Research

Gene Linked to a Rare Form of Progressive Hearing Loss in Males is Identified

A gene associated with a rare form of progressive deafness in males has been identified by an international team of researchers funded by the National Institute on Deafness and Other Communication Disorders. The gene, PRPS1, appears to be crucial in inner ear development and maintenance. The findings are published in the December 17 early online issue of the American Journal of Human Genetics.

"This discovery offers exciting therapeutic implications," said James F. Battey, Jr., M.D., Ph.D., director of the NIDCD. "Not only does it give scientists a way to develop a targeted treatment for hearing loss in boys with this disorder, it may also open doors to the treatment of other types of deafness, including some forms of acquired hearing loss."

The gene is associated with DFN2, a progressive form of deafness that primarily affects males. Boys with DFN2 begin to lose their hearing in both ears roughly between the ages of 5 and 15, and over the course of several decades will experience hearing loss that can range from severe to profound. Their mothers, who carry the defective PRPS1 gene, may experience hearing loss as well, but much later in life and in a milder form. Families with DFN2 have been identified in the United States, Great Britain, and China.

The NIDCD-funded researchers led by Xue Zhong Liu, M.D., Ph.D., of the University of Miami Miller School of Medicine, discovered that the PRPS1 gene encodes the enzyme phosphoribosylpyrophosphate (PRPP) synthetase 1, which produces and regulates PRPP (phospho-ribosylpyrophosphate), and appears to play a key role in inner ear development and maintenance. The four mutations identified in the PRPS1 gene cause a decrease in the production of the PRPP synthetase 1 protein that results in defects in sensory cells (called hair cells) in the inner ear, and eventually leads to progressive deafness.

"PRPS1 is an interesting example of a human disease gene in which gain of function or loss of function mutations cause several different and distinct hereditary disorders," says Dr. Liu. "Our findings emphasize the body's need for tight regulation of PRPP synthetase 1 since a drop in activity can lead to deafness." Other mutations in the PRPS1 gene have been linked to neurodegenerative disorders such as Arts syndrome and a form of Charcot-Marie Tooth disease, both of which feature deafness in the constellation of symptoms.

Knowing that a reduction in the amount of PRPP synthetase 1 is what causes deafness in DFN2, Liu and his colleagues are now exploring potential enzyme replacement therapies to either restore hearing or prevent further hearing loss in boys with DFN2. Since the PRPS1 mutations can be used as a genetic marker for DFN2, in the future at-risk boys could be tested at birth and immediately put on enzyme replacement therapy to reduce or prevent the hearing loss that would ordinarily come later in life.

In addition, the knowledge that scientists gather about the mechanisms of PRPS1 potentially could be used to develop treatments to combat acquired hearing loss, such as the hearing loss caused by drugs that are used in some chemotherapy regimens and treatments for HIV/AIDS. These are powerful and helpful medications, but they have the unfortunate side effect of damaging, even killing, hair cells in the inner ear. The results from this study open the possibility for improving these life-saving treatments by eliminating or reducing the disabling side effect of hearing loss.

In addition to NIDCD support, the following institutions collaborated in this study: Chinese PLA General Hospital, Beijing; University of Science and Technology of China, Hefei; Chinese Academy of Sciences, Hefei; Guizhou Provincial People�s Hospital, GuiYang, China; UCL Institute of Child Health, London; Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Second Medical University, Shanghai; Department of Genetics, Harvard Medical School, Boston; Massachusetts Eye and Ear Infirmary, Boston; and Howard Hughes Medical Institute, Boston.

NIDCD supports and conducts research and research training on the normal and disordered processes of hearing, balance, smell, taste, voice, speech and language and provides health information, based upon scientific discovery, to the public. For more information about NIDCD programs, see the Web site at www.nidcd.nih.gov.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Research

Rocking Embryos Might

Boost IVF Success

Hoping to improve pregnancy rates, researchers try to simulate motion of the human body.

THURSDAY, Jan. 21 (HealthDay News) -- Scientists say they boosted the success of in vitro fertilization in mice by gently rocking embryos before implanting them into the womb.

No evidence yet proves that the same technique would work with human embryos, but authors of a new study hope it might do just that.

"By making the cells feel more at home, we get better cells, which is key to having better infertility treatment," said study co-author Shu Takayama, an associate professor in the University of Michigan's department of biomedical engineering.

The idea of the research is to mimic the motion that an embryo feels traveling through the fallopian tube to the uterus. Human embryos created with the assistance of in vitro fertilization don't get the benefit of such exposure.

The mouse embryos that underwent the rocking treatment with the help of a specially designed device were healthier after four days and had more cells than those grown in dishes. About 77 percent of them resulted in pregnancies when implanted into female mice, compared to 55 percent of those grown in the petri dishes.

The report was published online in the journal Human Reproduction.

Clinical trials of the rocking device have begun in humans through a company formed by the study authors.

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Research

Should HPV Test Replace the

Pap Smear?

Italian researchers urge a change in test for cervical cancer, but U.S. experts are mixed.

By Amanda Gardner
HealthDay Reporter

TUESDAY, Jan. 19 (HealthDay News) -- DNA testing for the human papillomavirus should replace the Pap smear as the main way to screen women for cervical cancer, according to Italian researchers.

Their recommendation is based on a study that found that the human papillomavirus (HPV) test prevented more cases of cervical cancer than the conventional Pap smear. Results of the study were published online Jan. 19 in The Lancet Oncology.

The HPV test should become the screening tool of choice for women 35 and older, the researchers said. It could be done less frequently than the Pap test, which could be used only in women who have tested positive for HPV, they said.

The Pap smear, first introduced in the 1950s, looks for changes in the cervix that could lead to cervical cancer. The HPV test works a step further back in the process, looking to see if women are infected with HPV.

HPV causes cervical cancer, which remains a significant health problem, particularly in less resource-rich areas of the world.

DNA testing for HPV, though, does have drawbacks -- namely that it is less specific, meaning it is likely to pick up more false-positives, than a Pap smear. This results in many more callbacks for women to undergo further testing.

Using HPV as a primary screening tool results in a callback rate of about 25 to 30 percent, said Dr. Mark Einstein, a gynecologic oncologist and director of clinical research at Montefiore Medical Center in New York City. By contrast, Pap smears have a callback rate of about 5 to 7 percent, he said.

For their study, the Italian researchers compared HPV testing alone with HPV testing plus a Pap smear in 94,370 women aged 25 to 60 years old.

During the first phase of the study, women 35 to 60 who tested positive for HPV were given a cervical examination, called a colposcopy. Younger women got a colposcopy if their Pap smear was abnormal or if HPV results were positive several times, indicating that their body had not been able to clear the infection.

Screening for HPV DNA appeared more effective in older women, but the testing in younger women led to over-diagnosis of a particular type of cervical lesion, the study found.

Not all experts agree, though, that current practice would change based on the study's findings alone.

"I don't think this is going to change any strategies we do now, but I do think it's more evidence that HPV testing can predict who's going to develop cervical cancer," said Dr. Jay Brooks, chairman of hematology/oncology at Ochsner Health System in Baton Rouge, La. "HPV testing, in certain populations, can really predict who would benefit from treatment."

Einstein had a somewhat different take on the findings. "This shows that the strategy does work," he said. "It does make sense, it's cost-effective and effective. This is happening in single-payer health systems which have national screening. We're behind in the U.S."

The strategy makes particular sense in less-developed countries, where women could do an HPV test themselves with a "self swab" and then send the swab in for analysis, Einstein said.

In the United States, cervical cancer screening guidelines were changed in November. Women now are being told that they should get their first screening for cervical cancer -- including a Pap test -- at age 21. The previous recommendation was to start Pap tests three years after becoming sexually active or at age 21, whichever came first.

And, rather than have an annual Pap test, most women need to be screened every other year or less, depending on their age, according to the new guidelines.

