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Wednesday, February 25, 2009

The Essential Role of Protein in Repairing Damaged Cells Revealed

Researchers have discovered a key protein that plays two important roles in the the development of cancer.  It was long known that the protein Mre11 functioned as a "gatekeeper" to signal injury to the cell and prevent damaged cells from proliferating.  But know researchers have observed that the Mre11 protein also serves as a "caretaker," and can repair damaged DNA.

"Most proteins involved in responding to DNA damage that can cause cancer either help detect the damage and warn the rest of the cell, or help repair the damage," says David O. Ferguson, M.D., Ph.D., the study's lead author. Ferguson is an assistant professor of pathology at the U-M Medical School and a member of U-M's Comprehensive Cancer Center.

This research may yield cancer-prevention applications as scientists determine which cancers can cause a mutation in the Mre11 protein, and how to detect and prevent that mutation. 

Prior research has shown that the protein, Mre11, functioned as a "gatekeeper" to signal injury to the cell and prevent damaged cells from proliferating. Now, Ferguson and colleagues have discovered that in mammals, a function of the Mre11 protein also serves as a "caretaker," by repairing DNA.

Their findings, published in the journal Cell, could have important implications for cancer treatment by someday allowing oncologists to predict a tumor's sensitivity to radiation and other therapies, making it more vulnerable to treatment.

Under normal circumstances, the body's cells grow, divide and eventually die. When something damages a healthy cell's DNA -- such as radiation or exposure to a toxin -- a multiprotein complex steps in to repair the breakage and activate other fundamental cellular processes.

The MRN complex, comprised of the Mre11, Rad50 and NBS1 proteins, senses DNA damage, known as double-strand breaks, within the cell. The complex then transmits that information to an enzyme called the ATM (ataxia-telangiectasia mutated) checkpoint kinase.

The ATM kinase controls the cell's response to double-strand breaks, and slows cell growth to give the cell opportunities to repair them, says Ferguson.

When the MRN complex doesn't work properly, inherited human neurological diseases, such as ataxia-telangiectasia-like syndrome and Nijmegen breakage syndrome, result. Both feature MRN mutations and significantly predispose a person to immunodeficiency and cancer.

What Ferguson and colleagues discovered is that Mre11 not only senses and communicates damage, it also repairs DNA double-strand breaks by acting as a nuclease, an enzyme that modifies and processes the broken DNA ends.

Research details The researchers generated mouse models to examine the exact role of Mre11 in the MRN complex. They engineered two mouse strains, one in which Mre11 was disabled completely, and one in which only a single amino acid change was made.

What surprised researchers the most was that making that change to a single amino acid in Mre11 caused consequences as severe as when they eliminated the entire MRN complex.

Taking out the amino acid in Mre11 responsible for nuclease activity caused the mice to develop growth defects, chromosomal abnormalities and sensitivity to DNA-damaging agents. Therefore, researchers could say that the nuclease, or repair, activity of Mre11 proves critical for both MRN function and stability of the genetic material of the organism.

"First, Mre11 signals to the cell by activating the kinase, but it also acts in the repair of double-strand breaks via the nuclease functions. Therefore, it prevents the two individual steps that lead to cancer," Ferguson says.

Implications The work, called "virtuoso cell engineering" in a Cell preview article, holds particular promise for identifying mutations associated with many cancers.

"What's emerging in the literature from large-scale screening studies of human tumors is that Mre11 may be frequently mutated in certain cancers," Ferguson says.

"This may have implications for diagnoses because tumors associated with different mutations may have different prognoses and respond to different therapies," he says. In particular, mutations in Mre11 may predict how sensitive or resistant a particular tumor will be to treatments with DNA-damaging agents.

"The fact that we have now separated the functions of DNA repair from the checkpoint functions means we may have identified a target that can sensitize tumors to radiation and chemotherapeutic agents used in treating cancer."

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Can Leading Indicators in Nature Presage Environmental Disaster?

Economists use leading indicators - the drivers of economic performance - ­ to take the temperature of the economy and predict the future. Now, in a new study, scientists take a page from the social science handbook and use leading indicators of the environment to presage the potential collapse of ecosystems. The study suggests it may be possible to use nature's leading indicators to avert environmental disaster.

