Cell Phone Use May Have Effect on Brain Activity, but Health Consequences Unknown

In a preliminary study, researchers found that 50-minute cell phone use was associated with increased brain glucose metabolism (a marker of brain activity) in the region closest to the phone antenna, but the finding is of unknown clinical significance, according to a study in the February 23 issue of JAMA.

"The dramatic worldwide increase in use of cellular telephones has prompted concerns regarding potential harmful effects of exposure to radiofrequency-modulated electromagnetic fields (RF-EMFs). Of particular concern has been the potential carcinogenic effects from the RF-EMF emissions of cell phones. However, epidemiologic studies of the association between cell phone use and prevalence of brain tumors have been inconsistent (some, but not all, studies showed increased risk), and the issue remains unresolved," according to background information in the article. The authors add that studies performed in humans to investigate the effects of RF-EMF exposures from cell phones have yielded variable results, highlighting the need for studies to document whether RF-EMFs from cell phone use affects brain function in humans.

Nora D. Volkow, M.D., of the National Institutes of Health, Bethesda, Md., and colleagues conducted a study to assess if cell phone exposure affected regional activity in the human brain. The randomized study, conducted between January 1 and December 31, 2009, included 47 participants. Cell phones were placed on the left and right ears and brain imaging was performed with positron emission tomography (PET) with (18F)fluorodeoxyglucose injection, used to measure brain glucose metabolism twice, once with the right cell phone activated (sound muted) for 50 minutes ("on" condition) and once with both cell phones deactivated ("off" condition). Analysis was conducted to verify the association of metabolism and estimated amplitude of radiofrequency-modulated electromagnetic waves emitted by the cell phone. The PET scans were compared to assess the effect of cell phone use on brain glucose metabolism.

The researchers found that whole-brain metabolism did not differ between the on and off conditions. However, there were significant regional effects. Metabolism in the brain region closest to the antenna (orbitofrontal cortex and temporal pole) was significantly higher (approximately 7 percent) for cell phone on than for cell phone off conditions. "The increases were significantly correlated with the estimated electromagnetic field amplitudes both for absolute metabolism and normalized metabolism," the authors write. "This indicates that the regions expected to have the greater absorption of RF-EMFs from the cell phone exposure were the ones that showed the larger increases in glucose metabolism."

"These results provide evidence that the human brain is sensitive to the effects of RF-EMFs from acute cell phone exposures," the researchers write. They add that the mechanisms by which RF-EMFs could affect brain glucose metabolism are unclear.

"Concern has been raised by the possibility that RF-EMFs emitted by cell phones may induce brain cancer. … Results of this study provide evidence that acute cell phone exposure affects brain metabolic activity. However, these results provide no information as to their relevance regarding potential carcinogenic effects (or lack of such effects) from chronic cell phone use."

"Further studies are needed to assess if these effects could have potential long-term harmful consequences," the authors conclude.

Editorial: Cell Phone Radiofrequency Radiation Exposure and Brain Glucose Metabolism

The results of this study add information about the possible effects of radiofrequency emissions from wireless phones on brain activity, write Henry Lai, Ph.D., of the University of Washington, Seattle, and Lennart Hardell, M.D., Ph.D., of University Hospital, Orebro, Sweden, in an accompanying editorial.

"Although the biological significance, if any, of increased glucose metabolism from acute cell phone exposure is unknown, the results warrant further investigation. An important question is whether glucose metabolism in the brain would be chronically increased from regular use of a wireless phone with higher radiofrequency energy than those used in the current study. Potential acute and chronic health effects need to be clarified. Much has to be done to further investigate and understand these effects."

The editorial authors also question whether the findings of Volkow et al may be a marker of other alterations in brain function from radiofrequency emissions, such as neurotransmitter and neurochemical activities? "If so, this might have effects on other organs, leading to unwanted physiological responses. Further studies on biomarkers of functional brain changes from exposure to radiofrequency radiation are definitely warranted."

Journal References:

1. Henry Lai, Lennart Hardell. Cell Phone Radiofrequency Radiation Exposure and Brain Glucose Metabolism. JAMA, 2011; 305 (8): 828-829 DOI: 10.1001/jama.2011.201
2. Nora D. Volkow, Dardo Tomasi, Gene-Jack Wang, Paul Vaska, Joanna S. Fowler, Frank Telang, Dave Alexoff, Jean Logan, Christopher Wong. Effects of Cell Phone Radiofrequency Signal Exposure on Brain Glucose Metabolism. JAMA, 2011; 305 (8): 808-813 DOI: 10.1001/jama.2011.186

Courtesy: ScienceDaily

MIT Engineers Design New Nanoparticle That Could Lead to Vaccines for HIV, Malaria, Other Diseases

MIT engineers have designed a new type of nanoparticle that could safely and effectively deliver vaccines for diseases such as HIV and malaria.

The new particles, described in the Feb. 20 issue of Nature Materials, consist of concentric fatty spheres that can carry synthetic versions of proteins normally produced by viruses. These synthetic particles elicit a strong immune response -- comparable to that produced by live virus vaccines -- but should be much safer, says Darrell Irvine, corresponding author of the paper and an associate professor of materials science and engineering and biological engineering.

Such particles could help scientists develop vaccines against cancer as well as infectious diseases. In collaboration with scientists at the Walter Reed Army Institute of Research, Irvine and his students are now testing the nanoparticles' ability to deliver an experimental malaria vaccine in mice.

