Contact: Amy Molnar
John Wiley & Sons, Inc.
A new study examined the possible associations between occupation and the risk of dying from systemic autoimmune diseases and found that occupational exposures in farming and industry may be linked to higher death rates from these diseases.
More than 8 million Americans suffer from autoimmune diseases, in which the immune system attacks the body’s own tissues and several occupational exposures have been linked to systemic autoimmune diseases, which affect multiple organs. A new study published in the October issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis) examined the possible associations between occupation and the risk of dying from systemic autoimmune diseases and found that occupational exposures in farming and industry may be linked to higher death rates from these diseases.
Led by L.S. Gold and A.J. De Roos, of the Fred Hutchinson Cancer Research Center in Seattle, WA, researchers examined death certificate data from 26 states from 1984 to 1998. Any cases that listed a systemic autoimmune disease (for example, rheumatoid arthritis) as a cause of death, were included, as were disease types with a suspected systemic autoimmune disease origin (such as unspecified connective tissue disorder). Five control subjects matched by age, sex, race, year of death and geographic region were also selected. The researchers established each person’s longest-held occupation from the “usual occupation” listed on the death certificate. In addition, they examined specific exposures based on occupation and industry. These included asbestos, solvents, benzene, pesticides and other substances. Occupations involving significant exposure to the public (such as teachers, and waiters/waitresses) or animals were also tracked.
The results showed that some occupations involving exposure to the public (such as nurses and teachers) were associated with an increased risk of dying from a systemic autoimmune disease but this was not the case with all jobs involving public exposure (for example food service jobs). Farmers showed increased risk of death from systemic autoimmune disease, particularly for those who worked with crops versus livestock. In addition, several industrial occupations such as mining and textile machine operators, as well as timber cutting and logging had an increased risk of death from this group of diseases.
Further analysis showed that the same occupations and exposures were present in those who were older than the typical retirement age when they died, “implying that the occupational exposures were involved in a chronic pathogenic process leading to either disease incidence or slow progression of existing autoimmunity,” according to the authors. They suggest that the higher risk associated with jobs involving public contact may be due to exposure to multiple infectious agents leading to an autoimmune response.
The authors note that autoimmune diseases tend to be underreported on death certificates, and that the increased risk seen with certain occupations, such as teachers, may be due to the fact that these individuals have extensive health benefits even after retirement, and therefore better access to care. This would also help explain why other occupations that involve public contact but lower health insurance coverage, such as waiter/waitress, seemed to have a lower risk of death from autoimmune disease. However, not all the occupational associations they found are expected to be affected by insurance status.
“The size of our study allowed us to estimate associations between specific occupations and death from autoimmune diseases and to generate hypotheses that will be useful as starting points for future studies in this area,” the authors conclude. They note that future studies should focus on obtaining more detailed occupational histories from the groups found to be at increased risk.
Article: “Systemic Autoimmune Disease Mortality and Occupational Exposures,” L.S. Gold, M.H. Ward, M. Dosemeci, A.J. De Roos, Arthritis & Rheumatism, October 2007; (DOI: 10.1002/art.22880).
Mayo Clinic in Jacksonville
Thursday, September 27, 2007
JACKSONVILLE, Fla. — Researchers at Mayo Clinic in Jacksonville have discovered how loss of a gene can lead to accumulation of toxic proteins in the brain, resulting in a common dementia, and they say this mechanism may be important in a number of age-related neurological disorders.
In the Sept. 26 issue of the Journal of Neuroscience, the scientists demonstrate that absence of a gene known as progranulin leads to errant splicing of a protein that usually operates within the nucleus of a nerve cell (neuron). When cut these proteins move into the body of the cell, and begin to stick together and form a thicket that grows, eventually disrupting the normal functioning of the neuron, the researchers say.
Clumps of this protein, TDP-43, have been found in a number of older age dementias, including Alzheimer’s Disease (AD), Frontal Temporal Dementia (FTD), and in amyotrophic lateral sclerosis (ALS).
Not only does the study potentially explain why TDP-43 pathology is present in a number of neurodegenerative diseases, it also offers new research routes to take in looking for beneficial treatments, says the study’s lead investigator, Leonard Petrucelli, Ph.D. “Our work opens opportunities on possible future therapeutic applications, from approaches to novel drug discovery to the continued exploration of cell survival systems,” he says.