Ecosystems worldwide - lakes, ocean fisheries, coral reefs, forests, wetlands and rangelands - are under constant and escalating pressure from humans and many are on the brink of collapse, according to Stephen R. Carpenter, a University of Wisconsin-Madison professor of zoology and an author of the new study.

"It's a big problem because they are very hard to predict. It is hard to get a handle on statistically," says Carpenter of what ecologists call "regime shift," a disastrous change in the way an individual ecosystem functions. Such change can be dramatic, as in the collapse of the North Atlantic cod fishery or increasing desertification in Africa and the Middle East, and can have serious economic, political and social consequences.

The idea of using leading indicators in science is not new. Geologists use seismic indicators to try to predict earthquakes and physicians use measures of such things as cholesterol and blood pressure to try to predict patient health. But applying the same kind of monitoring and statistical tools to forecast the health of ecosystems and, ultimately, to prevent serious ecological harm is only now coming into play, says Carpenter.

In the new study, Carpenter, Reinette Biggs of Stockholm University and William A. Brock, an economist at UW-Madison, used northern Wisconsin¹s sport fishery as a laboratory to see if leading indicators of ecological collapse can be detected far enough in advance to avert disaster.

"The answer is - yes, if the policy interventions can be swift and - no, if there are delays," says Carpenter of the study's results.

Northern Wisconsin has the largest concentration of freshwater lakes in the world, and the sport fishery is a critical economic engine for the region. The researchers looked at two major threats to the fishery: overfishing and habitat destruction caused by lake home-building and the loss of trees that would otherwise fall into the lake and provide habitat for sport fish.

³If you are a fish, woody habitat is perfect. It¹s a place to hide and it has food. It¹s like a room with a refrigerator,² says Carpenter. ³But there is way less habitat in lakes with a lot of houses. We are particularly concerned about woody habitat loss.²

In both the case of habitat loss and the case of overfishing, indicators of potential harm to the fishery can be detected before a breakdown in the lake ecosystem occurs, Carpenter explains. "However, only in the case of overfishing can policy change fast enough to avert the damage. It is not possible to act fast enough to avert the damage from habitat destruction because it takes too long to grow the trees. In that case, you have to start over."

The key to avoiding disaster, Carpenter argues, is monitoring: "We really need to be monitoring and analyzing the data from these ecosystems as a way to keep them healthy. Otherwise, by the time the problem surfaces it is too late."

Carpenter says it is possible to sense impending ecosystem regime shifts by carefully monitoring the changing variables that are likely to damage an environment. For example, daily measuring of chlorophyll in a lake could reveal an impending transition to a state where water quality will decline to the point that plant and animal communities in the lake are at risk.

"The behavior of the system becomes extremely variable in the run up to change. You see a lot of variability, and right at the point of regime shift, it becomes very unstable," Carpenter notes.

According to Carpenter, in addition to expanded monitoring and analysis of ecosystem data, averting regime shifts depends on effective policy. Enabling society to respond more rapidly to information about looming change, he says, is necessary to keep ecosystems producing the things people need.

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Chemopreventive Agents in Black Raspberries Identified

Components of black raspberries have been found to potentially have a chemopreventive effect on cancer cells. The substance, a class of compound known as flavonoids, inhibited growth and stimulated apoptosis in the esophagus of rats treated with an esophageal carcinogen. Apoptosis can best be described as the self-cannabalization of a cell.

"Our data provide strong evidence that anthocyanins are important for cancer prevention," said the study's lead author, Gary D. Stoner, Ph.D., a professor in the department of internal medicine at Ohio State University.

Stoner and his team of researchers fed rats an anthocyanin-rich extract of black raspberries and found that the extract was nearly as effective in preventing esophageal cancer in rats as whole black raspberries containing the same concentration of anthocyanins. This study demonstrates the importance of anthocyanins as preventive agents in black raspberries and validated similar in vitro findings. It is among the first to look at the correlation between anthocyanins and cancer prevention in vivo.

Stoner and his colleagues have conducted clinical trials using whole berry powder, which has yielded some promising results, but required patients to take up to 60 grams of powder a day. "Now that we know the anthocyanins in berries are almost as active as whole berries themselves, we hope to be able to prevent cancer in humans using a standardized mixture of anthocyanins," said Stoner.