Vaccines protect the body by exposing it to an infectious agent that primes the immune system to respond quickly when it encounters the pathogen again. In many cases, such as with the polio and smallpox vaccines, a dead or disabled form of the virus is used. Other vaccines, such as the diphtheria vaccine, consist of a synthetic version of a protein or other molecule normally made by the pathogen.

When designing a vaccine, scientists try to provoke at least one of the human body's two major players in the immune response: T cells, which attack body cells that have been infected with a pathogen; or B cells, which secrete antibodies that target viruses or bacteria present in the blood and other body fluids.

For diseases in which the pathogen tends to stay inside cells, such as HIV, a strong response from a type of T cell known as "killer" T cell is required. The best way to provoke these cells into action is to use a killed or disabled virus, but that cannot be done with HIV because it's difficult to render the virus harmless.

To get around the danger of using live viruses, scientists are working on synthetic vaccines for HIV and other viral infections such as hepatitis B. However, these vaccines, while safer, do not elicit a very strong T cell response. Recently, scientists have tried encasing the vaccines in fatty droplets called liposomes, which could help promote T cell responses by packaging the protein in a virus-like particle. However, these liposomes have poor stability in blood and body fluids.

Irvine, who is a member of MIT's David H. Koch Institute for Integrative Cancer Research, decided to build on the liposome approach by packaging many of the droplets together in concentric spheres. Once the liposomes are fused together, adjacent liposome walls are chemically "stapled" to each other, making the structure more stable and less likely to break down too quickly following injection. However, once the nanoparticles are absorbed by a cell, they degrade quickly, releasing the vaccine and provoking a T cell response.

In tests with mice, Irvine and his colleagues used the nanoparticles to deliver a protein called ovalbumin, an egg-white protein commonly used in immunology studies because biochemical tools are available to track the immune response to this molecule. They found that three immunizations of low doses of the vaccine produced a strong T cell response -- after immunization, up to 30 percent of all killer T cells in the mice were specific to the vaccine protein.

That is one of the strongest T cell responses generated by a protein vaccine, and comparable to strong viral vaccines, but without the safety concerns of live viruses, says Irvine. Importantly, the particles also elicit a strong antibody response. Niren Murthy, associate professor at Georgia Institute of Technology, says the new particles represent "a fairly large advance," though he says that more experiments are needed to show that they can elicit an immune response against human disease, in human subjects. "There's definitely enough potential to be worth exploring it with more sophisticated and expensive experiments," he says.

In addition to the malaria studies with scientists at Walter Reed, Irvine is also working on developing the nanoparticles to deliver cancer vaccines and HIV vaccines. Translation of this approach to HIV is being done in collaboration with colleagues at the Ragon Institute of MIT, Harvard and Massachusetts General Hospital. The institute, which funded this study along with the Gates Foundation, Department of Defense and National Institutes of Health, was established in 2009 with the goal of developing an HIV vaccine.

Journal Reference:

1. James J. Moon, Heikyung Suh, Anna Bershteyn, Matthias T. Stephan, Haipeng Liu, Bonnie Huang, Mashaal Sohail, Samantha Luo, Soong Ho Um, Htet Khant, Jessica T. Goodwin, Jenelyn Ramos, Wah Chiu, Darrell J. Irvine. Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses. Nature Materials, 2011; 10 (3): 243 DOI: 10.1038/nmat2960

Courtesy: ScienceDaily

Blood Test May Find Markers of Bladder Cancer Risk

Knowing that it is impossible to catalog all the carcinogenic exposures a person has had in life and then assess them, Brown University researcher Carmen Marsit is looking for a more precise way to predict individual susceptibility to cancer. In a paper published online Feb. 22, 2011, in the Journal of Clinical Oncology, Marsit leads a team of scientists in describing a blood test that can accurately detect biomolecular markers of bladder cancer that risky exposures may have left behind.

The test measures a pattern of "methylation," a chemical alteration to DNA that affects which genes are expressed in cells, that Marsit's team determined is associated with bladder cancer. Methylation is affected by exposures in the environment, such as cigarette smoke and industrial pollutants, so many scientists believe that abnormal patterns of it in the body could be indicators of an increased likelihood of disease.

"What we might be measuring is an accumulated barometer of your life of exposures that then put you at risk," said Marsit, assistant professor of medical science in the Department of Pathology and Laboratory Medicine at the Warren Alpert School of Medicine at Brown University. "Will you ever really figure out if eating something when you were 12 gave you cancer? Instead we can use these kinds of markers as an integrated measure of your exposure history throughout your life."

Prediction or early detection?

To create the test, Marsit's team of scientists at Brown and Dartmouth studied the blood of 112 people who had bladder cancer and 118 who didn't. That gave them the tell-tale pattern of methylation to look for in immune system cells in the blood. Then, under properly blind conditions, they applied that test to the blood of a similar number of people who either had the cancer or didn't, and made their predictions.

They found that they could indeed determine who had the cancer and who didn't, based solely on the methylation pattern they observed. Controlling for the exposure to known risk factors like smoking that the patients reported, the researchers saw that people with the methylation pattern were 5.2 times more likely to have bladder cancer than people who did not have the pattern.

Because the samples used in the study came from people who already had the cancer, Marsit acknowledged that the scientists cannot be sure without further research whether the methylation markers in their immune system cells were predictors of cancer (i.e., they were present before the cancer began growing, as the team's hypothesis suggests) or simply indicated that the cancer was already there (i.e., they are a consequence of the cancer).

At a minimum, the study proves that the cancer is associated with a methylation pattern that can readily be detected in the blood, Marsit said. For cancers that are buried deep in the body and are therefore hard to detect, such as bladder cancer, a minimally invasive test that provides either prediction or early detection of cancer could make a big difference in improving a patient's prognosis, he added.

