OREGON STATE UNIVERSITY

scientific research and advances

New therapy halts progression of Lou Gehrig’s disease in mice

CORVALLIS, Ore. – Researchers at Oregon State University announced today that they have essentially stopped the progression of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, for nearly two years in one type of mouse model used to study the disease – allowing the mice to approach their normal lifespan.

The findings, scientists indicate, are some of the most compelling ever produced in the search for a therapy for ALS, a debilitating and fatal disease, and were just published in Neurobiology of Disease.

“We are shocked at how well this treatment can stop the progression of ALS,” said Joseph Beckman, lead author on this study, a distinguished professor of biochemistry and biophysics in the College of Science at Oregon State University, and principal investigator and holder of the Burgess and Elizabeth Jamieson Chair in OSU’s Linus Pauling Institute.

In decades of work, no treatment has been discovered for ALS that can do anything but prolong human survival less than a month. The mouse model used in this study is one that scientists believe may more closely resemble the human reaction to this treatment, which consists of a compound called copper-ATSM.

It’s not yet known if humans will have the same response, but researchers are moving as quickly as possible toward human clinical trials, testing first for safety and then efficacy of the new approach.

ALS was identified as a progressive and fatal neurodegenerative disease in the late 1800s, and gained international recognition in 1939 when it was diagnosed in American baseball legend Lou Gehrig. It’s known to be caused by the death and deterioration of motor neurons in the spinal cord, which in turn has been linked to mutations in copper, zinc superoxide dismutase.

Copper-ATSM is a known compound that helps deliver copper specifically to cells with damaged mitochondria, and reaches the spinal cord where it’s needed to treat ALS. This compound has low toxicity, easily penetrates the blood-brain barrier, is already used in human medicine at much lower doses for some purposes, and is well tolerated in laboratory animals at far higher levels. Any copper not needed after use of copper-ATSM is quickly flushed out of the body.

Experts caution, however, that this approach is not as simple as taking a nutritional supplement of copper, which can be toxic at even moderate doses. Such supplements would be of no value to people with ALS, they said.

The new findings were reported by scientists from OSU; the University of Melbourne in Australia; University of Texas Southwestern; University of Central Florida; and the Pasteur Institute of Montevideo in Uruguay. The study is available as open access in Neurobiology of Disease.

Using the new treatment, researchers were able to stop the progression of ALS in one type of transgenic mouse model, which ordinarily would die within two weeks without treatment. Some of these mice have survived for more than 650 days, 500 days longer than any previous research has been able to achieve.

In some experiments, the treatment was begun, and then withheld. In this circumstance the mice began to show ALS symptoms within two months after treatment was stopped, and would die within another month. But if treatment was resumed, the mice gained weight, progression of the disease once again was stopped, and the mice lived another 6-12 months.

In 2012, Beckman was recognized as the leading medical researcher in Oregon, with the Discovery Award from the Medical Research Foundation of Oregon. He is also director of OSU’s Environmental Health Sciences Center, funded by the National Institutes of Health to support research on the role of the environment in causing disease.

“We have a solid understanding of why the treatment works in the mice, and we predict it should work in both familial and possibly sporadic human patients,” Beckman said. “But we won’t know until we try.”

Familial ALS patients are those with more of a family history of the disease, while sporadic patients reflect the larger general population.

“We want people to understand that we are moving to human trials as quickly as we can,” Beckman said. “In humans who develop ALS, the average time from onset to death is only three to four years.”

The advances are based on substantial scientific progress in understanding the disease processes of ALS and basic research in biochemistry. The transgenic mice used in these studies have been engineered to carry the human gene for “copper chaperone for superoxide dismutase,” or CCS gene. CCS inserts copper into superoxide dismustase, or SOD, and transgenic mice carrying these human genes die rapidly without treatment.

After years of research, scientists have developed an approach to treating ALS that’s based on bringing copper into specific cells in the spinal cord and mitochondria weakened by copper deficiency. Copper is a metal that helps to stabilize SOD, an antioxidant protein whose proper function is essential to life. But when it lacks its metal co-factors, SOD can “unfold” and become toxic, leading to the death of motor neurons.

There’s some evidence that this approach, which works in part by improving mitochondrial function, may also have value in Parkinson’s disease and other conditions, researchers said. Research is progressing on those topics as well. 

The treatment is unlikely to allow significant recovery from neuronal loss already caused by ALS, the scientists said, but could slow further disease progression when started after diagnosis. It could also potentially treat carriers of SOD mutant genes that cause ALS.

This work has been supported by the Department of Defense Congressionally Directed Medical Research Program, the U.S. National Institutes of Health, the Amyotrophic Lateral Sclerosis Association, the Australian National Health and Medical Research Association, and gifts by Michael Camillo and Burgess and Elizabeth Jamieson to the Linus Pauling Institute.

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Joseph Beckman, 541-737-8867

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Copper, zinc superoxide dismutase
Copper, zinc superoxide dismutase

Forest corridors prove critical to biodiversity and pollination success in the tropics

CORVALLIS, Ore. – As tropical forests become increasingly broken up by roads, farm fields, pastures and other developments, corridors of trees provide vital pathways for pollinators and contribute to a rich diversity of plant species, scientists have confirmed.