"The goal is to potentially replace whole berry powder with its active components and then figure out better ways to deliver these components to tissues, to increase their uptake and effectiveness.

Ultimately, we hope to test the anthocyanins for effectiveness in multiple organ sites in humans," said Stoner.

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Monday, February 23, 2009

MRI Emerges as Vital Resource in Treatment of Back Pain

Magnetic resonance imaging (MRI) is a growing technology providing an increasing number of clinical benefits when used in the evaluation of back pain according to an article in the January 2009 issue of the Journal of the American Academy of Orthopaedic Surgeons. It is predicted that over the next several years, additional technical developments will allow MRI to provide even more useful orthopaedic benefits.

Co-author Victor M. Haughton, MD, department of radiology, University of Wisconsin Hospitals and Clinics says, "Because of the many different ways to gather this important information, MRI can be used to identify or display almost every type of spinal tissue or pathology. The imaging sequence can be modified to meet many different clinical needs." Those include: 

  • Back pain
  • Infection 
  • Tumor
  • Trauma and vascular disease
Researchers continue to find new ways to apply technologies that were previously used exclusively on other areas of the body. MRI which is considered safe, fast and versatile is now being used in several spinal applications such as:
MRI scans are produced by stimulating the protons in tissues and liquids (such as fat, muscle, spinal cord, and fluid in the spine) using radiofrequency waves in the presence of a magnetic field. MRI detects the amount of energy emitted from these protons. This technology makes MRI well suited to evaluate spaces between spinal vertebrae, bone marrow, the spinal canal, and in soft tissues. Therefore MRI has been shown to be useful for almost every spinal pathology including; diseases of the spinal cord, nerve roots, vertebrae, disks and blood vessels. With MRI there is no radiation risk to the patient.

Computed tomography (CT) has also improved in resolution and scanning speed and is often the only imaging method available for patients with pacemakers, nerve stimulators, or those who suffer from claustrophobia. For these individuals, CT can provide structural information needed for diagnosis in many back pain cases. However, CT does include some exposure to radiation.

MRI although a very important technology, should never take the place of a thorough medical history and physical examination. Also, there are often structural findings or "abnormalities" on MRI that are not clinically relevant and not necessarily related to a patient's symptoms. MRI findings must always correlate with the patient's clinical picture.

"The possibilities of magnetic resonance have not yet been realized. It is a rapidly evolving field. When we need tools to identify a possible herniated disk, the simplest type of MR imaging or CT imaging can be used successfully. However, if you want to find out which disk is causing pain, which nerve is firing, which metabolites are present in abnormal amounts, or how well the spinal elements are functioning, MR will provide the answers," adds Dr. Haughton.

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Assessment Technique Lets Scientists See Brain Aging Before Symptoms Appear

UCLA scientists have used innovative brain-scan technology developed at UCLA, along with patient-specific information on Alzheimer's disease risk, to help diagnose brain aging, often before symptoms appear. Published in the January issue of Archives of General Psychiatry, their study may offer a more accurate method for tracking brain aging.

Researchers used positron emission tomography (PET), which allows "a window into the brain" of living people and specifically reveals plaques and tangles, the hallmarks of neurodegeneration. The PET scans were complemented by information on patients' age and congnitive status and a genetic profile.

"Combining key patient information with a brain scan may give us better predictive power in targeting those who may benefit from early interventions, as well as help test how well treatments are working," said study author Dr. Gary Small, who holds UCLA's Parlow-Solomon Chair on Aging and is a professor at the Semel Institute for Neuroscience and Human Behavior at UCLA.

Scientists took PET brain scans of 76 non-demented volunteers after they had been intravenously injected with a new chemical marker called FDDNP, which binds to plaque and tangle deposits in the brain. Researchers were then able to pinpoint where these abnormal protein deposits were accumulating.

They reported that older age correlated with higher concentrations of FDDNP in the medial and lateral temporal regions of the brain, areas involved with memory, where plaques and tangles usually collect. The average age of study volunteers was 67.