The researchers in the paper write that testing for methylation in blood cells could also be similarly applicable to other cancers.

Other authors in addition to Marsit include Brown researchers Devin Koestler, Brock Christensen, Andres Houseman, and Karl Kelsey, and Dartmouth researcher Margaret Karagas.

The study was funded by the National Institutes of Health and the Flight Attendants Medical Research Institute.

Journal Reference:

1. Carmen J. Marsit, Devin C. Koestler, Brock C. Christensen, Margaret R. Karagas, E. Andres Houseman, Karl T. Kelsey. DNA Methylation Array Analysis Identifies Profiles of Blood-Derived DNA Methylation Associated With Bladder Cancer. Journal of Clinical Oncology, 2011; DOI: 10.1200/JCO.2010.31.3577

Courtesy: ScienceDaily

Compound Blocks Brain Cell Destruction in Parkinson's Disease; Findings May Open Door to First Protective Therapy

Scientists from the Florida campus of The Scripps Research Institute have produced the first known compound to show significant effectiveness in protecting brain cells directly affected by Parkinson's disease, a progressive and fatal neurodegenerative disorder.

Although the findings were in animal models of the disease, the effectiveness of the compound, combined with its potential to be taken orally, offers the tantalizing possibility of a potentially useful future therapy for Parkinson's disease patients. The results were published in two separate studies in the journal ACS Chemical Neuroscience.

"These studies present compelling data on the first oral, brain-penetrating inhibitor to show significant efficacy in preventing neurodegeneration in both mouse and rat models of Parkinson's disease," said team leader Philip LoGrasso, a professor in the Department of Molecular Therapeutics and senior director for drug discovery at Scripps Florida. "The compound offers one of the best opportunities we have for the development of an effective neuroprotective treatment."

The new small molecule -- labeled SR-3306 -- is aimed at inhibiting a class of enzymes called c-jun-N-terminal kinases (JNK). Pronounced "junk," these enzymes have been shown to play an important role in neuron (nerve cell) survival. As such, they have become a highly viable target for drugs to treat neurodegenerative disorders such as Parkinson's disease.

"A drug like SR-3306 that prevents neurodegeneration would be a quantum leap in the clinical treatment of Parkinson's because all current therapies treat only the symptoms of the disease, not the underlying pathologies," LoGrasso said.

Patients with Parkinson's disease suffer from the loss of a group of neurons in the substantia nigra pars compacta (SNpc), part of the midbrain involved in motor control. These cells produce dopamine, a neurotransmitter that plays a key role in motor reflexes and cognition. The disease also affects projecting nerve fibers in the striatum, a part of the forebrain filled with cells that interact with dopamine. Stopping the Progression of Neuron Destruction in Animal Models

The SR-3306 compound, which has been in development at Scripps Florida for several years, performed well in both cell culture and animal models. In cell culture, the compound showed greater than 90 percent protection against induced cell death of primary dopaminergic neurons, while in mouse models of induced neuron death, the compound showed protective levels of approximately 72 percent.

The scientists went one step further, testing the new compound in a rat model, which duplicates the physical symptoms often seen with the human disease -- a pronounced and progressive loss of motor skills. The results showed SR-3306 provided a protection level of approximately 30 percent in the brain, a level that reduced the dysfunctional motor responses by nearly 90 percent.

"It was a surprise that level of neuroprotection reduced the behavioral impact so strongly," LoGrasso said, "but it's indicative of how it might perform in human patients. While SR-3306 doesn't represent a cure, it does appear to have the potential of stopping the progression of the disease."

The new studies are part of a $7.6 million multiyear grant awarded to LoGrasso in 2008 by the National Institutes of Neurological Disorders and Stroke (NINDS). The grant will enable Scripps Research and potential partners to file an application for an investigational new drug (IND) -- the first step in the lengthy clinical trials process required by the U.S. Food and Drug Administration before a new drug can be brought to market.

The first authors of the study, "Small Molecule c-jun-N-terminal Kinase (JNK) Inhibitors Protect Dopaminergic Neurons in a Model of Parkinson's Disease," are Jeremy W. Chambers and Alok Pachori of Scripps Research. Other authors include Shannon Howard, Michelle Ganno, Donald Hansen Jr., Ted Kamenecka, Xinyi Song, Derek Duckett, Weimin Chen, Yuan Yuan Ling, Lisa Cherry, Michael D. Cameron, Li Lin, and Claudia H. Ruiz, also of Scripps Research.

The first author of the study, "JNK Inhibition Protects Dopamine Neurons and Provides Behavioral Improvement in a Rat 6-hydroxydopamine Model of Parkinson's Disease," is Candice E. Crocker of Dalhousie University, Halifax, Nova Scotia, Canada. Other authors include Susan Khan and Michael D. Cameron of Scripps Research, and Harold A. Robertson and George S. Robertson of Dalhousie.

Both studies were supported by the National Institutes of Health. Harold A. Robertson and George S. Robertson were supported by funding from the Atlantic Innovation Fund.