A study at the Las Cruces Biological Station in Costa Rica shows that when forests are linked by continuous corridors of trees, pollination has a greater likelihood of success. In contrast, when patches of forest are isolated from each other, pollinators are less abundant and plants frequently fail to reproduce.

More than 94 percent of flowering tropical plants and 75 percent of the worlds leading food crops require pollination by animals such as bees, bats and hummingbirds.

Researchers have found that forest corridors enable specialized hummingbirds that prefer such landscapes to travel longer distances from one patch of trees to another, increasing pollen exchange between forest patches. Such patches not only harbor more hummingbirds but also display greater rates of pollination than plants in areas that are isolated from each other.

These are among the results published today in the Proceedings of the Royal Society B, a technical journal, by scientists from the College of Forestry at Oregon State University and the Georg-August University Gottingen in Germany.

“This work presents tropical forest landowners with a simple, relatively inexpensive solution to enhancing biodiversity and pollination of native forest plants – connect forest patches with hedgerows and wooded corridors,” said Urs Kormann, the lead author of the study and a postdoctoral researcher at Oregon State. “This may complement national parks.”

“Wooded corridors remain abundant in many tropical landscapes,” said Matthew Betts, co-author and assistant professor at Oregon State. “But as agricultural land use is expanding rapidly, quick action will be required to avert the disappearance of corridor elements between fragments. Otherwise, there may substantial losses of connectivity between forest remnants, leading to accelerated biodiversity loss.”

The researchers performed field experiments and conducted observations to arrive at their findings. They measured rates of hummingbird visits to feeders and to live plants (Heliconia tortuosa) placed in forest patches. They tracked the flow of pollen from one patch to another and evaluated the presence of two groups of hummingbird species, one that prefers forested habitats and one that does not.

Simple wooded corridors can boost landscape connectivity for pollinators and animal-pollinated plants, the researchers wrote. Our findings may also apply to other organism groups that move along corridors, potentially providing other ecosystem services.

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Matt Betts, 541-737-3841; Urs Kormann, 0041-77-465-05-84 (Switzerland)

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Corridors1

Corridors2

Green hermit hummingbird

Over-hunting in Amazon threatens global carbon budget

CORVALLIS, Ore. – The vast forests of the Amazon store enormous amounts of carbon that help moderate the Earth’s temperature, but a new study shows that this carbon-storing capacity is being threatened by over-hunting.

Wide-scale reduction of fruit-eating large mammals – especially primates and tapirs – is changing the way seeds are dispersed in the Amazon and changing the composition of forests, the researchers say.

Results of the study are being published this week in Proceedings of the National Academy of Sciences.

“Large mammals including spider monkeys and wooly monkeys are fruit-eaters that historically have made up most of the frugivore (or fruit-eating) biomass in these forests,” said Taal Levi, an Oregon State University ecologist and author on the study. “There are many tree species with large seeds that rely on these primates to spread seeds through the forest.

“These large-seeded fruit trees are also slow-growing and populate the forest with dense wood that sequesters a great deal more carbon than in typically stored in trees dispersed by wind or smaller frugivores,” Levi added.

As technology has advanced and firearms have spread through tropical forests, hunting success has improved and these primates have been extirpated from vast areas, Levi pointed out.

“When large primates and tapirs, which are the largest frugivores in the neo-tropics, are lost, forests are eventually populated by plants whose seeds are more likely dispersed by wind, rodents or birds,” Levi said. “It is not the same aggregation of plants and it is affecting the Amazon’s carbon-storing ability.”

In fact, the researchers say, over-hunting occurs over much larger areas than the total area of the Amazon forest affected by deforestation. A relatively small loss in the amount of carbon stored in trees can lead to enormous declines in the amount of carbon stored in these vast forests.

The analysis of 166 wildlife surveys across the Amazon basin documents the loss of large primates. Levi’s computer model projects that this will result in more than three out of four plots losing forest biomass, with a (conservatively) estimated average loss of 2.5 to 3 percent.

Tapirs are another key seed disperser that is sensitive to over-hunting. When tapirs are lost in addition to large primates, nearly nine out of 10 plots will lose forest biomass with the loss (conservatively) projected to average about 5.8 percent.

“The loss of 2.5 to 5.8 percent of biomass may not sound like a lot,” Levi said, “but in an area as vast as the Amazon, the impact could be huge – a projected 313 billion kilograms of carbon not being absorbed.”

Levi said the economic value of such a loss on the world carbon markets could range between $5.91 trillion and $13.65 trillion.

The researchers studied data from 2,345 one-hectare forest plots scattered across the Brazilian Amazon containing nearly 130,000 large trees. Simulations showed that 77 to 88 percent of these plots will lose above-ground forest biomass when the forests are over-hunted and trees that require large primates or tapirs to regenerate are replaced by other trees on the same plots.