Thirty-four of the 76 volunteers carried the APOE-4 gene allele, which heightens the risk for developing Alzheimer's disease. This group demonstrated higher FDDNP levels in the frontal region of the brain, also involved in memory, than study participants without allele.

"We found that for many volunteers, the imaging scans reflected subtle brain changes, which take place before symptoms manifest," said Small, who is also director of the UCLA Center on Aging.
Small noted that the brain will try to compensate for any problems, which is why cognitive symptoms may not become apparent until much later.

"This type of scan offers an opportunity to see what is really going on in the brain," he said.
Another subset of the volunteers had mild cognitive impairment (MCI), a condition that increases the risk of developing Alzheimer's disease. These 36 volunteers had higher measures of FDDNP in the medial temporal brain regions than normal volunteers. Those who had both MCI and the APOE-4 gene had higher concentrations of FDDNP in the medial temporal brain regions than volunteers who had MCI but not APOE-4.

"We could see more advancing disease in those with mild cognitive impairment, who are already demonstrating some minimal symptoms," Small said. "Eventually, this imaging method, together with patient information like age, cognitive status and genetics, may help us better manage brain aging."
According to Small, in the future, brain aging may be controlled similarly to high cholesterol or high blood pressure. Patients would receive a brain scan and perhaps a genetic test to predict their risk. Medications and other interventions could be prescribed, if necessary, to prevent or delay future neurodegeneration, allowing doctors to protect a healthy brain before extensive damage occurs. The brain scans may also prove helpful in tracking the effectiveness of treatments.

PET, combined with the FDDNP probe, is the only imaging technology that offers a full profile of neurodegeneration that includes measures of both plaques and tangles ‹ the physical evidence of Alzheimer's disease in the brain.

"The fact that we can see tau tangles as well as amyloid plaques is critically important in early detection of brain aging, since the tangles are the first abnormal proteins that appear in the brain, long before dementia is clinically obvious to the physician," said Dr. Jorge R. Barrio, a study author and professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA.
Such subtleties allow more insight into how the plaques and tangles spread and ultimately how Alzheimer's disease may develop.

Currently, the new FDDNP-PET scans are used in a research setting, but clinical trials are in development to bring the technology to wider patient use.

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Star Light, Star Bright, Its Explanation is Out of Sight

A mysterious flash of light from somewhere near or far in the universe is still keeping astronomers in the dark long after it was first detected by NASA's Hubble Space Telescope in 2006. It might represent an entirely new class of stellar phenomena that has previously gone undetected in the universe, say researchers.

Astronomers commonly observe intense flashes of light from a variety of stellar explosions and outbursts, such as novae and supernovae. Hubble discovered the cosmic flash on February 21, 2006. It steadily rose in brightness for 100 days, and then dimmed back to oblivion after another 100 days.

The rise and fall in brightness has a signature that simply has never been recorded for any other type of celestial event. Supernovae peak after no more than 70 days, and gravitational lensing events are much shorter. Therefore, this observation defies a simple explanation, reports Kyle Barbary of the Lawrence Berkeley National Laboratory (LBNL) in Berkeley, Calif. He is describing the bizarre Hubble observation at the 213th meeting of the American Astronomical Society in Long Beach, Calif. "We have never seen anything like it," he concludes.

The spectral fingerprints of light coming from the object, cataloged as SCP 06F6, also have eluded identification as being due to any specific element. One guess is that the features are redshifted molecular carbon absorption lines in a star roughly one billion light-years away.

But searches through various astronomical survey catalogs for the source of the light have not uncovered any evidence for a star or galaxy at the location of the flash. The Supernova Cosmology Project at LBNL discovered it serendipitously in a search for supernovae.

Hubble was aimed at a cluster of galaxies 8 billion light-years away in the spring constellation Bootes. But the mystery object could be anywhere in between, even in the halo of our own Milky Way galaxy.

Papers published by other researchers since the event was reported in June 2006, have suggested a bizarre zoo of possibilities: the core collapse and explosion of a carbon rich star, a collision between a white dwarf and an asteroid, or the collision of a white dwarf with a black hole.

But Barbary does not believe that any model offered so far fully explains the observations. "I don't think we really know what the discovery means until we can observe similar objects in the future."