Journal References:

1. Jeremy W. Chambers, Alok Pachori, Shannon Howard, Michelle Ganno, Donald Hansen, Ted Kamenecka, Xinyi Song, Derek Duckett, Weimin Chen, Yuan Yuan Ling, Lisa Cherry, Michael D. Cameron, Li Lin, Claudia H. Ruiz, Philip LoGrasso. Small Molecule c-jun-N-Terminal Kinase Inhibitors Protect Dopaminergic Neurons in a Model of Parkinson’s Disease. ACS Chemical Neuroscience, 2011; 110207090626012 DOI: 10.1021/cn100109k
2. Candice E. Crocker, Susan Khan, Michael D. Cameron, Harold A. Robertson, George S. Robertson, Philip LoGrasso. JNK Inhibition Protects Dopamine Neurons and Provides Behavioral Improvement in a Rat 6-Hydroxydopamine Model of Parkinson’s Disease. ACS Chemical Neuroscience, 2011; DOI: 10.1021/cn1001107

Courtesy: ScienceDaily

Tiny gold particles can help doctors detect tumor cells circulating in the blood of patients with head and neck cancer, researchers at Emory and Georg

The detection of circulating tumor cells (CTCs) is an emerging technique that can allow oncologists to monitor patients with cancer for metastasis or to evaluate the progress of their treatment. The gold particles, which are embedded with dyes allowing their detection by laser spectroscopy, could enhance this technique's specificity by reducing the number of false positives.

The results are published online in the journal Cancer Research.

One challenge with detecting CTCs is separating out signals from white blood cells, which are similarly sized as tumor cells and can stick to the same antibodies normally used to identify tumor cells. Commercially available devices trap CTCs using antibody-coated magnetic beads, and technicians must stain the trapped cells with several antibodies to avoid falsely identifying white blood cells as tumor cells.

Emory and Georgia Tech researchers show that polymer-coated and dye-studded gold particles, directly linked to a growth factor peptide rather than an antibody, can detect circulating tumor cells in the blood of patients with head and neck cancer.

"The key technological advance here is our finding that polymer-coated gold nanoparticles that are conjugated with low molecular weight peptides such as EGF are much less sticky than particles conjugated to whole antibodies," says Shuming Nie, PhD, a professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. "This effect has led to a major improvement in discriminating tumor cells from non-tumor cells in the blood."

The particles are linked to EGF (epithelial growth factor), whose counterpart EGFR (epithelial growth factor receptor) is over-produced on the surfaces of several types of tumor cells.

Upon laser illumination, the particles display a sharp fingerprint-like pattern that is specific to the dye, because the gold enhances the signal coming from the dyes. This suggests that several types of nanoparticles could be combined to gain more information about the growth characteristics of the tumor cells. In addition, measuring CTC levels may be sensitive enough to distinguish patients with localized disease from those with metastatic disease.

"Nanoparticles could be instrumental in modifying the process so that circulating tumor cells can be detected without separating the tumor cells from normal blood cells," Nie says. "We've demonstrated that one tumor cell out of approximately one to ten million normal cells can be detected this way."

In collaboration with oncologists at Winship Cancer Institute, researchers used nanoparticles to test for CTCs in blood samples from 19 patients with head and neck cancer. Of these patients, 17 had positive signals for CTCs in their blood. The two with low signals were verified to have no circulating cells by a different technique.

"Although the results have not been compared or validated with current CTC detection methods, our 'one-tube' SERS technology could be faster and lower in costs than other detection methods," says Dong Moon Shin, MD, professor of hematology and oncology and otolaryngology, associate director of academic development for Winship Cancer Institute and director of the Winship Cancer Institute Chemoprevention Program. "We need to validate this pilot study by continuing with larger groups of patients and comparing with other tests."

Journal Reference:

1. X. Wang, X. Qian, J. J. Beitler, G. Chen, F. R. Khuri, M. M. Lewis, H. J. C. Shin, S. Nie, D. M. Shin. Detection of Circulating Tumor Cells in Human Peripheral Blood using Surface-Enhanced Raman Scattering Nanoparticles. Cancer Research, 2011; DOI: 10.1158/0008-5472.CAN-10-3069

Courtesy: ScienceDaily

Gene Mutations Linked to High Blood Pressure

Yale University researchers have identified two novel genetic mutations that can trigger hypertension in up to a third of patients suffering from a common cause of severe high blood pressure, they report in the Feb. 11 issue of the journal Science.

The findings are a major step in understanding the causes of high blood pressure, which afflicts one out of every three Americans, said Richard Lifton, Sterling Professor and chair of the Department of Genetics, professor of internal medicine and senior author of the paper. These findings may lead to a genetic screening test for this common cause of severe hypertension, he said.

Five to ten percent of patients with severe hypertension have tumors of the adrenal gland that produce a hormone called aldosterone. Removing these tumors can cure this form of hypertension. Sifting for clues by sequencing all of the genes from these tumors, and comparing their sequences to the patients' normal DNA, the researchers found that either one of two mutations of a single gene were found in 8 of 22 tumors studied. The investigators discovered that these mutations cause both aldosterone release and tumor formation by allowing the encoded protein, a potassium channel, to conduct sodium rather than only allowing potassium to pass through the channel.

In addition to causing these adrenal tumors, inherited mutations in the same gene were also found to be the cause of a rare familial form of severe hypertension.

The results underscore the value of whole exome sequencing, or decoding of all of a patient's genes rather than just a few suspect gene targets, said Lifton, who is an investigator for the Howard Hughes Medical Institute.

"This gene was not on anybody's list to sequence in an investigation of this disease," Lifton said. "We really hit the jackpot."

The project included investigators from Uppsaala University, New York Medical College and Henry Ford Hospital. Other authors affiliated with Yale are: Murim Choi, Ute I. Scholl, Peyman Björklund, Bixiao Zhao, Carol Nelson-Williams, Weizhen Ji, Yoonsang Cho, Aniruddh Patel, Clara J. Men, Elias Lolis, David S. Geller, Shrikant Mane and Tobias Carling.