Mayo investigators filled in this piece of the dementia puzzle by exploring possible connections between two recent ground-breaking discoveries. In July, 2006, Mayo researchers reported in Nature that a form of FTD not caused by tau accumulation in neurons was due to mutations in the progranulin gene. Progranulin produces a protein that helps neurons survive, and so far, the research group has found more than 40 different mutations in the gene can directly cause FTD.
The second study, reported in October, 2006, in Science by researchers at the University of Pennsylvania School of Medicine, found that the protein clogging brains of patients with FTD and ALS is TDP-43. The protein was recovered from post-mortem brain tissue and was found only in areas affected by the diseases. For example, in ALS patients it was found in the spinal cord motor neurons which control movement, and in patients with FTD, which is second most common form of dementia in people under age 65, clumps of TDP-43 were found in the frontal and temporal lobes which control the judgment and thought process disrupted in the disease. In its normal state, TDP-43 is believed to help genes produce proteins.
In this study, Mayo researchers investigated whether progranulin is involved in TDP-43 processing. Suppressing progranulin expression in neurons led to accumulation of TDP-43 fragments, they found, and further discovered that this cleavage depends on the caspase 3 enzyme. Caspases cut other proteins and thus play a crucial role in pushing a cell to die when it needs to. It makes sense that these caspase might be activated when progranulin is mutated, Dr. Petrucelli says, because loss of progranulin can activate cell death signaling. “We are now looking into how mutations in progranulin leads to an increase in caspase activity,” he says. “Progranulin could be acting a protective chaperone where it binds to TDP-43, and may protect it from cleavage.”
Theoretically, suppression of caspase 3 might stop the cutting and accumulation of TDP-43, but such a strategy could not work clinically given that caspases are needed throughout the body for normal functioning, Dr. Petrucelli says. “However, it might be possible to identify other compounds that specifically prevent the fragmentation and redistribution of TDP-43, and that is an issue we are now studying.”
At this point, researchers don’t know if progranulin mutations are present in ALS or in AD.
The study was funded by the Mayo Clinic Foundation and by the National Institute on Aging, part of the National Institutes of Health. In this study, Yong-Jie Zhang, Ph.D., and Ya-fei Xu, M.D., both of whom contributed equally as first authors, and other Mayo Clinic, Jacksonville, contributors include Dennis Dickson, M.D., and Rachel Bailey, B.S. Other authors include Chad Dickey, Ph.D., from the University of South Florida; Emanuele Buratt,i Ph.D., and Francisco Baralle, M.D., from the International Center for Genetic Engineering and Biotechnology in Trieste, Italy; and Stuart Pickering-Brown, Ph.D., from the University of Manchester in the United Kingdom.
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WASHINGTON, Sept. 26 2007 — Consuming large amounts of caffeine while taking acetaminophen, one of the most widely used painkillers in the United States, could potentially cause liver damage, according to a preliminary laboratory study reported in the Oct. 15 print issue of ACS’ Chemical Research in Toxicology, a monthly journal. The toxic interaction could occur not only from drinking caffeinated beverages while taking the painkiller but also from using large amounts of medications that intentionally combine caffeine and acetaminophen for the treatment of migraine headaches, menstrual discomfort and other conditions, the researchers say.
Health experts have warned for years that consuming excess alcohol while taking acetaminophen can trigger toxic interactions and cause liver damage and even death. However, this is the first time scientists have reported a potentially harmful interaction while taking the painkiller with caffeine, the researchers say.
While the studies are preliminary findings conducted in bacteria and laboratory animals, they suggest that consumers may want to limit caffeine intake — including energy drinks and strong coffee — while taking acetaminophen.
Chemist Sid Nelson, Ph.D., and colleagues, of the University of Washington in Seattle, tested the effects of acetaminophen and caffeine on E. coli bacteria genetically engineered to express a key human enzyme in the liver that detoxifies many prescription and nonprescription drugs. The researchers found that caffeine triples the amount of a toxic byproduct, N-acetyl-p-benzoquinone imine (NAPQI), that the enzyme produces while breaking down acetaminophen. This same toxin is responsible for liver damage and failure in toxic alcohol-acetaminophen interactions, they say.
In previous studies, the same researchers showed that high doses of caffeine can increase the severity of liver damage in rats with acetaminophen-induced liver damage, thus supporting the current finding.