All-sky surveys for variable phenomena, such as those to be conducted with the planned Large Synoptic Survey Telescope, may ultimately find similar transient events in the universe.

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Hubble Finds Stars that Go Ballistic

Even some stars go ballistic, racing through interstellar space like bullets and tearing through clouds of gas.

Images from NASA's Hubble Space Telescope reveal 14 young, runaway stars plowing through regions of dense interstellar gas, creating brilliant arrowhead structures and trailing tails of glowing gas. These arrowheads, or bow shocks, form when the stars' powerful stellar winds, streams of matter flowing from the stars, slam into surrounding dense gas. The phenomenon is similar to that seen when a speeding boat pushes through water on a lake.

"We think we have found a new class of bright, high-velocity stellar interlopers," says astronomer Raghvendra Sahai of NASA's Jet Propulsion Laboratory in Pasadena, Calif., and leader of the Hubble study. "Finding these stars is a complete surprise because we were not looking for them. When I first saw the images, I said 'Wow. This is like a bullet speeding through the interstellar medium.' Hubble's sharp 'eye' reveals the structure and shape of these bow shocks."

The astronomers can only estimate the ages, masses, and velocities of these renegade stars. The stars appear to be young - just millions of years old. Their ages are based partly on their strong stellar winds.

Most stars produce powerful winds either when they are very young or very old. Only very massive stars greater than 10 times the Sun's mass have stellar winds throughout their lifetimes. But the objects observed by Hubble are not very massive, because they do not have glowing clouds of ionized gas around them. They are medium-sized stars that are a few to eight times more massive than the Sun. The stars are not old because the shapes of the nebulae around aging, dying stars are very different, and old stars are almost never found near dense interstellar clouds.

Depending on their distance from Earth, the bullet-nosed bow shocks could be 100 billion to a trillion miles wide (the equivalent of 17 to 170 solar system diameters, measured out to Neptune's orbit). The bow shocks indicate that the stars are traveling fast, more than 112,000 miles an hour (more than 180,000 kilometers an hour) with respect to the dense gas they are plowing through, which is roughly five times faster than typical young stars.

"The high-speed stars were likely kicked out of their homes, which were probably massive star clusters," Sahai says.

There are two possible ways this stellar expulsion could have happened. One way is if one star in a binary system exploded as a supernova and the partner got kicked out. Another scenario is a collision between two binary star systems or a binary system and a third star. One or more of these stars could have picked up energy from the interaction and escaped the cluster.

Assuming their youthful phase lasts only a million years and they are moving at roughly 112,000 miles an hour, the stars have traveled about 160 light-years.

Runaway stars have been seen before. The Infrared Astronomical Satellite (IRAS), which performed an all-sky infrared survey in 1983, spied a few similar-looking objects. The first observation of these objects was in the late 1980s. But those stars produced much larger bow shocks than the stars in the Hubble study, suggesting that they are more massive stars with more powerful stellar winds.

"The stars in our study are likely the lower-mass and/or lower-speed counterparts to the massive stars with bow shocks detected by IRAS," Sahai explains. "We think the massive runaway stars observed before were just the tip of the iceberg. The stars seen with Hubble may represent the bulk of the population, both because many more lower-mass stars inhabit the universe than higher-mass stars, and because a much larger number are subject to modest speed kicks."

Astronomers have not spotted many of these stellar interlopers before because they are hard to find. "You don't know where to look for them because you cannot predict where they will be," Sahai says. "So all of them have been found serendipitously, including the 14 stars we found with Hubble."

Sahai and his team used Hubble's Advanced Camera for Surveys to examine 35 objects that appeared as bright infrared sources in the IRAS archive. They were looking for long-lived pre-planetary nebulae, puffed-up aging stars on the verge of shedding most of their outer layers to become glowing planetary nebulae. Instead, the astronomers stumbled upon the runaway stars.

The team is planning follow-up studies to search for more interlopers, as well as study selected objects from this Hubble survey in greater detail to understand their effects on their environment.

"One of the questions that these very showy encounters raise is what effect they have on the clouds," says team member Mark Morris of the University of California, Los Angeles. "Is it an insignificant flash in the pan, or do the strong winds from these stars stir up the clouds and thereby slow down their evolution toward forming another generation of stars?"