Cervical cancer rates have dropped more than 50 percent in the last 30 years in the United States, according to the guidelines. That decline has been largely attributed to widespread use of the Pap test.

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Research

Why We Keep Looking

and Looking for Lost Items

Understanding this response has practical application, expert says.

SUNDAY, Jan. 17 (HealthDay News) -- Looking for something? New research provides insight into why we miss things when they're uncommon.

"We know that if you don't find it often, you often don't find it," said Jeremy Wolfe of Harvard Medical School. "Rare stuff gets missed." Wolfe's comments came in a news release from Cell Press, which published a study on the phenomenon online Jan. 14 in Current Biology.

Anyone who's ever tried to find the so-called needle in a haystack knows of what he speaks. But why does this happen?

In a new study, researchers say that people who look for common things don't stop. "When nothing is there, they don't give up on the response," Wolfe said. "It's all terribly adaptive behavior for a beast in the world. If you know berries are there, you keep looking until you find them. If they are never there, you don't spend your time hunting."

When something is rare, we try hard to look for it, but "we aren't well-built for that and make more errors than we'd like," he said.

What to do in places like airports, where security screeners have to look for uncommon objects like weapons? Wolfe said it might be wise to prime people at the beginning of shifts by having them search for common things, then let them go on duty and look for rare things.

The researchers plan to test their theories in airports and in health clinics, where medical employees look for rare things like tumors.

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Research

Moderate Radiation Tied to Heart

Disease, Stroke

Study does not clarify whether exposure from scans raises risk.

FRIDAY, Jan. 15 (HealthDay News) -- New research based on the experiences of atomic-bomb survivors has found a link between exposure to moderate levels of radiation and higher levels of heart disease and stroke.

It's not clear, however, if the radiation directly causes the diseases, nor is it clear if there's a link between lower doses and the health problems.

High doses of radiation to the heart, head or neck have been shown to boost the risk of heart disease or stroke later in life. But the effect of lower doses -- 1 gray (Gy) or less -- needs clarification, experts say, at least in part because of the increasing use of medical scans that rely on radiation.

Average radiation exposure from medical procedures is considerably lower and usually measured in milligray (mGy). An abdominal X-ray exposes the recipient to 1.4 mGy (0.0014 Gy), and an abdominal CT scan puts out a radiation dose of 8.0 mGy (0.008 Gy), according to background information in a news release from BMJ. The journal published a report on the new research online Jan. 15.

For the study, researchers from the Radiation Effects Research Foundation in Japan examined the medical records of 86,611 Hiroshima and Nagasaki atomic-bomb survivors who were followed from 1950 to 2003. All had been exposed to radiation doses from 0 to 4 Gy, with 86 percent exposed to less than 0.2 Gy.

After taking into account the possible effects of such factors as smoking, education and obesity, the researchers determined that the rates of stroke and heart disease went up among those who were exposed to doses higher than 0.5 Gy, which they labeled moderate. They did not clarify how lower doses affected risk.

In an accompanying commentary, Mark Little, of Imperial College London, agreed with the researchers that future study should explore whether low doses of radiation affect the body's biological mechanisms in similar ways.

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Research

HHS HealthBeat

(December 10, 2009)

Living to prevent stroke

Listen to Tip Interested? Take the Next Step

From the U.S. Department of health and Human Services, I’m Ira Dreyfuss with HHS HealthBeat.

Some of the most common things that lead to strokes don’t have to happen. Researcher Paula Yoon of the Centers for Disease Control and Prevention tells us what they are:

"The most common risk factors for stroke are high blood pressure, heart disease, diabetes, and cigarette smoking. So maintaining a healthy lifestyle that includes a healthy diet, physical activity every day, and not smoking are really the most important steps a person can take to prevent stroke." (15 seconds)

Yoon says about three quarters of all strokes happen to people over the age of 65, but she says strokes can happen at any age. When they do, it’s crucial to get medical help immediately, such as by calling 9-1-1. There are potentially life-saving medications for stroke, but they have to be given in the first few hours.

Learn more at hhs.gov.

HHS HealthBeat is a production of the U.S. Department of Health and Human Services. I’m Ira Dreyfuss.

Last revised: December, 10 2009

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Research

Rheumatoid Arthritis Drug Lowers

Flu Shot Effectiveness

But patients should still get vaccinated, researchers say.

MONDAY, Jan. 11 (HealthDay News) -- New research offers a caution to rheumatoid arthritis patients who take the drug rituximab (Rituxan): The flu vaccine is safe, but it's ineffective during the first six months following treatment with Rituxan.

The researchers also found that previous flu vaccination does help provide some protection against the flu, and the vaccine won't make the arthritis symptoms worse.

The study findings are published in the January issue of Arthritis & Rheumatism.

Rheumatoid arthritis, which is caused when the immune system attacks the body, affects about 4.6 million people around the world. Doctors recommend that these patients get vaccinated against influenza each year -- including the H1N1 swine flu this year -- because they have weakened immune systems.

The new study, by Dr. Sander van Assen and colleagues at the University Medical Center Groningen in the Netherlands, included rheumatoid arthritis patients who took rituximab or methotrexate, as well as a group of healthy people.

Those who took rituximab took longer to develop immunity to flu after being vaccinated, the researchers found.

"Individuals who have compromised immune systems, such as with rheumatoid arthritis, are at risk for complications from contracting the flu virus," van Assen said in a news release from the American College of Rheumatology. "We recommend yearly influenza vaccination for all rheumatoid arthritis patients and pre-emptive vaccination for flu should be considered by those patients who start rituximab treatment."

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Research

New York Autopsies Show 2009 H1N1 Influenza Virus Damages Entire Airway

In fatal cases of 2009 H1N1 influenza, the virus can damage cells throughout the respiratory airway, much like the viruses that caused the 1918 and 1957 influenza pandemics, report researchers from the National Institutes of Health (NIH) and the New York City Office of Chief Medical Examiner. The scientists reviewed autopsy reports, hospital records and other clinical data from 34 people who died of 2009 H1N1 influenza infection between May 15 and July 9, 2009. All but two of the deaths occurred in New York City. A microscopic examination of tissues throughout the airways revealed that the virus caused damage primarily to the upper airway—the trachea and bronchial tubes—but tissue damage in the lower airway, including deep in the lungs, was present as well. Evidence of secondary bacterial infection was seen in more than half of the victims.

The team was led by James R. Gill, M.D., of the New York City Office of Chief Medical Examiner and New York University School of Medicine, and Jeffery K. Taubenberger, M.D., Ph.D., of the National Institute of Allergy and Infectious Diseases (NIAID) at NIH. The findings are reported in the Archives of Pathology & Laboratory Medicine, now available online and scheduled to appear in the February 2010 print issue.

“This study provides clinicians with a clear and detailed picture of the disease caused by 2009 H1N1 influenza virus that will help inform patient management,” says NIAID Director Anthony S. Fauci, M.D. “In fatal cases of 2009 H1N1 influenza, it appears the novel pandemic influenza virus produces pulmonary damage that looks very much like that seen in earlier influenza pandemics.”

The new report also underscores the impact 2009 H1N1 influenza is having on younger people. While most deaths from seasonal influenza occur in adults over 65 years old, deaths from 2009 H1N1 influenza occur predominately among younger people. The majority of deaths (62 percent) in the 34 cases studied were among those 25 to 49 years old; two infants were also among the fatal cases.

Ninety-one percent of those autopsied had underlying medical conditions, such as heart disease or respiratory disease, including asthma, before becoming ill with 2009 H1N1 influenza. Seventy-two percent of the adults and adolescents who died were obese. This finding agrees with earlier reports, based on hospital records, linking obesity with an increased risk of death from 2009 H1N1 influenza.