“People should be informed about this potentially harmful interaction,” Nelson says. “The bottom line is that you don’t have to stop taking acetaminophen or stop taking caffeine products, but you do need to monitor your intake more carefully when taking them together, especially if you drink alcohol.”
Nelson points out that the bacteria used in the study were exposed to ‘megadoses’ of both acetaminophen and caffeine, much higher than most individuals would normally consume on a daily basis. Most people would similarly need to consume unusually high levels of these compounds together to have a dangerous effect, but the toxic threshold has not yet been determined, he says.
Certain groups may be more vulnerable to the potentially toxic interaction than others, Nelson says. This includes people who take certain anti-epileptic medications, including carbamazepine and phenobarbital, and those who take St. John’s Wort, a popular herbal supplement. These products have been shown to boost levels of the enzyme that produces the toxic liver metabolite NAPQI, an effect that will likely be heightened when taking both acetaminophen and caffeine together, he says.
Likewise, people who drink a lot of alcohol may be at increased risk for the toxic interaction, Nelson says. That’s because alcohol can trigger the production of yet another liver enzyme that produces the liver toxin NAPQI. The risks are also higher for those who take large amounts of medications that combine both acetaminophen and caffeine, which are often used together as a remedy for migraine headaches, arthritis and other conditions.
The researchers are currently studying the mechanism by which this toxic interaction occurs and are considering human studies in the future, they say. The National Institutes of Health funded the initial animal and bacterial studies.
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“Cooperative Binding of Acetaminophen and Caffeine within the P450 3A4 Active Site,” tx7000702
Print publication date: Oct. 15, 2007
ASAP (online) date: 9-26-07
Contact: Michael Bernstein
American Chemical Society
The song of the canary aids the quest to create medium spiny neurons
Paying close attention to how a canary learns a new song has helped scientists open a new avenue of research against Huntington’s disease – a fatal disorder for which there is currently no cure or even a treatment to slow the disease.
In a paper published Sept. 20 in the Journal of Clinical Investigation, scientists at the University of Rochester Medical Center have shown how stem-cell therapy might someday be used to treat the disease. The team used gene therapy to guide the development of endogenous stem cells in the brains of mice affected by a form of Huntington’s. The mice that were treated lived significantly longer, were healthier, and had many more new, viable brain cells than their counterparts that did not receive the treatment.
While it’s too early to predict whether such a treatment might work in people, it does offer a new approach in the fight against Huntington’s, says neurologist Steven Goldman, M.D., Ph.D., the lead author of the study. The defective gene that causes the disease has been known for more than a decade, but that knowledge hasn’t yet translated to better care for patients.
“There isn’t much out there right now for patients who suffer from this utterly devastating disease,” said Goldman, who is at the forefront developing new techniques to try to bring stem-cell therapy to the bedside of patients. “While the promise of stem cells is broadly discussed for many diseases, it’s actually conditions like Huntington’s – where a very specific type of brain cell in a particular region of the brain is vulnerable – that are most likely to benefit from stem-cell-based therapy.”
The lead authors of the latest paper are Abdellatif Benraiss, Ph.D., research assistant professor at the University, and former post-doctoral associate Sung-Rae Cho, Ph.D., now at Yonsei University in South Korea.
The latest results have their roots in research Goldman did more than 20 years ago as a graduate student at Rockefeller University. In basic neuroscience studies, Goldman was investigating how canaries learn new songs, and he found that every time a canary learns a new song, it creates new brain cells called neurons. His doctoral thesis in 1983 was the first report of neurogenesis – the production of new brain cells – in the adult brain, and opened the door to the possibility that the brain has a font of stem cells that could serve as the source for new cells.
The finding led to a career for Goldman, who has created ways to isolate stem cells. These techniques have allowed Goldman’s group to discover the molecular signals that help determine what specific types of cells they become, and re-create those signals to direct the cells’ development. Benraiss has worked closely with Goldman for more than 10 years on the Huntington’s project.
“The type of brain cell that allows a canary to learn a new song is the same cell type that dies in patients with Huntington’s disease,” said Goldman, professor of Neurology, Neurosurgery, and Pediatrics, and chief of the Division of Cell and Gene Therapy. “Once we worked out the molecular signals that control the development of these brain cells, the next logical step was to try to trigger their regeneration in Huntington’s disease.”