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Six Things Women Should Know About the Pap Test

January is Cervical Cancer Awareness Month and The University of Texas M. D. Anderson Cancer Center shares important information about the cervical cancer screening exam, the Pap test.

For many women, their annual Pap test is not something to look forward to; however, this test has the potential to make a huge difference in the lives of women everywhere. The Pap test detects cell changes, which may cause cervical cancer. If these cell changes are found and treated early, cervical cancer may be prevented.

Andrea Milbourne, M.D., associate professor in M. D. Anderson's Department of Gynecologic Oncology, explores six facts women should know about this important test.

1. Increased sexual activity equals increased need for a Pap test.

Increased sexual activity raises a woman¹s risk for acquiring the human papilloma virus (HPV). While HPV can be harmless, it also can cause cervical cancer by changing normal cells in the cervix.

"Because condoms do not provide 100 percent protection against HPV, women who are sexually active and not in a monogamous relationship need to be even more vigilant about following cervical cancer screening guidelines," Milbourne said.

2. The HPV vaccine is a supplement, not a replacement for the Pap test.

Getting the HPV vaccine, or encouraging young female family members to consider it, is a great first step toward cervical cancer prevention. That being said, the vaccine is in no way a substitute for the Pap test.

"The vaccine may give women a false sense of security," Milbourne said. "And because getting a Pap test is not what most women consider a favorite activity, getting the vaccine might cause them to procrastinate even more to make an appointment for their next Pap test."

Because the HPV vaccine does not protect against all types of HPV, or other sexually transmitted diseases, it cannot be the only method of cervical cancer prevention. Women also should remember that cervical cancer doesn¹t have many visible symptoms, which makes the Pap test significantly important in preventing cervical cancer.

3. Women should prepare for an upcoming Pap test.

Milbourne recommends a few tips to help women prepare for an upcoming test: * Avoid douching or using vaginal medicines, spermicidal foams, creams or jellies 48 hours before the test. * Do not have sexual intercourse 48 hours before the test. * Reschedule a Pap test appointment if an unexpected heavy menstrual flow occurs on the day of the exam.

"Lubricants, spermicides, douching and sexual activity can interfere with the interpretation of Pap test results, potentially leading to incorrectly interpreted results or the need for repeat tests," Milbourne said.

4. A woman is never too old to get her Pap test.

Of all the benefits that might come with growing older, skipping a regular Pap test for a sexually active woman over age 65 is not one of them.

As female life expectancy gets longer, many women continue to enjoy sexually active lives throughout their sixties and into their seventies.

"For women over age 65, cervical cancer is rare, but it does happen," Milbourne said. "If you are over age 65, sexually active and not in a monogamous relationship, you should continue your annual Pap test, as you are still susceptible to HPV, which can cause cervical cancer."

5. Women can afford a Pap test.

"Without health insurance or access to affordable health care, a Pap test can be costly," Milbourne said. "For women who can not afford a Pap test, there may be places in your community where you can get one for free."

For information on where to get a free or low-cost Pap test, call the National Cancer Institute¹s Cancer Information Service at 1-800-4-CANCER. Pap tests also are sometimes covered by Medicaid and are covered every two years by Medicare or every year for certain women at higher risk. For more information, call 1-800-MEDICARE.

6. Before the Pap test, cervical cancer was a leading cause of death in American women.

The American Cancer Society estimates that about 3,870 women died from cervical cancer in the United States during 2008. This number is low compared to annual statistics for other more common cancer types, such as breast or lung cancer, but what most people do not know is that cervical cancer was once one of the most common causes of cancer death in American women.

As the Pap test became a standard test for American women, doctors were able to find abnormal changes in the cervix before cancer developed. Between 1955 and 1992, the cervical cancer death rate declined by 74 percent.

"While the cervical cancer death rate continues to decline in the United States, women in countries where Pap tests are not as readily available or affordable still face the challenges, shared by American women more than 50 years ago," Milbourne said.

Cervical cancer is the second largest cause of female cancer deaths worldwide, according to the World Health Organization, with 288,000 deaths each year. About 510,000 cases of cervical cancer are reported each year ­ nearly 80 percent are in developing countries.