Journal Reference:

1. M. Choi, U. I. Scholl, P. Yue, P. Bjorklund, B. Zhao, C. Nelson-Williams, W. Ji, Y. Cho, A. Patel, C. J. Men, E. Lolis, M. V. Wisgerhof, D. S. Geller, S. Mane, P. Hellman, G. Westin, G. Akerstrom, W. Wang, T. Carling, R. P. Lifton. K Channel Mutations in Adrenal Aldosterone-Producing Adenomas and Hereditary Hypertension. Science, 2011; 331 (6018): 768 DOI: 10.1126/science.1198785

Courtesy: ScienceDaily

Virus, Parasite May Combine to Increase Harm to Humans

A parasite and a virus may be teaming up in a way that increases the parasite's ability to harm humans, scientists at the University of Lausanne in Switzerland and Washington University School of Medicine in St. Louis recently reported in Science.

When the parasite Leishmania infects a human, immune system cells known as macrophages respond. However, some Leishmania strains are infected with a virus that can trigger a severe response in macrophages, allowing the parasite to do more harm in animal infections. In humans, the parasite's viral infection may be why some strains of Leishmania in Central and South America tend to cause a disfiguring form of disease that erodes the soft tissues around the nose and mouth.

"This is the first reported case of a viral infection in a pathogen of this type leading to increased rather than reduced pathogenicity," says Stephen Beverley, PhD, the Marvin M. Brennecke Professor and head of the Department of Molecular Microbiology at Washington University School of Medicine. "It raises a number of important questions, including whether we can use antiviral strategies to reduce the damage caused by forms of Leishmania that carry viruses."

Leishmania infection, known as leishmaniasis, affects an estimated 12 million people worldwide. It is mainly spread by sand fly bites and is a major public health problem in the Mediterranean basin, Asia, Africa, the Middle East, Central and South America and a potential hazard to travelers and military personnel. Symptoms include large skin lesions, fever, swelling of the spleen and liver, and, in more serious forms of the disease, disfigurement and death.

The study brought together two different lines of investigation in Europe and the Americas.

Nicolas Fasel, PhD, professor of biology and medicine at the University of Lausanne, and Nancy Saravia, PhD, of the International Center for Medical Training and Investigation in Cali, Columbia, have been studying the causes of mucocutaneous leishmaniasis, a particularly harmful form of the disease that destroys the soft tissues of the nose and mouth. This type of infection is frequently associated with Leishmania Viannia, a subgenus of Leishmania strains prevalent in Central and South America.

In tests in mice and hamsters using parasite strains taken from the wild, Fasel and Saravia showed that only some Viannia strains spread rapidly and cause high levels of inflammation and damage similar to that seen in mucocutaneous leishmaniasis.

A breakthrough came when researchers realized that the rapid, highly damaging form of infection relied on an immune system sensor protein called TLR3. This protein is found in intracellular vesicles, which are compartments inside macrophages also known to host the parasite.

"Those vesicles are where the rendezvous between host, parasite and virus takes place," Fasel says. "TLR3 normally helps the immune system fight infections, but when we deleted it in mice and repeated the experiment, infections with virus-infected Leishmania were less harmful."

Researchers sorted the Leishmania into viral-infected and non-infected strains and found that the more serious infections in laboratory animals were much more likely to be caused by viral-infected Leishmania.

Beverley's group has been exploring the role of viral infections of Leishmania in the evolution of the RNA interference pathway, which can help fight viruses.

"Surprisingly many Leishmania species have lost the RNAi interference pathway, and one force contributing to this loss could be the successful infection of the parasite by viruses," he says. "This hints at the possibility of an evolutionary trade-off, suggesting that the loss of RNAi could be balanced if the parasite gained some type of advantage when infected by a virus."

To ensure that genetic differences in the wild strains weren't interfering with the results, Lon-Fye Lye, PhD, staff scientist, and Suzanne Hickerson, senior research technician, both of Beverley's lab, supplied lines of genetically identical Leishmania with and without the virus. As in the prior comparisons, virally-infected Leishmania caused more disease and provoked a stronger response from macrophages.

According to Beverley, the results suggest that some viral infections in Leishmania may be improving the parasite's chances to infect the mammalian host's immune cells. He speculates that this increased pathogenicity may be one evolutionary trade-off that makes losing the RNAi pathway worthwhile for Leishmania and other microbes.

"How the virally increased pathogenicity arises is now a fascinating question in its own right," Beverley says. "It could teach us a great deal about how Leishmania causes a severe form of the disease and potentially offer new opportunities for its cure."

Funding from Swiss National Science Foundation, Foundation Pierre Mercier and the National Institutes of Health supported this research.

Journal Reference:

1. A. Ives, C. Ronet, F. Prevel, G. Ruzzante, S. Fuertes-Marraco, F. Schutz, H. Zangger, M. Revaz-Breton, L.-F. Lye, S. M. Hickerson, S. M. Beverley, H. Acha-Orbea, P. Launois, N. Fasel, S. Masina. Leishmania RNA Virus Controls the Severity of Mucocutaneous Leishmaniasis. Science, 2011; 331 (6018): 775 DOI: 10.1126/science.1199326

Courtesy: ScienceDaily

Boosting Body's Immune Response May Hold Key to HIV Cure

Australian scientists have successfully cleared a HIV-like infection from mice by boosting the function of cells vital to the immune response.A team led by Dr Marc Pellegrini from the Walter and Eliza Hall Institute showed that a cell signaling hormone called interleukin-7 (IL-7) reinvigorates the immune response to chronic viral infection, allowing the host to completely clear virus. Their findings were released in the February 3 edition of the journal Cell.