Huntington’s is an inherited disorder that affects about 30,000 people in the U.S. A defective gene results in the death of vital brain cells known as medium spiny neurons, resulting in involuntary movements, problems with coordination, cognitive difficulties, and depression and irritability. The disease usually strikes in young to mid adulthood, in a patient’s 30s or 40s; there is currently no way to slow the progression of the disease, which is fatal.
Stem cells offer a potential pool to replace neurons lost in almost any disease, but first scientists must learn the extensive molecular signaling that shapes their development. The fate of a stem cell depends on scores of biochemical signals – in the brain, a stem cell might become a dopamine-producing neuron, perhaps, or maybe a medium spiny neuron, cells that are destroyed by Parkinson’s and Huntington’s diseases, respectively.
To do this work, Goldman’s team set up a one-two molecular punch as a recipe for generating new medium spiny neurons, to replace those that had become defective in mice with the disease. The team used a cold virus known as adenovirus to carry extra copies of two genes into a region of the mouse brain, called the ventricular wall, that is home to stem cells. This area happens to be very close to the area of the brain, known as the neostriatum, which is affected by Huntington’s disease.
The team put in extra copies of a gene called Noggin, which helps stop stem cells from becoming another type of cell in the brain, an astrocyte. They also put in extra copies of the gene for BDNF (brain-derived neurotrophic factor), which helps stem cells become neurons. Basically, stem cells were bathed in a brew that had extra Noggin and BDNF to direct their development into medium spiny neurons.
The results in mice, which had a severe form of Huntington’s disease, were dramatic. The mice had several thousand newly formed medium spiny neurons in the neostriatum, compared to no new neurons in mice that weren’t treated, and the new neurons formed connections like medium spiny neurons normally do. The mice lived about 17 percent longer and were healthier, more active and more coordinated significantly longer than the untreated mice.
The experiment was designed to test the idea that scientists could generate new medium spiny neurons in an organism where those neurons had already become sick. Now that the capability has been demonstrated, Goldman is working on ways to extend the duration of the improvement. Ultimately he hopes to assess this potential approach to treatment in patients.
“This offers a strategy to restore brain cells that have been lost due to disease. That could perhaps be coupled with other treatments currently under development,” said Goldman. Many of those treatments are being studied at the University, which is home to a Huntington’s Disease Center of Excellence and is the base for the Huntington Study Group.
In addition to Benraiss, Cho, and Goldman, other authors include former Cornell graduate student Eva Chmielnicki, Ph.D.; Johns Hopkins neurosurgeon Amer Samdani, M.D., now at Shriners Children’s Hospital in Philadelphia; and Aris Economides of Regeneron Pharmaceuticals. The work was funded by the National Institute of Neurological Disorders and Stroke, the Hereditary Disease Foundation, and the High Q Foundation.
Contact: Tom Rickey
University of Rochester Medical Center
Time to stand up and be counted, say oncologists
Barcelona, Spain: Recent political decisions have had serious consequences for European oncology, said Professor John Smyth at ECCO 14, the European Cancer Conference, today (Monday 24 September 2007). Professor Smyth, President of the Federation of European Cancer Societies (FECS) said that the new European CanCer Organisation (ECCO) would take an active role in engaging with policymakers to ensure that future legislation did not have a similarly negative impact.
Professor Smyth cited the Clinical Trials Directive and the recent Directive on Physical Agents (Electromagnetic Fields) as two examples of legislation that had had a major negative impact on oncology in Europe. “In the first, the academic oncology community woke up too late and found that the administrative and financial burden of running clinical trials had increased to the extent that many simply gave up,” he said. “Now the Directive on Electromagnetic Fields looks as though it may stop all MRI scanning in Europe. We simply cannot continue to bury our heads in the sand on these issues, which affect doctors and patients alike.”
Forthcoming topics of concern were the problems of international collaboration on stem cell research where European countries had widely differing legislation, and the whole area of the escalating cost of cancer treatment. “The successful development of many new anti-cancer drugs in recent years is challenging every health economic programme in Europe,” said Professor Smyth. “It is imperative to find ways to improve the cost effectiveness of cancer treatment in general, and particularly the use of drugs. Improving the cost effective use of medicines is a major priority for industry, politicians and the public at large.
“Due to these new and improved treatments, screening, and earlier and better diagnosis, cancer patients are living longer and better lives. But how will the huge financial burden on society that this implies be met” ECCO will be asking governments and the European Commission to consider these issues as a matter or urgency.”