The researchers examined tissue samples from the 34 deceased individuals to assess how 2009 H1N1 influenza virus damaged various parts of the respiratory system. “We saw a spectrum of damage to tissue in both the upper and lower respiratory tracts,” says Dr. Taubenberger. In all cases, the uppermost regions of the respiratory tract—the trachea and bronchial tubes—were inflamed, with severe damage in some cases. In 18 cases, evidence of damage lower down in the finer branches of the bronchial tubes, or bronchioles, was noted. In 25 cases, the researchers found damage to the small globular air sacs, or alveoli, of the lungs.

“This pattern of pathology in the airway tissues is similar to that reported in autopsy findings of victims of both the 1918 and 1957 influenza pandemics,” notes Dr. Taubenberger.

The researchers also examined 33 of the 34 cases for evidence of pulmonary bacterial infections. Of these cases, 18 (55 percent) were positive for such infections. Not all of those individuals who had bacterial pneumonia along with 2009 H1N1 virus infection had been hospitalized, however, indicating that some had acquired their bacterial infections outside of a health-care setting. This raises the possibility, say the authors, that community-acquired bacterial pneumonia is playing a role in the current pandemic. “Even in an era of widespread and early antibiotic use,” write the authors, “bacterial pneumonia remains an important factor for severe or fatal influenza.”

Computerized tomography (CT) lung images were available in four cases of pulmonary bacterial infection. In all four cases, the CT scans showed an abnormality known as ground-glass opacity, which are patches of rounded haze not seen in normal lung images. It is not known, say the researchers, whether the abnormalities detected by CT in the four cases also occur in people who have milder H1N1 infections. They call for additional investigation into the utility of CT scans as a tool to help clinicians identify and better treat severe H1N1 infections.

---

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at

The National Institutes of Health (NIH)—The Nation's Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit

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Insights into How HIV Evades Immune System

New details about how antibodies bind the human immunodeficiency virus (HIV) may help bring researchers closer to creating an effective HIV vaccine.

Artist’s illustration of HIV.

Vaccines typically work by triggering the immune system to produce antibodies that help to beat infections. But most antibodies can't latch onto and neutralize HIV. The proteins on the surface of the virus mutate rapidly and change shape continuously. They're also covered with immune-evading carbohydrates called glycans.

NIH scientists recently focused on one of these HIV surface proteins, called gp120. HIV uses what are called envelope spikes, or trimers, to bind and infect cells. These spikes support three gp120 molecules, which HIV uses to grip and to gain entry into the cells it infects.

Researchers had a major breakthrough in 2007 when they identified an unchanging region of gp120 as a potential site of viral weakness. Further studies, however, found that the vast majority of antibodies that bound to this site don't block HIV from infecting cells. Dr. Peter D. Kwong at the Vaccine Research Center of NIH's National Institute of Allergy and Infectious Diseases (NIAID) headed a research team investigating how the virus resists these antibodies.

The scientists revealed the virus's trick in the November 20, 2009, edition of Science. They determined the crystal structures of two poorly neutralizing human antibodies in complex with gp120. These antibodies bind to gp120, they found, with a key portion of the protein swung in or flared out. When swung in or flared out, gp120 doesn’t fit into the shape required to form the functional viral spike. In contrast, when a rare neutralizing antibody called b12 binds, gp120 is in the shape required to form the functional spike.

Most antibodies to gp120 don't bind its functional form, the researchers found. That's why they can't effectively neutralize HIV. "When an antibody binds to something that's quite flexible, it induces or selects shapes that are not necessarily appropriate for function," Kwong explains. "In the functional viral spike, gp120 assumes a very specific shape. Most antibodies can't see that particular shape."

This study highlights the challenge of generating HIV-neutralizing antibodies. Most gp120 appears as inactive single molecules or in viral debris. Future vaccines will have to generate antibodies to target the site of vulnerability on gp120 in the envelope spike. "We now know the factors guarding the site," Kwong says. "The next step is learning how to overcome those barriers."

Kwong points out that people with HIV can generate antibodies to this site—in fact, that's how it was discovered in the first place. "We just haven't yet learned how to do that by vaccination," he says, "but we're working on it."

—by Harrison Wein, Ph.D.

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Medical and science information

Spiritual Needs Rank High as Death

From Cancer Nears

Being 'at peace with God' affects medical choices, study finds.

By Serena Gordon
HealthDay Reporter

FRIDAY, Dec. 18 (HealthDay News) -- Addressing the spiritual needs of someone with advanced cancer could be just as important as taking care of their medical needs, a new study suggests.

When asked what was important to them at the end of their lives, people dying of cancer ranked two factors highest: pain control and being at peace with God, the study found.

"Medicine tends to focus on the more scientific aspects of the person, and we've made wonderful strides in improving patient care, but there's another important component of patient health: spirituality," explained Dr. Tracy Anne Balboni, a radiation oncologist at the Dana-Farber Cancer Institute in Boston and the study's lead author. "This is clearly an area where some important advancements can be made."

The researchers discovered that people with advanced cancer were far more likely to choose hospice care when their spiritual needs had been addressed. And among those who were very religious, meeting spiritual needs increased the odds that a terminal patient would choose to forgo aggressive, yet often unsuccessful, medical treatments, the study found.

However, at least six of 10 people with advanced cancer reported that their spiritual needs were only minimally or not at all supported.

Results of the study were published online Dec. 14 in the Journal of Clinical Oncology.

Earlier research had found that the most religious patients are much more likely to choose aggressive treatments during their last week of life in an attempt to prolong their life -- even if those treatments don't improve their quality of life. Aggressive treatments include mechanical ventilation and cardiopulmonary resuscitation.

"A religious person might think they need to do aggressive care," said Balboni, adding that they may feel it's wrong to give up. "But, if the medical team engages them more, they can help them understand that it's not necessarily against their religion to forgo futile medical procedures."

The new study involved 670 people with advanced cancer from seven treatment centers in the Northeast and Texas. The final analysis included information from 343 people who later died and whose caregivers completed a post-death interview. The average time between the start of the study and the person's death was 116 days.

For purposes of the study, spiritual care was defined as patient-perceived support of their spiritual needs by their medical team and the receipt of pastoral care services.

Most people (60 percent) said that their spiritual needs either hadn't been met or were minimally supported at the start of the study, and 54 percent had not received pastoral care visits. In the final week of life, 73 percent of the participants received hospice care, and 17 percent received aggressive care.

Those who had greater spiritual support from their medical team, including doctors, nurses, chaplains and more, reported a higher quality of life as they neared death than did those who felt unsupported spiritually.

People who felt they were getting better spiritual support were 3½ times more likely to receive hospice care. And among highly religious people, those whose spiritual needs were supported were five times more likely to receive hospice care and five times less likely to receive aggressive medical care, the study reported.

"We found that patients whose spiritual needs were well-supported seemed to transition to hospice more frequently and had a marked reduction in the use of aggressive care," Balboni said.

Yet despite the findings, said Dr. Harold G. Koenig, co-director of the Center for Spirituality, Theology and Health at Duke University Medical Center, "few people are getting their spiritual needs met by the medical system."

"Many doctors are uncomfortable discussing spirituality and haven't been trained to do so," he said. "And churches have a role, too. Although it's not a popular topic, churches need to talk about the end of life in the pulpit. People don't know theologically what they're supposed to do."

Religious people, Koenig said, are often left to think they should always have hope and should always "give God a chance to provide a miracle." Hospice care, though, can often provide spiritual guidance and help people prepare for death, he said.

Doctors don't need to actually provide spiritual care, Koenig said, but it's important for physicians to acknowledge their patients' spiritual needs and make sure they're addressed by pastoral care or hospice. "The doctor does have to be the one to orchestrate this," he said.

But if someone's spiritual needs are not being met, Koenig and Balboni agreed that the person -- or a friend or family member -- needs to speak up. And if the patient's doctor doesn't feel qualified to discuss end-of-life spiritual issues, the doctor should be able to refer you to someone who can.