Dr Pellegrini, from the institute's Infection and Immunity division, said the finding could lead to a cure for chronic viral infections such as HIV, hepatitis B and C, and bacterial infections such as tuberculosis, which are significant economic and global health burdens.

Current approaches to curing chronic infections tend to focus on generating a long-lived immune response to a specific disease. Dr Pellegrini, working with colleagues Mr Simon Preston and Mr Jesse Toe, and collaborators Professors Pamela Ohashi and Tak Mak from the Ontario Cancer Institute, argues that long-lived immune responses to chronic diseases are not always effective, and has instead concentrated on how the immune response can be manipulated to better fight infection.

"Viruses such as HIV and hepatitis B and C overwhelm the immune system, leading to establishment of chronic infections that are lifelong and incurable," Dr Pellegrini said. "Despite tremendous efforts, long-lived immune responses for some of these viruses are ineffective, because the body is so overrun by virus that the immune system, in particular T cells, just give up trying to battle the infection. Some people have coined the phrase 'immune exhaustion' to explain the phenomenon. Our approach is to discover some of the mechanisms that cause this immune exhaustion, and manipulate host genes to see if we can boost the natural immune response in order to beat infection."

The team investigated the role of IL-7, a naturally-occurring immune hormone, in a mouse model of HIV infection. IL-7 is a cytokine (cell signalling hormone) that plays a critical role in immune system development and maintenance.

"We found that IL-7 boosted the immune response in a pretty profound fashion, such that animals were able to gradually clear the virus without too much collateral tissue damage," Dr Pellegrini said.

Further investigations revealed that, at the molecular level, IL-7 switched off a gene called SOCS-3.

"In an overwhelming infection, SOCS-3 becomes highly activated and suppresses the immune response, probably as a natural precaution to prevent 'out-of-control' responses that cause collateral damage to body tissue," Dr Pellegrini said. "In the case of these overwhelming infections, the immune system effectively slams on the brakes too early, and the infection persists."

Mr Preston, who worked on the SOCS-3 studies, said that switching off the SOCS-3 gene boosted the immune system and helped the animals to completely eliminate the infection.

"The key for us was figuring out that turning off SOCS-3 only really worked when it was within T cells," Mr Preston said. "It allowed the immune response to boost the number of virus-specific T cells and have an immune response good enough to eliminate the virus without initiating an immune response that was too large and would make the animal sick."

Dr Pellegrini said the research had provided excellent ideas for new therapies that could target and boost host immune cells to fight disease, rather than targeting the disease itself.

"The findings could help to develop drugs that target some of these host molecules, such as SOCS-3, and turn them off for very short, defined periods of time to reinvigorate the T cells, allowing them to regroup to fight infection," he said.

This research was supported by the Australian National Health and Medical Research Council, the Canadian Institute for Health and the Cancer Research Institute.

Journal Reference:

1. Marc Pellegrini, Thomas Calzascia, Jesse G. Toe, Simon P. Preston, Amy E. Lin, Alisha R. Elford, Arda Shahinian, Philipp A. Lang, Karl S. Lang, Michel Morre et al. IL-7 Engages Multiple Mechanisms to Overcome Chronic Viral Infection and Limit Organ Pathology. Cell, Feb 3, 2011 DOI: 10.1016/j.cell.2011.01.011

Courtesy: ScienceDaily

How the Body’s Frontline Defense Mechanism Determines If a Substance Is a Microbe

The Proceedings of the National Academy of Sciences has just published an article describing how the first line of defense of the human immune system distinguishes between microbes and the body's own structures. The basis of this recognition mechanism has been unclear since the key protein components were discovered over 30 years ago -- and has now finally been cracked by researchers at the University of Helsinki, Finland.

When a microbe has infected us, the first defense mechanism that attacks it is a protein-based marking and destruction system called complement. It usually suffices that foreign targets are marked as enemy while our own targets are left untouched, so that white blood cells attack only foreign targets like bacteria, viruses and parasites.

Researchers at the Haartman Institute and the Institute of Biotechnology at the University of Helsinki have, as a result of years of work, been able to show how complement distinguishes foreign structures from our own structures -- all days before antibodies have a chance to develop. The key to unlocking the problem was when the groups of Sakari Jokiranta and Adrian Goldman in Helsinki, along with David Isenman's group in Canada, were able to solve the structure of two components of the system at atomic resolution. The structure revealed a stunning unexpected arrangement: factor H bound two of the C3bs, which mark foreign targets, in two different ways. Laboratory tests showed that this actually happened: to recognize our own cells, factor H binds not only C3b but also the cell surface at the same. Thus, the system mark only foreign structures for destruction by the white blood cells.

This new understanding of how host and foreign structures are distinguished by the front-line defense mechanism also explains how the severe and often fatal form of disease "Hemolytic Uremic Syndrome" (HUS) starts. This rare disease often occurs in children and can be caused by genetic defects in factor H or in C3b, or else by the disruption of factor H activity by antibodies. Some of these patients have had to have complete liver-kidney transplants because of the severity of the disease.

The research's surprising and wide-reaching result will be important not only in terms of advancing basic immunological research but also in the diagnosis and treatment of very sick children.

Journal Reference:

1. T. Kajander, M. J. Lehtinen, S. Hyvarinen, A. Bhattacharjee, E. Leung, D. E. Isenman, S. Meri, A. Goldman, T. S. Jokiranta. Dual interaction of factor H with C3d and glycosaminoglycans in host-nonhost discrimination by complement. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1017087108

Courtesy: ScienceDaily

Benefits of Outdoor Exercise Confirmed

A systematic review carried out by a team at the Peninsula College of Medicine and Dentistry has analysed existing studies and concluded that there are benefits to mental and physical well-being from taking exercise in the natural environment. Their findings are published in the research journal Environmental Science and Technology on February 4th 2011.