ECCO will bring together major players in cancer research, treatment, and care in order to create awareness of patients’ wishes and needs, encourage progressive thinking in cancer policy, education, and training, and continue to promote European cancer research and its application through the organisation of multi-disciplinary meetings and conferences, he said.
“The difference between the new ECCO and the old FECS will be that the new organisation has decided to take a far more active role in engaging with policymakers to promote the interests of both cancer patients, those who care for them; and those without whose research there would be no advances in treatment and care,” he said. “For too long oncologists have sat back and said that getting involved in politics is not their business, and recent events have shown us that this is an attitude which is no longer sustainable.”
The last two years had given ample opportunity for reflection, said Professor Smyth. “Not only did we consult our members, but we also carried out an audit of many players in oncology, patient groups, media, and other stakeholders. They all told us the same thing – they wanted to see a democratic, representative, and visionary organisation tackle the problems that are currently besetting oncology science and practice. An organisation that would provide consistently dependable information on the state of oncology in Europe, and through that information provision would strive to improve the lot of everyone involved in cancer.
“It is a daunting task, but one that needs to be undertaken. And we will do our very best to carry it out.”
Notes for Editors:
1. Invitations to join ECCO (http://www.ecco-org.eu/) have been sent to the FECS Founding Members: EACR, EONS, ESSO, ESMO, ESTRO, and SIOP Europe.
Members and Advisory Council: EANO, EORTC, ESGO, ESO, ESOP, Euroskin, and EUSOMA, EBMT, ECL, Europa Donna, FAC, OECI, and UICC.
2. The Clinical Trials Directive 2001/20/EC came into force in 2004. Its aim was to harmonise national legislation on the conduct of clinical trials and to create a level playing field for European clinical research. In fact it seems to have had the opposite effect, with academic researchers finding that the extra administrative and financial burden that it imposes impedes severely their chances of carrying independent, objective research.
3. The Physical Agents (Electromagnetic Fields) Directive 2004/40/EC is intended to protect workers from electromagnetic radiation. However, its implementation in its current form would effectively ban all MRI scanning in Europe, since the limits it sets to occupational radiation exposure would mean that anyone working or moving near MRI equipment will breach them, thus making it possible for them to sue their employers.
Phase of illness plays large role in distress; Interventions should be targeted to spouses along with patients
ANN ARBOR, Mich. – A cancer diagnosis affects more than just the patient. A new study from researchers at the University of Michigan Comprehensive Cancer Center finds spouses report similar physical and emotional quality of life as the patient.
The study found that what really impacted emotional distress – among both patients and their spouses – was whether the patient was newly diagnosed, facing a recurrence or living with advanced disease.
Researchers looked at 263 men with prostate cancer and their spouses. Participants were recruited from three large cancer centers. Both the men and their wives completed questionnaires that assessed quality of life, including physical, social, family, emotional and functional issues. Patients and spouses each reported on their own quality of life.
The researchers found little difference in quality of life between patients and spouses, but found significant differences based on the phase of their illness. Couples coping with advanced disease had significantly poorer overall quality of life.
“The spouses of advanced cancer patients are really carrying the load. Cancer is a devastating illness, and a patient’s primary resource is the partner, who often doesn’t have the information she needs to deal with these complex problems. This isn’t just a common cold – this is the person you love and care about dealing with a life-threatening illness,” says lead study author Laurel Northouse, Ph.D., R.N., co-director of the Socio-Behavioral Program at the U-M Comprehensive Cancer Center and Mary Lou Willard French Professor of Nursing at the U-M School of Nursing.
Results of the study appear in the Sept. 20 issue of the Journal of Clinical Oncology.
Spouses reported lower confidence than patients in their ability to manage the illness, and more uncertainty about the illness. Patients also reported more social support than did spouses.
“Doctors, nurses and even family and friends often focus mainly on the patient who has cancer and don’t realize the illness has enormous ramifications on the family, especially the spouse,” Northouse says.
The researchers urge more health care interventions aimed at emotional distress for both patients and caregivers. At the same time, caregivers should recognize they too are emotionally affected by this illness and seek appropriate support. Patients also can play a role by encouraging their spouse to be actively involved in their care.