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Clinical Research Training Offered by the NIH Clinical Center has Record Enrollment

Educational courses offered annually by the National Institutes of Health Clinical Center have record enrollments for the 2009-2010 term.

Introduction to Principles and Practice of Clinical Research covers the basics of how to conduct clinical research. This year, 1,296 students are enrolled — 462 in the on-site program at the NIH Clinical Center in Bethesda, Md. Another 834 students are participating through video links to 26 sites around the world. The course has had nearly 9,000 enrollees since its inception in 1995. Topics include an introduction to clinical research and its history; clinical research from a patient�s perspective; data analysis techniques; ethical and regulatory issues; and how to plan, design and fund clinical research studies.

Principles of Clinical Pharmacology has 813 students this year — 385 at NIH and 428 participating through video cast to 21 other locations. The course is designed for researchers interested in the clinical pharmacologic aspects of drug development and use. More than 5,000 students have enrolled since the course was first offered in 1998.

Ethical and Regulatory Aspects of Clinical Research covers a broad range of issues central to the ethical conduct of clinical research. This year, 293 students are participating at the Clinical Center and through video cast to six locations. Nearly 4,000 students have taken this course since it began in 1999.

"This program, made of three courses, was initiated to help improve how clinical research, research involving patient-volunteers, is carried out. The training is comprehensive and easy to access," said Dr. John I. Gallin, director of the Clinical Center, the clinical research hospital at NIH. "Our goal is to help prepare the next generation of clinical researchers and ensure that current clinical research is safe, efficient, and ethical."

"Clinical research is a multidisciplinary enterprise, and these courses attract the full range of health professionals," said Dr. Frederick P. Ognibene, Clinical Center deputy director for educational affairs and strategic partnerships and director of the Office of Clinical Research Training and Medical Education.

In the United States, Introduction to the Principles and Practice of Clinical Research is available through videocast to sites that include Howard University, Walter Reed Army Medical Center, and Children�s National Medical Center in Washington; Oklahoma State University�s Department of Nutritional Services; and Harbor UCLA Medical Center in Torrance, Calif. Registrants from around the world also view the course, including students at medical and technical universities in China, Peru, Burkina Faso (West Africa), Pakistan, and South Korea.

Principles of Clinical Pharmacology is videocast this year to sites that include University of California, Los Angeles, Case Western Reserve University, and hospitals in South Korea and Peru. Videocast sites for the ethics course include National Cancer Institute facilities in Frederick, Md., St. Elizabeths Hospital in Washington., the U.S. Naval Medical Research Center Detachment in Peru and the Western Institute Review Board in Washington.

More information about this and other educational opportunities at the NIH Clinical Center is online, http://clinicalcenter.nih.gov/training.

The NIH Clinical Center (CC) is the clinical research hospital for the National Institutes of Health. Through clinical research, physician-investigators translate laboratory discoveries into better treatments, therapies and interventions to improve the nation's health. For more information, visit http://clinicalcenter.nih.gov.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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Genetic Test May Someday Help Spot Breast Cancer

Positioning of genes could aid in detecting whether cells are cancerous, experts say

URL of this page: http://www.nlm.nih.gov/medlineplus/news/fullstory_92814.html (*this news item will not be available after 03/09/2010)

HealthDayWednesday, December 9, 2009

WEDNESDAY, Dec. 9 (HealthDay News) -- A new method of testing for breast tumors might one day all but eliminate false positives and false negatives from breast cancer diagnosis, new research suggests.

Within the cell nucleus, chromosomes and individual genes occupy specific locations relative to one another. That organization can change for many reasons, but one of them is cancer.

Researchers from the U.S. National Cancer Institute have honed in on several genes that have a different physical position inside the nucleus in invasive breast cancer cells than in normal breast tissue cells. A change in the position of one gene in particular, HES5, predicted invasive breast cancer nearly all of the time, they found.

The discovery suggests that looking at three-dimensional properties of the cell could one day be used as a new method of diagnosing breast cancer.

"Our hope is that our method would be useful as an early marker," said Tom Misteli, a cell biologist at the National Cancer Institute and the study's lead author. "We know that the position of the gene changes before the activity changes. That is a very, very early event in the tumor formation."

The study was published online Dec. 7 in the Journal of Cell Biology.

Typically, breast tumors are detected by a mammogram, which is basically an X-ray of the breast, or when a woman or her doctor feels a lump. To determine if the mass is cancerous or benign, a doctor would order a biopsy, which involves the removal of a small tissue sample that is then analyzed by a pathologist.

A pathologist looks at such factors as the shape and arrangement of cells to determine if a sample is cancerous. Some cancers are relatively easy to discern, said Dr. Victor Vogel, a breast cancer expert and the American Cancer Society's national vice president for research. But a few cases are judgment calls that even the most experienced pathologist isn't sure about, he said.

"It's just not black and white all the time," Vogel said.

Pathologists can have particular difficulty discerning the difference between non-cancerous hyperplasia, or an excess of cells, and ductal carcinoma in situ, a non-invasive and highly treatable form of breast cancer. At times it can be also difficult to tell the difference between ductal carcinoma in situ and invasive ductal carcinoma, a more aggressive and life threatening form of cancer.

"That's why this paper is so important," Vogel said. "What every pathologist and every patient wants is more diagnostic certainty."

Using 11 normal human breast tissue samples and 14 invasive cancer tissue samples, the researchers identified eight genes that were frequently repositioned in cancer specimens. They found that the repositioning of the gene HES5 indicated breast cancer in nearly all samples.

Previous research had implicated HES5 with cancer, according to background information in the study. In the new study, the researchers also found that changes in the location of several other combinations of two or three genes also indicated cancer with high accuracy.

"If validated in a larger number of samples, we envision that this approach may be a useful first molecular indicator of cancer after an abnormal mammogram," Misteli said. "Our method of cancer diagnosis is not limited to breast cancer and may be applied to any cancer type in which repositioned genes can be identified."

The next step, he said, is to replicate the findings using more tissue samples. "We think this method will be used in combination with conventional methods [such as mammogram and biopsy] but will make detection a lot stronger."

SOURCES: Tom Misteli, Ph.D., cell biologist and senior investigator, U.S. National Cancer Institute, Bethesda, Md.; Victor Vogel, M.D., national vice president, research, American Cancer Society, Atlanta; Dec. 7, 2009, Journal of Cell Biology, online

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Caffeine Doesn't Sober You Up

Finding suggests alcoholic 'energy' drinks could boost risks from intoxication

URL of this page: http://www.nlm.nih.gov/medlineplus/news/fullstory_92809.html (*this news item will not be available after 03/09/2010)

HealthDayWednesday, December 9, 2009

WEDNESDAY, Dec. 9 (HealthDay News) -- Downing a cup or two of coffee after a few belts of liquor won't sober you up enough to get you safely behind the wheel of a car, new research concludes.

Alcohol may lessen the effects of caffeine, but caffeine doesn't mitigate the impaired decision-making brought on by alcohol, the study found.

The implications of the study are also especially important for younger people, to whom many of the new high-octane, alcohol-caffeine combination drinks are marketed, the researchers added.

"Caffeine decreases the sedative effects of alcohol but it doesn't improve cognitive function, which means that decision-making processes may be compromised," said Thomas Gould, co-author of the study published in the current issue of the journal Behavioral Neursocience. "People assume they're not as drunk as they are and the impaired cognition that remains may lead to poor choices and decision-making. And people often drink more when it's a caffeine-alcohol mix."

"Caffeine doesn't change blood alcohol levels and it doesn't change things as far as being able to make proper choices, and those can lead to very dire consequences," added Gould, director of Brain and Cognitive Sciences at Temple University in Philadelphia.

"Alcohol and coffee are not a good mix," agreed Jean Bidlack, a professor of pharmacology and physiology at the University of Rochester Medical Center in New York.