The research team, supported by the NIHR Peninsula Collaboration in Leadership for Applied Health Research and Care (PenCLAHRC, part of the NIHR family of health and research initiatives) in collaboration with the European Centre for the Environment and Human Health (ECEHH), analysed data from a number of sources including 11 randomised and non-randomised control trials incorporating information from 833 adults.

Eligible trials were those that compared the effects of outdoor exercise initiatives with those conducted indoors and which reported at least one physical or mental well-being outcome in adults or children.

The study found that most trials showed an improvement in mental well-being: compared with exercising indoors, exercising in natural environments was associated with greater feelings of revitalisation, increased energy and positive engagement, together with decreases in tension, confusion, anger and depression. Participants also reported greater enjoyment and satisfaction with outdoor activity and stated that they were more likely to repeat the activity at a later date.

However, none of the identified studies measured the effects of physical activity on physical well-being, or the effect of natural environments on sticking to exercise.

On balance this review has identified some promising effects on self-reported mental well-being immediately following exercise in the natural environment, as opposed to those reported following exercise indoors. This is a first step towards vindicating the positive effects of programmes such as the Green Gym and Blue Gym, and innovative interventions by medical practitioners that include exercise outdoors as part of holistic treatments for those suffering from depression and similar psychological ailments.

At present research analysts are working with a paucity of high quality evidence, and one significant outcome from this study is the urgent need for there to be further research in this area. Large, well-designed longer-term trials in populations who might benefit most from the potential advantages of outdoor exercise are needed to fully analyse the effects of outdoor exercise on mental and physical well-being. Studies are also required that measure the influence of such effects on the sustainability of physical activity.

Dr. Jo Thompson-Coon, PenCLAHRC Research Fellow, commented: "The hypothesis that there are added beneficial effects to be gained from exercising in the natural environment is very appealing and has generated considerable interest. By using the data currently available to us we have added strength to the link between mental and physical well-being and outdoor exercise, but further research and longer, tailor-made and focused trials are needed to better understand this link."

The senior author of the study, Professor Michael Depledge, Chair of Environment and Human Health at the ECEHH, added: "Some 75 per cent of the European population now live in urban environments, so that increasing efforts need to be made to re-connect people with nature via programmes such as the Green Gym and Blue Gym. Our research, which brings together data from a wide variety of sources, adds significant weight to the case for spending more time in the natural environment as members of the public and their clinicians fight to counteract the negative outcomes of modern living, such as obesity and depression. We look forward to conducting the further research and trials required to establish the evidence-base for introduction of outdoor activity into general lifestyle to complement therapeutic intervention."

Professor Stuart Logan, Director -- Institute of Health Service Research and Director -- PenCLAHRC, at the Peninsula College of Medicine & Dentistry, said: "This is just the sort of project that PenCLAHRC is designed to support. It reflects the aim of the National Institute for Health Research in establishing CLAHRCs around the UK -- locally identified and undertaken research that translates to improved health and well-being and that both benefits the local community and contributes to the production of research evidence. This is an exciting project with immense potential."

Journal Reference:

1. J. Thompson Coon, K. Boddy, K. Stein, R. Whear, J. Barton, M. H. Depledge. Does Participating in Physical Activity in Outdoor Natural Environments Have a Greater Effect on Physical and Mental Wellbeing than Physical Activity Indoors? A Systematic Review. Environmental Science & Technology, 2011; : 110203115102046 DOI: 10.1021/es102947t

Courtesy: ScienceDaily

How Fusion Protein Triggers Cancer

What happens when two proteins join together? In this case, they become like a power couple, where the whole is greater than the sum of the parts.API2 and MALT1 are two proteins that become fused together in a subset of lymphomas. The API2 part of the fusion connects with an enzyme called NIK. When it does, MALT1 comes in for the kill, splitting NIK in two, a process called cleavage.

The result? NIK is stronger than ever. It sheds its "conscience" by removing a regulatory region of the enzyme that forces NIK to behave and self-destruct. Consequently, NIK acts like a renegade protein, making cancer cells that grow, spread and resist traditional treatments.

This is the picture researchers at the University of Michigan Comprehensive Cancer Center uncovered in a study publishing in the Jan. 28 issue of Science. Led by a husband and wife team, Linda McAllister-Lucas, M.D., Ph.D., and Peter C. Lucas, M.D., Ph.D., U-M researchers coordinated an international effort that included contributions from laboratories in Great Britain and Belgium.

The API2-MALT1 fusion protein appears 30 percent to 40 percent of the time in a type of B-cell lymphoma called mucosa-associated lymphoid tissue, or MALT, lymphoma. It's never seen in any other cells.

"NIK is a critical hub that's been implicated in other B-cell cancers. Cleavage of NIK by this fusion oncoprotein suggests a new way of activating NIK, and further supports that NIK represents a potential target for developing new therapies," says McAllister-Lucas, associate professor of pediatric hematology/oncology at the U-M Medical School.

The protein fusion itself is also a potential treatment target. Neither API2 nor MALT1 alone can cause a ripple effect on NIK. It happens only when the two fuse together, with API2 providing the access for MALT1 to cause the split. Without the fusion, NIK cleavage does not happen.

"A particularly exciting feature to this discovery is that the critical cancer-causing event involves a kinase -- NIK -- and a protease -- API2-MALT1. Both kinases and proteases are considered druggable, meaning they are potential targets for developing drugs that block their activity," says Lucas, assistant professor of pathology at the U-M Medical School.