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New Malaria Drug May Meet Resistance Says Expert

This year, the U.S. Food and Drug Administration is expected to approve the first malaria drug to contain artemisinin, a wormwood derivative from China that has proven effective for malaria in Africa and Asia. Although there are only about 1,500 reported cases of malaria treated in this country each year, this approval would also make the drug available to the military and to Americans planning to go abroad. However, worldwide malaria is still one of the most serious infectious diseases, affecting 2 to 3 billion people, with up to two million deaths annually.

The drug, named Coartem, is made by the Swiss company Novartis. It combines artemether, an artemesinin derivative, with lumefantrine, a drug developed by Chinese scientists, which does not kill parasites as quickly but lingers in the blood a while longer. By mopping up parasites that artemisinin misses, lumefantrine helps prevent resistance that would defeat the drug, as has occurred with other therapies like chloroquine.

According to University of Pennsylvania pharmacologist Doron Greenbaum, Ph.D., although the exact mechanism by which artemisinin kills parasites is still open to considerable debate, the drug likely acts against one or more protein targets that may make it susceptible to resistance that has developed to most other drugs. Drug resistance to artemisinin has already been shown to occur in the laboratory, and reports have already surfaced about potential resistance in malaria endemic regions like southeast Asia. Thus the potential success of Coartem treatment for malaria should be greeted with cautious optimism knowing that resistance is likely to arise and that other new drugs will need to be developed quickly.

Dr. Greenbaum recently reported that small molecule defensin-mimetic compounds discovered by Radnor, Penn.-based biopharmaceutical company PolyMedix, irreversibly kill P. falciparum while sparing human red blood cells. Plasmodium species are responsible for the nearly five hundred million cases of malaria worldwide and as many as two million deaths, most of them in children. As with antimicrobial agents, first-line malaria agents are losing effectiveness due to development of resistance to drugs by the target organisms.

Dr. Greenbaum demonstrated that PolyMedix¹s compounds kill P. falciparum irreversibly, meaning the cells do not recover when the agent is depleted. Irreversible killing distinguishes a ³cidal,² or true killing mechanism, from a ³static² mechanism that holds the infectious agent at bay while the body¹s immune system fights off the infection. ³If we treat for ten hours and remove the compound, the parasites never recover,² notes Dr. Greenbaum. Many antimicrobial and antifungal drugs are of the static variety.

PolyMedix antibiotics are small-molecule non-peptide mimetics of natural host defense peptides that higher animals use to fight infections. In humans these molecules, known as defensins, are about thirty amino acids in length. Although structurally quite dissimilar, defensins and PolyMedix¹s compounds share a common characteristic that is responsible for their anti-infective activity. Both molecules are facially amphiphilic, meaning they possess several polar, or charged chemical groups on one side of the molecule, and hydrophobic groups on the other side. They are believed to work by inserting themselves inside the lipid bilayers of cells that are deficient in cholesterol, thereby causing the cells to rupture and die. Therefore these molecules kill pathogens by targeting membranes rather than proteins. Dr. Greenbaum hypothesizes that this mechanism is employed against both bacteria and Plasmodium.

³As far as we know, the PolyMedix defensin-mimetics are the only anti-infectives with such a biophysical mechanism of action, directly targeting the membrane, whether bacterial, fungal, or parasitic," says Dr. Greenbaum. ³This makes resistance unlikely to develop. Any biochemical/protein-based mechanism of action is susceptible to resistance via efflux or target mutation."

The complex lifecycle of P. falciparum makes malaria difficult to treat once it is established. The organism typically enters the body through a mosquito bite, soon takes residence in the liver, and then migrates to red blood cells. It is the last stage that gives rise to the chronic disease known as malaria. During their lifecycle the organisms take on several distinct morphologic and biological forms. PolyMedix¹s defensin-mimetics show very high killing efficacy against all stages of red cell infection. The next step is to see if the compounds can clear infection in a mouse model, in the liver phase, as well as the red cell stage.