The U.S. Food and Drug Administration is looking into the safety and legality of making and selling popular alcohol drinks that contain caffeine. In November, the agency sent letters to nearly 30 manufacturers of such drinks, which are marketed under names such as "Joose," "Spykes" and "Sparks," asking them to show why their products are safe and under what authority they think they can sell them.

According to an FDA news release, up to 26 percent of college students consume these high-octane beverages.

"There is a folklore that caffeine can sober you up," Gould said. "We were explicitly testing to see if caffeine could improve alcohol-induced deficits in cognition."

Gould's team observed the behavior of mice that had been given ethanol, caffeine, or a combination of the two, in a specially designed maze.

Mice under the influence of ethanol had less anxiety and a reduced ability to learn, although they moved around more. This basically meant they were bumping into things they should have known were there.

Conversely, caffeine produced anxiety while decreasing both locomotion and learning.

When given together, ethanol interfered with caffeine's anxiety-producing effect, but caffeine could not restore ethanol's effects on learning. What you got was a laid-back mouse prone to taking risks and not knowing it was taking risks, the researchers said.

"This adds to the growing body of evidence that individuals who combine caffeinated energy drinks with alcohol may be inadvertently putting themselves at greater risk due to poor decision-making and the misperception that their judgment is intact," said Jeffrey T. Parsons, chairman of psychology at Hunter College in New York City.

"One of the cautions [about the new study] is that this is an animal model, so we need to do more research to test this with humans. But I think the take-home message is a rum and coke isn't going to stop you from being intoxicated and potentially making bad decisions," he added.

Added Bonnie Levin, an associate professor of neurology at the University of Miami Miller School of Medicine, "Younger people are already more prone to risk-taking and impulsive decision-taking."

SOURCES: Thomas Gould, Ph.D., associate professor, psychology, and director, Brain and Cognitive Sciences, Temple University, Philadelphia; Bonnie Levin, Ph.D., associate professor, neurology, University of Miami Miller School of Medicine; Jean Bidlack, Ph.D., professor, pharmacology and physiology, University of Rochester Medical Center, Rochester, N.Y.; Jeffrey T. Parsons, Ph.D., professor and chairman, psychology, Hunter College, New York City; December 2009 Behavioral Neuroscience

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Bone Marrow Transplants May Cure Sickle Cell in Adults

Previously, only children could get transplants because adults were thought to be too sick to handle the procedure

URL of this page: http://www.nlm.nih.gov/medlineplus/news/fullstory_92818.html (*this news item will not be available after 03/09/2010)

HealthDayWednesday, December 9, 2009

WEDNESDAY, Dec. 9 (HealthDay News) -- Researchers say that a new method of bone marrow transplantation cured nine out of 10 adult patients with sickle cell disease, an inherited condition that causes bouts of severe pain, organ damage and sharply limits life expectancy.

Adults have typically not been candidates because they were thought to be too sick to handle the high doses of chemotherapy and radiation necessary to prep the body for the procedure, explained senior study author Dr. John Tisdale, a senior investigator in the molecular and clinical hematology branch at the U.S. National Institutes of Health.

Until now, transplantation was generally reserved for more resilient children, whose bodies had not yet suffered as much damage from sickle cell disease.

But the new method allows for a less grueling pre-transplantation routine, one that even adults with severe sickle cell can tolerate.

More than 70,000 Americans suffer from sickle cell disease, and it is especially common among blacks. People with the disease have abnormal, crescent-shaped hemoglobin. The abnormal cells have difficulty passing through small blood vessels, causing blockages and damaging tissues. Over time, the damage can lead to stroke and severe bouts of pain in the chest, arms, legs, chest and abdomen. Sickle cell disease also damages the kidneys, liver and spleen, leaving people, especially children, more susceptible to infection, said Dr. Lanetta Jordan, chief medical officer for the Sickle Cell Disease Association of America.

Treatments include prophylactic antibiotics to fight infections, blood transfusions and hydroxyurea, the only drug U.S. Food and Drug Administration-approved drug for treating sickle cell, Jordan said.

In the new study, Tisdale and his colleagues gave 10 patients ages 16 to 45 with severe sickle cell disease alemtuzumab, a drug used to suppress immune system T-cells; relatively low doses of radiation; and sirolimus, an immune suppressant to fight rejection. Marrow donors were siblings with matched HLA (human leukocyte antigen) markers in their blood.

None of the patients experienced graft-versus-host disease, one of the most common and potentially fatal complications of bone marrow transplants, in which the body rejects the new bone marrow.

After 30 months, all of them are alive, and nine of the patients had successful grafts and are considered cured of sickle cell disease, according to the study.

"It's been transforming for these patients," Tisdale said. "These were the sickest of the sick patients. Some were in the hospital every other week for pain or other crises. Today, some have gone back to school and to work. One patient had a baby."

The last item is important, because in conventional bone marrow transplants, high doses of chemotherapy drugs and radiation typically destroy fertility. However, the lower level of radiation used in the new method does not seem to do this.

The study is published in the Dec. 10 issue of the New England Journal of Medicine.

Conventional bone marrow transplants cure sickle cell disease by first using chemotherapy and radiation to wipe out the person's own marrow, which makes the faulty red blood cells. The marrow is replaced with stem cells from a donor's marrow, which then takes over and begins to produce new, healthy red blood cells.

But when doing the new bone marrow transplants, the researchers noted that not all of the patient's own marrow was wiped out. Some remained and seemed to co-exist with the donor marrow without causing problems, Tisdale said.

"That meant we didn't necessarily have to kill the entire bone marrow of the patient to make this work," Tisdale said, opening the possibility of using an even less toxic means of preparing the body for transplant.

Though most patients in the study are still taking immune-suppressant drugs, researchers hope to eventually wean them off the medications.

Dr. Miguel Abboud, a pediatric hematology/oncology specialist and a professor of pediatrics at the American University of Beirut Medial Center, in Lebanon, said the new protocol is promising, especially since it could eventually include those who don't have an HLA-matched sibling.

"The findings are very significant because adults with very severe sickle cell disease have decreased life expectancy and multiple morbidities but have limited therapeutic options," said Abboud, who wrote an accompanying editorial. "In the past these patients were excluded from transplant studies as they are very poor candidates for high dose chemotherapy regimens. This study makes it possible to offer this subset of patients with severe sickle cell disease stem cell transplants."

Dr. Lakshmanan Krishnamurti, a pediatric hematologist/oncologist at the University of Pittsburgh and director of the Sickle Cell Program at Children's Hospital of Pittsburgh, has done bone marrow transplants in children, also using a less toxic protocol.

"This is an important paper and a big step forward for the field," Krishnamurti said. "Now we are able to say, 'OK, young adults or not so young adults can be transplanted successfully.' That is a very big deal."

SOURCES: John Tisdale, M.D., senior investigator, molecular and clinical hematology branch, U.S. National Heart, Lung, and Blood Institute and U.S. National Institute of Diabetes and Digestive and Kidney Diseases, U.S. National Institutes of Health, Bethesda, MD; Lanetta Jordan, M.D., M.P.H., chief medical officer, Sickle Cell Disease Association of America, Baltimore; Miguel Abboud, M.D., professor of pediatrics, American University of Beirut Medical Center, Beirut, Lebanon; Lakshmanan Krishnamurti, M.D., pediatric hematologist/oncologist, University of Pittsburgh and director, Sickle Cell Program at Children's Hospital, Pittsburgh, Pa.; Dec. 10, 2009, New England Journal of Medicine

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Behavioral Training Improves Connectivity and Function in the Brain

Children with poor reading skills who underwent an intensive, six-month training program to improve their reading ability showed increased connectivity in a particular brain region, in addition to making significant gains in reading, according to a study funded in part by the National Institute of Mental Health (NIMH). The study was published in the Dec. 10, 2009, issue of Neuron.