“Patients need to recognize this illness affects their partners as well as themselves. They need to find a way to be supportive of their partner; for example, including them in interactions with physicians so the partners get the information they desperately want. Work as a team together to deal with the illness. I think patients may underestimate the needs of their partners to get information. Those partners need first-hand information. If they’re able to go into the consultation, they’re able to get their questions answered,” Northouse says.
In addition to Northouse, study authors were James Montie, M.D., Valassis Professor of Urologic Oncology and chair of urology at U-M; Howard Sandler, M.D., U-M professor of radiation oncology; Maha Hussain, M.D., U-M professor of internal medicine and urology; Kenneth Pienta, M.D., U-M professor of internal medicine and urology; David Smith, M.D., U-M professor of internal medicine and urology; Darlene Mood, Ph.D., and Jeffrey Forman, M.D., both from Wayne State University and Karmanos Cancer Center; Martin Sanda, M.D., from Harvard Medical School; and Trace Kershaw, Ph.D., from Yale University.
Funding for the study was from the National Cancer Institute.
Reference: Journal of Clinical Oncology, Vol. 25, No. 27, Sept. 20, 2007
Contact: Nicole Fawcett
University of Michigan Health System
PHILADELPHIA — Researchers at the University of Pennsylvania School of Medicine and the Agency for Healthcare Research and Quality (AHRQ) have developed a framework to help hospital managers, physicians, and nurses handle the tough challenges of implementing health information technology (HIT) by directly addressing the unintended consequences that undermine safety and quality.
As documented in a 2005 JAMA article by Penn’s Ross Koppel, PhD, computerized physician order entries, CPOE for short, reduce medication errors due to transcription or hand-writing deficiencies but produce many unintended consequences. For example, in some CPOE systems, physicians must enter the patient’s weight before ordering some types of medications. Physicians will often insert an estimated weight just to order the desired medication, without being able to indicate it as an estimation. That number is then used by subsequent physicians for medications requiring more careful weight measurements. Koppel is the Principal Investigator of an AHRQ-supported study of hospital workplace culture and medication error at Penn’s Center for Clinical Epidemiology and Biostatistics and a faculty member in Penn’s Sociology Department.
In this new paper, co-authors Koppel, AHRQ’s Michael I. Harrison, PhD, and Shirly Bar-Lev, PhD, from the Ruppin Academic Center, Israel, show managers and clinicians how to avoid or catch unintended consequences before they cause lasting harm. This study appears in the September issue of the Journal of American Medical Informatics Association – JAMIA.
Use of sophisticated HIT in hospitals is increasing dramatically. In addition to CPOE, other examples in which unintended consequences can occur are decision support systems and electronic medical records. Health care facilities are investing millions of dollars in health care information technology as they seek to improve patient care, safety, efficiency, and cost savings. Yet the results are often disappointing, say the researchers.
“Managers and clinicians need to prevent more undesirable side effects and recognize unforeseeable consequences early on,” says lead author Harrison. “Then they can take steps to remedy them before damage mounts.”
The authors demonstrate how new HIT changes workplace processes and how practitioners alter these technologies during use. The authors call their new paradigm “Interactive Sociotechnical Analysis.”
“We are strong proponents of HIT,” say Harrison and Koppel. “But introducing HIT is not like adding a fax machine. HIT involves a whole set of activities and interactions with existing IT, people, the built environment, and with other systems. These interactions generate unpredictable developments. We map these developments to inspire greater awareness of IT implementation problems and increased action to improve new IT systems.”
“Decision makers are taking unnecessary risks if they wait for HIT projects to run for a year or two before doing a post-hoc evaluation,” observes Harrison. “Real time evaluations can reveal unintended consequences as they emerge, allowing remedial action to be taken.”
This release can be viewed at http://www.pennhealth.com/news
PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System.
Penn’s School of Medicine is currently ranked #3 in the nation in U.S.News & World Report’s survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals — its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation’s first hospital; and Penn Presbyterian Medical Center — a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.
Contact: Karen Kreeger
University of Pennsylvania School of Medicine
Intercampus initiative works to increase participation in clinical trials; first phase of study to focus on cancer
Sept. 13, 2007
NEW YORK — Before a new treatment becomes available, researchers must recruit hundreds or thousands of patients to participate in clinical research trials. But finding these patients is often difficult. Many potential candidates are unaware of the studies or unable to participate due do logistical hurdles. As a result, patients miss out on opportunities for novel treatment approaches — and beneficial new therapies take longer to reach the public.