PolyMedix's lead defensin-mimetic antibiotic compound, PMX-30063, is currently in human clinical testing, and is intended to be developed as a broad anti-Staph agent. The first Phase I clinical results with PMX-30063 were announced in December 2008.
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Stroke Belt: Deaths Tied to Non-Traditional Risk Factors

Southerners die from stroke more than in any other U.S. region, but exactly why that happens is unknown. A new report by researchers at the University of Alabama at Birmingham (UAB) and the University of Vermont underscores that geographic and racial differences are not the sole reasons behind the South's higher stroke death rate.

The data is from UAB's Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, which has enrolled more than 30,200 U.S. participants. The study confirms a greater-than 40 percent higher stroke death rate in eight southeastern states known as the Stroke Belt ­ Alabama, Arkansas, Georgia, Louisiana, Mississippi, North and South Carolina and Tennessee.

After factoring in age, race and sex-related factors, the predicted stroke risk was only slightly higher in Stoke Belt states compared to other regions (10.7 percent versus 10.1 percent), said George Howard, Dr.PH., professor of biostatistics in UAB's School of Public Health and a REGARDS principal. That risk was calculated using nine known risk factors common to stroke screening.

"We found geographic and racial differences are useful in predicting stroke risk, but they only explain less than half the picture. Something else is happening," Howard said. "It could be exposure to allergens in the home, it could be micronutrients in drinking water or it could be other factors considered non-traditional because they don't fall into the list of nine factors commonly used to predict stroke risk."

The findings are reported in the Annals of Neurology.

All minority groups, including Native Americans, Hispanics and African-Americans, face a significantly higher risk for stroke and death from stroke compared to whites, and research is focused on exactly why that is, said Mary Cushman, M.D., of the University of Vermont, the study¹s lead author. Continued analysis of REGARDS data and follow-up study will determine other stroke risk factors and their significance.

One detail that emerged in the Annals of Neurology study is that the prevalence of diabetes and hypertension was up to five percentage points higher in the Southeast. That means interventions to reduce geographic disparities in diabetes and hypertension ­ including boosting diabetes screening rates and follow-up care ­ could also reduce geographic disparities in stroke death, Howard said.

REGARDS already has spawned more than 50 accompanying research reports. The study is a research partnership that includes UAB's Departments of Epidemiology, Biostatistics and Preventive Medicine, UAB's Center for Aging and the Center for the Study of Community Health, the University of Vermont in Burlington, the University of Arkansas for Medical Sciences in Little Rock, the University of Cincinnati, Indiana University in Indianapolis, the Alabama Neurological Institute in Birmingham, the Medical University of South Carolina in Charleston and Wake Forest University School of Medicine in Winston-Salem, N.C.

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Friday, February 20, 2009

Replacing Your Total Hip Replacement

Thousands of patients undergo total hip replacement surgery each year in order to help alleviate pain associated with debilitating hip disease and other related hip problems, but there is limited information regarding why many of those hip replacements fail.

So researchers analyzed data from about fifty thousand patients who had to have their hip replacements revised. Based on new diagnosis and procedure codes specifically for hip replacement revision, they were able to identify certain trends.
Researchers found the most common reasons for patients needing subsequent hip replacement surgery include:

    * Dislocation of the implant
    * Loosening of the implant
    * Infection ­ such as staph infections either around the time of surgery or later through the bloodstream

“The reason why this study is important is because up until now it has been believed that the most common reason why hip replacements fail is because the bearing surface wears out. Although our study confirmed that problems related to bearing surface wear do cause hip replacements to fail, we found that other problems ­ including dislocation, implant loosening, and infection - may be even more common causes of hip replacement failure,” explains Bozic. “This suggests that in addition to research aimed at developing better implants, we also need to direct new research efforts to improve care in those three areas.”

Bozic also noted that there are other benefits to having this type of information. “One of our goals is to use these new diagnoses and procedure codes related to hip replacement to help create a national joint replacement registry which is what has been done in many other developed countries. Every patient who has a joint replacement gets entered into a national database and is tracked over time. It allows us to know specifically what happened to their hip replacement and when.”

Results from the study indicate there are things within the surgeon’s control such as surgical technique and the way the implant is installed that physicians should be thinking about as potential causes for failure as opposed to just design factors related to the implants. “Although we now have a better understanding as to why hip replacements fail, we need to do more detailed studies to find out the reasons why dislocation and infection are common causes of hip replacement failure,” said Bozic.

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