"We have known that behavioral training can enhance brain function." said NIMH Director Thomas R. Insel, M.D. "The exciting breakthrough here is detecting changes in brain connectivity with behavioral treatment. This finding with reading deficits suggests an exciting new approach to be tested in the treatment of mental disorders, which increasingly appear to be due to problems in specific brain circuits."

For the study, Timothy Keller, Ph.D., and Marcel Just, Ph.D., both of Carnegie Mellon University, randomly assigned 35 poor readers ages 8–12, to an intensive, remedial reading program, and 12 to a control group that received normal classroom instruction. For comparison, the researchers also included 25 children of similar age who were rated as average or above-average readers by their teachers. The average readers also received only normal classroom instruction.

Four remedial reading programs were offered, but few differences in reading improvements were seen among them. As such, results for participants in these programs were evaluated as a group. All of the programs were given over a six month schooling period, for five days a week in 50-minute sessions (100 hours total), with three students per teacher. The focus of these programs was improving readers’ ability to decode unfamiliar words.

Using a technology called diffusion tensor imaging (DTI), the researchers were able to measure structural properties of the children’s white matter, the insulation-clad fibers that provide efficient communication in the central nervous system. Specifically, DTI shows the movement of water molecules through white matter, reflecting the quality of white matter connections. The better the connection, the more the water molecules move in the same direction, providing a higher "bandwidth" for information transfer between brain regions.

At the outset of the study, poor readers showed lower quality white matter than average readers in a brain region called the anterior left centrum semiovale. Six months later, at the completion of the intensive training, the poor readers showed significant increases in the quality of this region. Children who did not receive the training did not show this increase, suggesting that the changes seen in the remedial training group were not due to natural maturation of the brain.

In an effort to further pinpoint the mechanism underlying this change, the researchers deduced that a process called myelination may be key. Myelin is akin to electrical insulation, allowing for more rapid and efficient communication between nerve cells in the brain. However, the directional association between brain changes and reading improvements remains unclear — whether intensive training brings about increased myelination that results in improved word decoding skills, or whether improved word decoding skills leads to changes in reading habits that result in greater myelination.

"Our findings support not only the positive effects of remediation and rehabilitation for reading disabilities, but may also lead to improved treatments for a range of developmental conditions related to brain connectivity, such as autism," noted Just.

The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the www.nimh.nih.gov.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Depression, peers top influences on youth violence

URL of this page: http://www.nlm.nih.gov/medlineplus/news/fullstory_92629.html (*this news item will not be available after 03/03/2010)

Thursday, December 3, 2009

By Anne Harding

NEW YORK (Reuters Health) - Kids who are depressed and have delinquents for friends may be the most likely to lash out violently at others, according to a new study in The Journal of Pediatrics.

The amount of time a youth spent watching violent TV or playing violent video games didn't have anything to do with whether he or she would commit violent acts in real life, Dr. Christopher J. Ferguson of Texas A&M University and his colleagues found.

Ferguson and his team also found that while kids whose parents were psychologically abusive to their intimate partners were more likely to engage in violence, being exposed to a parent's physical abuse of a partner wasn't a factor.

Overall, the researchers found, the factors that did increase the risk of violent behavior had pretty small effects. Based on the findings, they say, future research should probably look at groups of risk factors, rather than focusing on a single one.

A lot of media attention tends to get focused on individual factors, like playing violent video games, Ferguson noted, even when there's no evidence that they're connected with violent behavior.

He and his colleagues investigated the interplay among various risk factors for violent behavior by looking at 603 children 10 to 14 years old and their parents or guardians. Most of the children were Hispanic. Fifteen percent of the children said they had committed non-violent crimes, while 12 percent said they had taken part in violent criminal behavior.

As mentioned, the strongest risk factors for violent behavior were depression and having delinquent peers, the researchers found. Others included a parent's psychological abuse of a partner, antisocial personality, negative relationships with adults, and family conflict.

Based on the findings, Ferguson said it probably makes sense to target programs to prevent youth violence at "depressed kids who are hanging out with other kids who are probably in the same boat."

The good news, he added, is that youth violence has been going down in the US since the late 1960s. "Things are improving for youth globally for the most part, contrary to what most people think today," Ferguson said.

SOURCE: The Journal of Pediatrics, December 2009.

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NIH Awards $20.4 Million for Biomedical Research in Rhode Island and South Carolina

Awards Enhance Research Infrastructure, Increase Competitiveness

Providing adequate research infrastructure, mentoring and training opportunities for biomedical researchers in the fields of regenerative medicine and stem cell biology are the goals of two new Centers of Biomedical Research Excellence (COBRE) awards announced today by the National Institutes of Health. Administered by the National Center for Research Resources (NCRR), the five-year grants totaling $20.4 million have been awarded to Rhode Island Hospital and Clemson University.

The COBRE program supports multidisciplinary centers that concentrate on one core area of research in order to strengthen biomedical faculty research capability and enhance research infrastructure. COBREs are a component of the Institutional Development Award (IDeA) program, which is designed to improve the competitiveness of investigators in states that historically have not received significant levels of competitive NIH research funding.

The new COBRE at Rhode Island Hospital will focus on stem cell biology aimed at identifying unique approaches to tissue reconstruction in lung and marrow diseases. This research may lead to the development of new treatments. One of the main objectives of this COBRE will be to translate basic stem cell studies into clinical trials on tissue restoration or correction.

The Clemson COBRE will concentrate on tissue restoration with the goal of relieving end-stage organ failure and tissue loss. As part of the Clemson COBRE award, several core facilities will be established including a cell and molecular engineering core.

"The COBRE program lays the groundwork to establish and strengthen institutional biomedical research capacity," said NCRR Director Barbara Alving, M.D. "The awards to Rhode Island Hospital and Clemson will create world-class core facilities and assemble talented investigators with the goal of identifying new health discoveries and treatments."

Through the IDeA program, NCRR supports institutions and communities in 23 states and Puerto Rico with grants to fund multiple areas of research and reach out to diverse populations.

New COBRE Awards: For full descriptions of the following awards visit www.ncrr.nih.gov/COBRE/2009-11.

Rhode Island Hospital
$11.1 million
Stem Cell Biology: New Directions in Clinical and Basic Research
Principal Investigator: Peter Quesenberry, M.D.

Clemson University
$9.3 million
South Carolina COBRE Center of Biomaterials for Tissue Regeneration (SCBIOMAT)
Principal Investigator: Naren Vyavahare, Ph.D.

NCRR announced last month that 11 of the existing COBRE centers received a total of $117 million in competitive continuation funding. (See http://www.ncrr.nih.gov/research_infrastructure/2009_COBRE_Awards.asp)

For more general information about the IDeA program, visit www.ncrr.nih.gov/idea.

The National Center for Research Resources (NCRR), a part of NIH, provides laboratory scientists and clinical researchers with the resources and training they need to understand, detect, treat and prevent a wide range of diseases. NCRR supports all aspects of translational and clinical research, connecting researchers, patients and communities across the nation. For more information, visit www.ncrr.nih.gov.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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Recovery Act Funding Seeks to Help Understand Basic Secrets of Aging

The National Institute on Aging (NIA), part of the National Institutes of Health, today announced two major awards to advance exciting areas of basic research on aging. Grants for studies to determine the potential healthy aging effects of rapamycin, a compound involved in regulating cell growth, and to understand the causes of protein misfolding — when a protein is either not formed correctly or damaged afterwards — that lead to age-related disease are made possible through American Recovery and Reinvestment Act funding. These grants are part of the $5 billion that President Obama announced Sept. 30 on the National Institutes of Health campus.

"This is a remarkable time in aging research. Our knowledge about the basic biology of aging has grown rapidly in recent years, and the studies supported with Recovery Act funds provide a wonderful opportunity to build on what we know in some key areas," said NIA Director Richard J. Hodes, M.D. "These studies, at the cellular level, will increase our understanding of some of the basic biological processes that occur with passage of time."