In a new initiative, researchers at Weill Cornell Medical College (WCMC) and Cornell’s College of Agriculture and Life Sciences (CALS) have teamed up to develop strategies to better understand and enhance patient participation in clinical trials. The project, called Improving Methods for Patient Accrual to Clinical Trials (IMPACT), is one of several recent efforts at WCMC to foster clinical research programs across the medical spectrum.
“Low patient accrual in clinical trials poses a serious problem for the advancement of medical science,” said John Leonard, professor of medicine at WCMC, attending physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center and co-leader of the study.
The time required to conduct clinical trials is widely recognized as a limiting step in moving novel treatments forward, Leonard said. For example, less than 2 percent of patients choose to participate in clinical trials for cancer therapies across the United States. Even a modest increase of 2 to 3 percentage points would make a major impact, meaning the difference between completing a study in two years instead of three years — and potentially resulting in thousands of lives saved if the standard of care is improved more rapidly.
“Hundreds of studies have sought to identify and overcome barriers to enrollment. This project is the first to assess the problem from a socio-psychological perspective using the specialized methods of risk communication,” said Katherine McComas, principal leader of IMPACT and assistant professor of communication at Cornell. “We will be using two proven approaches — the model of Risk Information Seeking and Processing, and Theory of Planned Behavior. These will allow us to examine specific factors that influence how patients inform themselves about a clinical trial and decide whether to participate.”
IMPACT investigators will collaborate with The Leukemia and Lymphoma Society, which has helped finance the first phase of the project, including a national survey on attitudes toward participation in clinical trials. The funding will also support a doctoral student in the Department of Communication.
“Our aim is to provide data-supported recommendations for strategies to improve the accrual of patients in clinical trials,” said Andrew Dannenberg, also a co-leader of the IMPACT project, professor of medicine at WCMC and attending physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
Future phases of the study will develop specific tools to better educate patients about clinical trials and break down common barriers to participation, Dannenberg added, “so that new therapies for many disorders can be more rapidly designed and evaluated in order to deliver their maximal benefit.”
14 September 2007
The area covered by sea ice in the Arctic has shrunk to its lowest level this week since satellite measurements began nearly 30 years ago, opening up the Northwest Passage – a long-sought short cut between Europe and Asia that has been historically impassable.
In the mosaic image above, created from nearly 200 images acquired in early September 2007 by the Advanced Synthetic Aperture Radar (ASAR) instrument aboard ESA’s Envisat satellite, the dark gray colour represents the ice-free areas while green represents areas with sea ice.
Leif Toudal Pedersen from the Danish National Space Centre said: “We have seen the ice-covered area drop to just around 3 million sq km which is about 1 million sq km less than the previous minima of 2005 and 2006. There has been a reduction of the ice cover over the last 10 years of about 100 000 sq km per year on average, so a drop of 1 million sq km in just one year is extreme.
“The strong reduction in just one year certainly raises flags that the ice (in summer) may disappear much sooner than expected and that we urgently need to understand better the processes involved.”
Arctic sea ice naturally extends its surface coverage each northern winter and recedes each northern summer, but the rate of overall loss since 1978 when satellite records began has accelerated.
The most direct route of the Northwest Passage (highlighted in the top mosaic by an orange line) across northern Canada is shown fully navigable, while the Northeast Passage (blue line) along the Siberian coast remains only partially blocked. To date, the Northwest Passage has been predicted to remain closed even during reduced ice cover by multi-year ice pack – sea ice that survives one or more summers. However, according to Pedersen, this year’s extreme event has shown the passage may well open sooner than expected.
The previous record low was in 2005 when the Arctic area covered by sea ice was just 4 million sq km. Even then, the most direct Northwest Passage did not fully open.
The Polar Regions are very sensitive indicators of climate change. The UN’s Intergovernmental Panel on Climate Change showed these regions are highly vulnerable to rising temperatures and predicted the Arctic would be virtually ice free by the summer of 2070. Still other scientists predict it could become ice free as early as 2040 due to rising temperatures and sea ice decline.
Because sea ice has a bright surface, the majority of solar energy that hits it is reflected back into space. When sea ice melts, the dark-coloured ocean surface is exposed. Solar energy is then absorbed rather than reflected, so the oceans get warmer and temperatures rise, making it difficult for new ice to form.
