The biological containment system we developed is sufficient by itself on conferring attenuation, the inability to cause disease symptoms, and ability to deliver an antigen to induce protective immunity," Curtiss said. "We have high expectations that this delivery system will be safe and effective when administered to animals and humans."

A key to the project, according to Curtiss, is "turning a foe into a friend." That foe is the salmonella bacterium—the leading cause of human food-borne illness and which is currently in the news due to contaminated tomatoes and other food crops. Curtiss' team, through genetic know-how, has developed a variety of ways to tame salmonella in the lab and use it as a delivery vector for vaccines.

"We try to genetically modify the salmonella bacterium to eliminate its harmful effects -- the diarrhea, gut inflammation and fluid secretion -- while keeping the wherewithal to induce immunity against the bacteria causing pneumonia or other infectious diseases," Curtiss said. Several in his research team attack the problem from different angles, with some focusing on weakening salmonella, others boosting the immune response and others optimizing the self-destruct mechanism.

Speaking about the application of a pneumonia antigen, team leader Wei Kong, of the Biodesign Institute, said: "If we tried to use live Streptococcus pneumoniae causing pneumonia for a vaccine, we would obviously kill the patient. The benefit of a live vaccine that uses a weakened form of salmonella, is that the salmonella can be taken up through the intestinal lining and stimulate an immune response by using just a portion of the bacteria causing pneumonia that itself is not deadly."

In experiments, the genetically modified Salmonella enterica bacterium colonizes the lymph tissues of the host and manufactures a protein from the S. pneumoniae bacterium, which then triggers a strong antibody response. Unlike most vaccines that are entirely manufactured by a vaccine company, the attenuated recombinant salmonella vaccine after entry into the immunized individual serves as its own factory to produce (manufacture) the protective antigens (proteins) from the S. pneumoniae pathogen. This ability to cause manufacture in the immunized individual dramatically decreases the cost of such vaccines to make them affordable for use in the developing world, Curtiss said.

An important factor for the research team was to genetically program the S. enterica bacterium to destroy itself so that it is not released into the environment, Curtiss said.

"Biological containment systems are important to address the potential risk posed by any unintentional release of the modified salmonella into the environment," he explained. The salmonella life cycle is balanced to allow enough time to enter the body and build an immune response, while leading to cell death by bursting the cells and preventing the vaccine strain from spreading into the environment.

"The data show that the system we have devised results in cell lysis in the absence of arabinose and clearance of the strain from host tissues," the researchers state in the PNAS article.

"More importantly, our strain was fully capable of delivering a test antigen and inducing a robust immune response comparable to that of a vaccine strain without this containment system, thereby demonstrating that this system has all of the features required for biological containment of a recombinant attenuated salmonella vaccine," they added.

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The research was funded by the U.S. Department of Agriculture and the National Institutes of Health.

Sources:
Roy Curtiss, (480) 727-0445
Wei Kong, (480) 727-9591

European Society for Medical Oncology :Treatment delays result in poor outcomes for men with breast cancer

Men who develop breast cancer are often not treated until the disease has spread to the point that treatment becomes difficult, new results show.

Although most breast cancer patients are women, men make up roughly 1% of cases, Dr. Marina Garassino from the Orion Collaborative Group reports at the ESMO Conference Lugano (ECLU), organized by the European Society for Medical Oncology.

Her group conducted a retrospective analysis of 146 men with invasive breast cancer who were diagnosed between 1990 and 2007 across the 12 institutions in the ORION collaborative group.

What they found was that the disease often had already reached an advanced stage when the men were diagnosed. In 50% of cases the cancer had already reached the lymph nodes, a development that increases the likelihood of metastatic spread to other parts of the body.

All the men underwent surgery to remove their cancer. After surgery, 48 received radiotherapy and 100 received adjuvant chemotherapy or hormone therapy. After a median follow-up of 5.2 years, the estimated 10-year disease-free survival rates were 80% for men with the earliest stages of disease, and 44% for those with the largest tumors.

When the researchers looked at the characteristics of the tumors, they found that 73% were positive for estrogen receptors and/or progesteron receptors. Among a sub-group of 41 patients, 48.7% had tumors that overexpressed the protein HER-2/neu, which is an indication of an aggressive tumor.

"Male breast cancer is a rare disease and not well known," Dr. Garassino said. "It is treated the same way as female breast cancer, although our large retrospective series suggests that it has somewhat different histological characteristics."

If treated early enough, the disease is highly responsive to hormone therapy, Dr. Garassino said. In those cases, the prognosis may even be better than in women, she added. An ongoing case-control trial is examining this suggestion.

"What is important for people to know is that most of the patients in our study had a delay in their diagnosis due to the fact that a mass in their breast was misunderstood," Dr. Garassino said. "Therefore it is important that every mass in a man's breast must immediately be considered suspicious."

"Better understanding of male breast cancer will also provide better insights for treating these patients with modern targeted therapies", the researcher added. "We are currently conducting a molecular study on tissues to define help characteristics that might be important for this purpose."