Study in Mice to Determine Possible Healthy Effects of Rapamycin

NIA has awarded $5.2 million over the next two years to the University of Texas Health Science Center in San Antonio to determine the effects of rapamycin on the health of mice.

"In a recent study, a team of researchers reported that rapamycin extended the median and maximal lifespan of mice, when the drug was fed to the mice beginning in middle age. With Recovery Act funding, we can more quickly follow up on these exciting and provocative findings," said Felipe Sierra, Ph.D., director of NIA's Division of Aging Biology.

Rapamycin — an inhibitor of the mTOR pathway that helps to regulate cell growth and proliferation and that is used to help suppress the immune system in people undergoing organ transplant — is one of many compounds being studied for effects that might be similar to those of calorie restriction. Calorie restriction, very low calorie but nutritious diets that have been tested in laboratory animals and on a limited basis in humans, has been found to have variety of positive effects on health and longevity. Despite these findings, calorie restriction may not be practical or safe for most people.

The study, led by Arlan Richardson, Ph.D., will seek answers to three questions:

1. How does rapamycin affect models of age-related human diseases in mice?
2. How does rapamycin affect normal physiology?
3. By what mechanisms does rapamycin work?

"Under normal circumstances, it took over 10 years of research to demonstrate that caloric restriction retarded age-related diseases and increased healthspan. However, Recovery Act funding will allow us to determine in two years if rapamycin can retard or reduce age-related diseases and improve quality of life in mice," said Richardson.

The team will test rapamycin's effects on multiple models of Alzheimer's disease, atherosclerosis, cardiovascular disease, Parkinson's disease, kidney disease and cancer. In addition, investigators will look at rapamycin's effects on the physiology and behavior of healthy mice, focusing special attention on the response to infection, metabolism, movement and cardiac function.

Study to Develop New Technologies to Monitor Protein Folding

NIA has awarded $1 million to Northwestern University in Evanston, Ill., and the Salk Institute in La Jolla, Calif., and $1 million to The Scripps Research Institute in La Jolla, to develop new technologies — biosensors — that will monitor aging and age-related disease by focusing on protein folding.

The proper folding of proteins in cells, or proteostasis, is important for health. Like a three-dimensional puzzle, sections of a protein naturally fold into shapes and then arrange themselves to align to each other to produce the final active protein. A protein's function in the body depends on these folding patterns. If a protein is formed incorrectly or becomes damaged and then misfolds, it disrupts the pattern. As a consequence, the protein does not perform its normal function or cannot be properly disposed of by cellular machinery. These problems and consequences on cellular proteostasis may lead to disease.

"Scientists already know that proper protein folding may be affected by age. Protein misfolding inhibits the body's ability to respond to environmental and/or physiological stresses and cues and could lead to age-related diseases like Alzheimer's or Parkinson's. This Recovery Act funding provides an opportunity to better understand the role of proteostasis and the aging environment in which protein misfolding occurs," said NIA's Sierra.

The Recovery Act funding will also support the development of the Proteostasis Aging Sensor Consortium (PASC) comprised of five investigators, representing leaders in the fields of protein folding, human cell biology and aging. The highly complementary skill sets of these investigators will create synergy to implement these new technologies within the time frame of the Recovery Act funding.

The researchers from Northwestern University led by Richard Morimoto, Ph.D., and from the Salk Institute led by Andrew Dillin, Ph.D., will develop new tools to detect protein misfolding first in a worm model and then in mammalian tissue culture cells. Researchers from The Scripps Research Institute led by William Balch, Ph.D., Jeffery Kelly, Ph.D., and Rockland Wiseman Ph.D., will use some of the tools developed by the Northwestern and Salk teams as well as their own to test protein misfolding in different compartments of mammalian cells in culture and in mice. The five investigators established the PASC to coordinate collaboration in the design, test and use of all the tools designed to follow protein folding and misfolding in cells.

"Aging is highly complex, involving multiple and variable metabolic and biochemical parameters. These studies could lead to first-in-class biosensors that would detect key features of the aging environment and its response to stress and disease," said Richard Morimoto, Ph.D., principal investigator and professor of biochemistry, molecular biology and cell biology at Northwestern University. "Ultimately, biosensors aim to enable researchers to monitor disease progression and the response to therapeutic intervention in real time."

The NIA leads the federal effort supporting and conducting research on aging and the medical, social and behavioral issues of older people. For more information on research and aging, go to www.nia.nih.gov.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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Recovery Funds Advance Alzheimer's Disease Research

American Recovery and Reinvestment Funds are being used to promote the national research efforts to better understand, diagnose and treat Alzheimer's disease. The National Institute on Aging (NIA), part of the National Institutes of Health, has targeted promising areas of research in granting the awards, such as new and ongoing studies to identify additional risk factor genes associated with Alzheimer's, improve diagnostic tools, find biomarkers, develop therapies, conduct clinical trials and explore preventive measures.

"We are delighted to announce the award of Recovery Act funds to many dedicated, hardworking scientists committed to advancing scientific discovery into Alzheimer's disease and cognitive impairment," said NIA Director Richard J. Hodes, M.D. "Over the next two years, the recipients will use this unprecedented boost in research funds to help reach our ultimate goal of understanding age-related cognitive decline and reducing the individual and societal burden of this devastating disease."

More than 100 Alzheimers or Alzheimer's-related research grants were awarded under the Recovery Act. The full list of NIH grants can be found at http://grants.nih.gov/recovery/. The grants featured here highlight how these funds will expand research. Some of the funding will advance the work of existing NIA initiatives that benefit from large-scale collaborative, interdisciplinary research:

The Neuroimaging Initiative — Identifying brain changes before symptoms appear

The Alzheimer's Disease Neuroimaging Initiative (ADNI) will receive $24 million in stimulus funds — half from the NIA and half contributed by the NIH Office of the Director — to further groundbreaking research to establish neuroimaging and biomarker measures. These funds will enable researchers — and ultimately practicing physicians — to track changes in the living brain as older people transition from normal cognitive aging to amnestic mild cognitive impairment (MCI), in which individuals have a memory deficit but generally retain other cognitive abilities, and from MCI to Alzheimers disease. ADNI, a research partnership supported primarily by the NIA with private sector support through the Foundation for NIH, seeks to find neuroimaging and other biological markers that can be used to detect Alzheimer's disease progression and measure the effectiveness of potential therapies.

The original ADNI involved the study of 800 people who ranged from normal to those with late-stage MCI or overt Alzheimers disease. This new grant expands the scope of ongoing research under ADNI by allowing for the enrollment of participants at an earlier stage of MCI, when symptoms are milder. Furthermore, the funding for this new grant will allow ADNI investigators to extend the length of the original study to better assess changes in individuals over time. All of the participants will have neuroimaging scans and blood and cerebrospinal fluid analyses to look for changes in the brain.

The overall impact of the added funding will be increased knowledge of the sequence and timing of events leading to MCI and Alzheimers disease and development of better clinical and imaging/fluid biomarker methods for early detection and for monitoring the progression of these conditions. This will facilitate clinical trials of treatments to slow disease progression and will ultimately contribute to the prevention of Alzheimers disease. Just this year, ADNI made a significant step forward in developing a test to help diagnose the beginning stages of Alzheimers disease sooner and more accurately by measuring levels of two biomarkers — tau and beta-amyloid proteins — in cerebrospinal fluid.

"Researchers and clinicians need imaging and biomarker tools to detect and understand the very earliest signs of pathology that cause changes in the brain some 10 to 20 years before any clinical symptoms of cognitive impairment or Alzheimer's may appear,"said ADNI Principal Investigator Michael Weiner, M.D., of the San Francisco Department of Veterans Affairs Medical Center and the University of California, San Francisco. "This grant will help us in our goal of establishing a panel of biomarkers that predict those at risk of developing the disease and also reveal which therapies may be effective in treating the disease or preventing its progression."