The Arctic is one of Earth’s most inaccessible areas, so obtaining measurements of sea ice was difficult before the advent of satellites. For more than 20 years, ESA has been providing satellite data to the cryosphere communities. Currently, ESA is contributing to the International Polar Year (IPY) – a large worldwide science programme focused on the Arctic and Antarctic.
Since 2006, ESA has supported Polar View, a satellite remote-sensing programme funded through the Earthwatch GMES Service Element (GSE) that focuses on the Arctic and the Antarctic.
In 2009, ESA will make another significant contribution to cryosphere research with the launch of CryoSat-2. The observations made over the three-year lifetime of the mission will provide conclusive evidence on the rates at which ice cover is diminishing.
Sept. 13, 2007 ANN ARBOR, Mich.—Using atom-level imaging techniques, University of Michigan researchers have revealed important structural details of an enzyme system known as “Mother Nature’s blowtorch” for its role in helping the body efficiently break down many drugs and toxins.
The research has been detailed in a series of papers, the most recent published online this month in the journal BBA Biomembranes.
The system involves two proteins that work cooperatively. The first, cytochrome P450, does the actual work, but only when it gets a boost from the second protein, cytochrome b5. To complicate matters, the two proteins can interact only when both are bound to a cell membrane. That makes it difficult to use traditional techniques to discern the structural details that are crucial to the interaction, said Ayyalusamy Ramamoorthy, who leads the research group.
For instance, X-ray crystallography, often used to determine protein structures, requires separating the molecules from their membrane environment. Because part of cytochrome b5 sticks to the membrane, such separations involve breaking the molecule at the sticking point, which happens to be the part that controls its interaction with cytochrome P450. So while crystallography can offer some information on structure, it can’t provide insights into exactly what goes on between P450 and b5 during their cozy, membrane-bound encounters, Ramamoorthy said.
However, the technique his lab uses—solid state NMR spectroscopy—can produce detailed images of proteins in the membrane environment, not only revealing molecular structure but also showing how a particular protein nestles into the membrane. Cytochrome b5 presented a challenge even to that versatile method, though, because the molecule has three parts that all behave differently: the rigid, sticky portion that buries into the cell membrane, a highly mobile, water-soluble portion, and a less mobile “linker” that connects the other two parts.
But by tweaking their technique, the researchers were able to get high-resolution images of all three portions.
“The challenge was something like having a room full of people and trying to get good photos of every one of them,” said Ramamoorthy, an associate professor of chemistry and Biophysics. “With one picture, you probably can’t do it. But if you say, ‘Everyone over age 50 stand up,’ and you take one picture, and then you ask for another age group and take another picture, and so on, you have a better chance.”
By spinning their samples (or aligning the molecules in the magnetic field), the researchers were able to differentiate parts of the molecule based not on age group, as in the photo analogy, but by mobility. “With the techniques we designed, we were able to observe the rigid portion separately from the highly mobile and less mobile portions,” Ramamoorthy said.
In the first part of the work, published in the Journal of the American Chemical Society in May, the researchers described the membrane-spanning segment of cytochrome b5, revealing for the first time its helical shape and the way it tilts in relation to the membrane. In the new work published in BBA Biomembranes, they determined that once both molecules are bound in the membrane, cytochrome b5 modulates the motion and the structure of cytochrome P450. More work is in progress to determine the detailed high-resolution structures of these two proteins.
Ramamoorthy’s team also is studying other membrane-associated proteins, a group that includes many biologically important molecules.
“These proteins are involved in all major diseases, everywhere in the body, and are therefore primary targets for pharmaceutical applications,” Ramamoorthy said. “In my opinion, solving the structures of membrane proteins should be the highest priority for structural biologists in the coming years.”
Ramamoorthy collaborated on the most recent work with Lucy Waskell, a professor of anesthesiology and a physician at the Department of Veterans Affairs Medical Center.
A leader in this area of research, Ramamoorthy has organized several major international symposia on the field at the University of Michigan, edited a special issue in the journal BBA-Biomembranes, published a number of papers in leading journals, and brought out a book on NMR Spectroscopy of Biological Solids. Ramamoorthy said that this area of research will grow considerably at U-M from implementing plans to set up a high magnetic field solid-state NMR spectrometer facility and an NIH-funded program.
More information on Ramamoorthy
Contact: Nancy Ross-Flanigan
Phone: (734) 647-1853
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