MALT lymphomas that carry the API2-MALT1 fusion protein tend to be more aggressive and more resistant to treatment. The result is larger tumors and increased spread throughout the body.

The researchers found that once NIK becomes stable, it triggers a series of downstream reactions that make cells more likely to metastasize and more resistant to current treatments.

These effects were reversed when researchers turned off NIK, suggesting that either blocking NIK or preventing NIK from becoming stable by blocking the protein fusion, could halt the growth and spread of MALT lymphoma tumors.

While NIK inhibitors are being investigated, these therapies are not currently available.

Non-Hodgkin lymphoma statistics: 65,540 Americans will be diagnosed with non-Hodgkin lymphoma this year and 20,210 will die from the disease, according to the American Cancer Society. MALT lymphoma accounts for 8 percent of non-Hodgkin lymphomas.

Additional authors: Shaun Rosebeck, Lisa Madden, Xiaohong Jin, Shufang Gu, Ingrid J. Apel, all from U-M; Alex Appert, Rifat A. Hamoudi and Ming-Qing Du, from University of Cambridge, UK; Heidi Noels, Xavier Sagaert, Peter Van Loo and Mathijs Baens from Catholic University Leuven, Belgium

Funding: Shirley K. Schlafer Foundation, Elizabeth Caroline Crosby Fund, University of Michigan Comprehensive Cancer Center, Leukemia and Lymphoma Research UK, Research Foundation-Flanders and National Cancer Institute.

Journal Reference:

1. Shaun Rosebeck, Lisa Madden, Xiaohong Jin, Shufang Gu, Ingrid J. Apel, Alex Appert, Rifat A. Hamoudi, Heidi Noels, Xavier Sagaert, Peter Van Loo, Mathijs Baens, Ming-Qing Du, Peter C. Lucas, and Linda M. Mcallister-Lucas. Cleavage of NIK by the API2-MALT1 Fusion Oncoprotein Leads to Noncanonical NF-κB Activation. Science, Vol. 331, No. 6016, Jan. 28, 2010 DOI: 10.1126/science.1198946

Courtesy: ScienceDaily

A Mix of Tiny Gold and Viral Particles, and the DNA Ties That Bind Them

Scientists have created a diamond-like lattice composed of gold nanoparticles and viral particles, woven together and held in place by strands of DNA. The structure -- a distinctive mix of hard, metallic nanoparticles and organic viral pieces known as capsids, linked by the very stuff of life, DNA -- marks a remarkable step in scientists' ability to combine an assortment of materials to create infinitesimal devices.

The research, done by scientists at the University of Rochester Medical Center, Scripps Research Institute, and Massachusetts Institute of Technology, was published recently in Nature Materials.

While people commonly think of DNA as a blueprint for life, the team used DNA instead as a tool to guide the precise positioning of tiny particles just one-millionth of a centimeter across, using DNA to chaperone the particles.

Central to the work is the unique attraction of each of DNA's four chemical bases to just one other base. The scientists created specific pieces of DNA and then attached them to gold nanoparticles and viral particles, choosing the sequences and positioning them exactly to force the particles to arrange themselves into a crystal lattice.

When scientists mixed the particles, out of the brew emerged a sodium thallium crystal lattice. The device "self assembled" or literally built itself.

The research adds some welcome flexibility to the toolkit that scientists have available to create nano-sized devices.

"Organic materials interact in ways very different from metal nanoparticles. The fact that we were able to make such different materials work together and be compatible in a single structure demonstrates some new opportunities for building nano-sized devices," said Sung Yong Park, Ph.D., a research assistant professor of Biostatistics and Computational Biology at Rochester.

Park and M.G Finn, Ph.D., of Scripps Research Institute are corresponding authors of the paper.

Such a crystal lattice is potentially a central ingredient to a device known as a photonic crystal, which can manipulate light very precisely, blocking certain colors or wavelengths of light while letting other colors pass. While 3-D photonic crystals exist that can bend light at longer wavelengths, such as the infrared, this lattice is capable of manipulating visible light. Scientists foresee many applications for such crystals, such as optical computing and telecommunications, but manufacturing and durability remain serious challenges.

It was three years ago that Park, as part of a larger team of colleagues at Northwestern University, first produced a crystal lattice with a similar method, using DNA to link gold nanospheres. The new work is the first to combine particles with such different properties -- hard gold nanoparticles and more flexible organic particles.

Within the new structure, there are actually two distinct forces at work, Park said. The gold particles and the viral particles repel each other, but their deterrence is countered by the attraction between the strategically placed complementary strands of DNA. Both phenomena play a role in creating the rigid crystal lattice. It's a little bit like how countering forces keep our curtains up: A spring in a curtain rod pushes the rod to lengthen, while brackets on the window frame counter that force, creating a taut, rigid device.

Other authors of the paper include Abigail Lytton-Jean, Ph.D., of MIT, Daniel Anderson, Ph.D., of Harvard and MIT, and Petr Cigler, Ph.D., formerly of Scripps Research Institute and now at the Academy of Sciences of the Czech Republic. Park's work was supported by the National Institute of Allergy and Infectious Diseases.

Journal Reference:

1. Petr Cigler, Abigail K. R. Lytton-Jean, Daniel G. Anderson, M. G. Finn, Sung Yong Park. DNA-controlled assembly of a NaTl lattice structure from gold nanoparticles and protein nanoparticles. Nature Materials, 2010; 9 (11): 918 DOI: 10.1038/nmat2877

Courtesy: ScienceDaily