The grant was awarded to the Northern California Institute for Research and Education, a nonprofit research foundation affiliated with the San Francisco VA Medical Center. ADNI is the largest public-private partnership on brain research under way at the NIH. In addition to the NIA, the federal ADNI partners are the National Institute of Biomedical Imaging and Bioengineering, also part of NIH, and the U.S. Food and Drug Administration, another agency of the U.S. Department of Health and Human Services.

The AD Genetics Consortium and more " Identifying genes affecting risk for late-onset Alzheimers

A grant of more than $5.4 million will add 3,800 Alzheimer's patients and an equal number of people free of the disease to a previously funded study by the Alzheimer Disease Genetics Consortium (ADGC). Gerard Schellenberg, Ph.D., University of Pennsylvania School of Medicine, Philadelphia, leads the consortium, which aims to identify the additional risk factor genes for late-onset Alzheimer's disease. All of these study participants are currently enrolled in the NIA-funded national network of 29 Alzheimer's Disease Centers. When added to the samples from other sources, this will make available one of the largest collections of samples to perform genome-wide association studies (GWAS) in an effort to identify the susceptibility and protective genes influencing the onset and progression of late-onset disease. The large number of DNA samples brought together in this study may enable the researchers to detect genes whose individual effects in the disorder may be small but may still play a role.

The ADGC will use research infrastructures previously established by NIA to store and make available to qualified researchers DNA samples, datasets containing a wealth of information about participants, and genetic analysis data. The combined resources will allow scientists also to search for genes associated with a number of traits associated with Alzheimer's, as well as for genes related to cognitive decline.

"This funding will bring us closer to identifying the elusive genetic variations that contribute to overall risk and development of late-onset Alzheimer's disease," said Marcelle Morrison-Bogorad, Ph.D., director of the NIA Division of Neuroscience. "With this large sample size and the rapid DNA sample and data sharing, there are tremendous opportunities for defining new disease pathways that could lead to the development of new therapies."

Additionally, $4.7 million in Recovery Act funds will be used for another important study — a GWAS project examining cognitive decline in older African-Americans. Denis Evans, M.D., of Rush University Medical Center in Chicago, will collect and analyze the DNA of 4,140 elderly African-Americans enrolled in NIA-funded aging studies already taking place in Chicago and Indianapolis. Data from this analysis will also be shared with the ADGC to help identify risk factor genes for cognitive decline and late-onset Alzheimer's. The study will assess the associations of over 900,000 genetic markers with other co-morbidities, including stroke and high blood pressure.

Another $820,000 in Recovery Act funds will advance Alzheimer's genetics research by developing methods for identifying combinations of genes that might influence age-related risk of AD. The role of different forms of translocase of outer mitochondrial membrane (TOMM40), a gene that makes a protein thought to play a role in disease onset, will be studied by Allen Roses, M.D., of the Duke University School of Medicine in Durham, N.C.; Roses discovered the link between the apolipoprotein E (APOE)-epsilon 4 gene and increased risk for late-onset Alzheimer's disease. This new study will investigate whether particular variants of TOMM40 that tend to co-occur with the APOE3 gene also interact with that gene, and if this interaction plays a role in the age of disease onset.

Additional Recovery Act research opportunities

Other studies made possible by the Recovery Act range from clinical trials to epigenomic studies to translational research:

Drug, exercise clinical trials — A clinical trial exploring whether low doses of an anti-epileptic seizure drug, levetiracetam, can improve memory and affect brain function in people with MCI will be conducted with $1.2 million in support. Michela Gallagher, Ph.D., of Johns Hopkins University, Baltimore, will use functional MRI to visualize activity in the hippocampus — a brain area that becomes overactive in MCI patients — while the clinical trial participants receiving either the drug or a placebo engage in memory tasks. In another trial, researchers will examine how exercise training, cognitive training, or a combination of both, might impact immune and inflammatory biomarkers and cognitive health in older adults with MCI. The randomized trial, under a $1 million grant to David Lowenstein, Ph.D., of the University of Miami, will examine a broad array of outcomes and will include Hispanic and non-Hispanic volunteers.

Epigenetics/translational research — A $1 million grant will support a study exploring whether changes in histone acetylation (an epigenetic, or non-genetic factor that causes genes to behave differently) are one way in which a variety of life experiences may influence the risk of developing age-related cognitive decline and dementia. David Bennett, M.D., of Rush University Medical Center, Chicago, will use brain tissues from the NIA-funded Memory and Aging Project and the Religious Orders Study to examine this question. Another epigenomics grant of $819,000 will be used in translational research to test whether overexpressing histone deacetylase (HDAC1) with small molecule probes in the brain may demonstrate therapeutic potential for Alzheimers and stroke patients. Li-Huei Tsai, Ph.D., of Massachusetts Institute of Technology, Boston, will lead the study, which seeks to find out whether abnormal regulation of the protein may play a role in neurological disorders.

The NIA leads the federal effort supporting and conducting research on aging and the medical, social and behavioral issues of older people. For more information on research and aging, go to www.nia.nih.gov.The NIA provides information on age-related cognitive change and neurodegenerative disease specifically at its Alzheimers Disease Education and Referral (ADEAR) Center site at www.nia.nih.gov/Alzheimers. To sign up for e-mail alerts about new findings or publications, please visit either website.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Research

Genetic Changes Tied to Common Form of Parkinson's Disease

Changes in 2 genes known to contain mutations causing rare familial forms of Parkinson's disease have been linked with the more common, sporadic form of the disease.

Parkinson's disease is a progressive neurologic disorder caused by the degeneration of nerve cells in the portion of the brain that controls movement. It affects about 1.5 million Americans. The likelihood of developing the disorder increases with age and involves a combination of environmental and genetic risk factors.

To better understand the genetic contributors, an international research team embarked upon the largest genome-wide association study of Parkinson's disease reported to date. Genome-wide association studies analyze large amounts of DNA to identify subtle genetic variations that contribute to disease. The researchers were led by Dr. Andrew B. Singleton of NIH’s National Institute on Aging (NIA) and Dr. Thomas Gasser of the University of Tubingen in Germany and the German Center for Neurodegenerative Disease. The team was supported in part by NIA, NIH’s National Institute of Neurological Disorders and Stroke (NINDS), National Cancer Institute (NCI) and National Institute of Environmental Health Sciences (NIEHS).

The researchers first analyzed DNA samples of over 1,700 Europeans with Parkinson's disease and about 4,000 without it. In the November 15, 2009, online issue of Nature Genetics, the scientists reported that mutations in the alpha-synuclein (SNCA) gene and microtubule associated protein tau (MAPT) are risk factors for sporadic Parkinson's disease. These initial findings were replicated in a similar group of over 3,300 people with Parkinson's disease and over 4,500 without it.

The researchers exchanged data with colleagues performing a similar study of Japanese people. This second group also found a strong association for SNCA, but not for MAPT. They uncovered evidence for 2 additional risk variants that were then confirmed in the European study. The first, named Park16, was strongest in the Japanese population. The second variant is close to the gene LRRK2, which Singleton and Gasser's groups had previously linked to an inherited form of Parkinson's disease.

These findings support the idea that the sporadic and rare familial forms of Parkinson's disease are related. "With this better understanding of the underlying genetic variants involved in the progress of this disorder, we have more insight into the causes and underlying biology of this disease," says Singleton. "We hope this new understanding will one day provide us with strategies to delay, or even prevent, the development of Parkinson's disease."

"Future genome-wide association studies involving greater numbers of DNA samples will likely reveal additional common genetic risk factors. As we continue to use these and other novel approaches to understand complex diseases, we move closer to a complete understanding of the genetic basis of Parkinson's disease," says NIA Director Dr. Richard J. Hodes.

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