Carlos Peres, a research ecologist with the University of East Anglia and lead author on the study, said the research uncovers an important – and perhaps under-appreciated – link between wildlife and climate change.

“Amazonian forest wildlife has been declining through a combination of habitat destruction, habitat degradation and overhunting since the 1950s,” Peres said, “but until now there was a poor understanding of the status of wildlife populations in hunted forests that otherwise remain intact and free of human disturbance.

“We show that dense-wooded, large-seeded Amazonian tree species are replaced by light-wooded trees that produce smaller seeds, which continue to be dispersed in over-hunted forests by more resilient smaller mammal and bird species,” he added.

Levi said trying to manage the forests by manually dispersing seeds would be impractical because of the vastness of the Amazonian forests. There also is evidence that seeds that go through the digestive tract of large mammals are more likely to germinate having been cleansed of flesh that attracts fungal pathogens and other natural enemies.

“Seeds that fall from trees contain a lot of pulp,” Levi said, “and in tropical climates become excellent petri dishes for fungus to colonize.”

The researchers say the key to protecting optimal forest composition is to recognize the importance of hunting and better manage it.

“These findings highlight an urgent need to manage the sustainability of game hunting in both protected and unprotected tropical forests, and place full biodiversity integrity, including populations of large frugivorous vertebrates, firmly in the agenda of reducing emissions from deforestation and forest degradation (REDD+) programs,” the authors noted in the article.

Other authors on the PNAS article are from the National Institute of Amazonian Research and Fiocruz Amazonia.

 

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Taal Levi, 541-737-4067, taal.levi@oregonstate.edu

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Photo of grey wooly monkey (by Carlos Peres): https://flic.kr/p/Crcxvt

Oregon State launches humanitarian engineering program

CORVALLIS, Ore. - The Oregon State University College of Engineering has recently launched a humanitarian engineering program like few others in the nation, partly as a response to a growing number of students who want to make an impact both locally and globally.

Undergraduate students can now minor in this field, taking classes that emphasize the importance of socio-cultural, economic, environmental and resource management factors. Work in ethics, social justice and cross-cultural communication is also part of the program.

Humanitarian engineering emphasizes science and engineering-based solutions that help to improve the human condition, access to basic human needs, the quality of life or level of community resilience. OSU’s program is one of only a few in the nation based in an academic curriculum.

The program reflects an engaged concept of service and the university’s historic land grant mission, officials say. Through it, students will explore case studies of development projects and a historic perspective on humanitarian interventions.

One OSU student who understands that concept is Grace Burleson, a graduating senior majoring in mechanical engineering. She grew up as a missionary child and was raised by parents with a passion for helping underserved populations.

“When I got to college, I loved my engineering coursework but never got excited by applying it to things like cars or computers,” said Burleson. “I began research in humanitarian engineering and landed an internship in Uganda, working where I developed a sustainable business plan for the construction, distribution and maintenance of BioSand water filters.”                    

As a formalized academic program, humanitarian engineering will contribute to the effort of the OSU College of Engineering to become a recognized model as an inclusive and collaborative community.

“The program is attracting a more diverse group of prospective students than is typically attracted to engineering, including women,” said mechanical engineering professor Kendra Sharp, who directs the program, and was appointed the first Richard and Gretchen Evans Professor in Humanitarian Engineering.

OSU is also one of just 10 universities nationwide to offer a Peace Corps Master’s International program in engineering. The university was the first in Oregon to join this initiative, which allows graduate students in several disciplines to get a master’s degree while doing a full 27-month term of service in the Peace Corps.

Multiple student organizations, including Oregon State’s award-winning Engineers Without Borders chapter and the American Society of Civil Engineering student chapter, have also been working on water, energy and other projects in the developing world. 

“Students at Oregon State receive an accredited engineering degree, so adding on this minor opens many more doors and perspectives with how we look at engineering,” said Burleson. “It creates a gateway for really exciting and impactful projects.”

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Krista Klinkhammer, 541-737-4416

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Kendra Sharp, 541-737-5246

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Engineering outreach
Engineering study in Uganda

Liver recovery difficult even with improved diet, but faster if sugar intake is low

CORVALLIS, Ore. – Liver damage caused by the typical “Western diet” – one high in fat, sugar and cholesterol that’s common in developed countries such as the United States – may be difficult to reverse even if diet is generally improved, a new study shows.

The research, published today in PLOS ONE by scientists from Oregon State University, found that a diet with reduced fat and cholesterol helped, but did not fully resolve liver damage that had already been done – damage that in turn can lead to more serious health problems, such as cirrhosis or even cancer.

This study, done with laboratory animals, showed that diets low in fat and cholesterol could in fact aid with weight loss, improved metabolism and health. But even then, if the diet was still high in sugar there was much less liver recovery, the scientists concluded.

The findings are significant, scientists say, because liver problems such as nonalcoholic fatty liver disease are surging in the U.S., affecting 10-35 percent of adults and an increasing number of children. The incidence of this problem can reach more than 60 percent in obese and type-2 diabetic populations.

“Many people eating a common American diet are developing extensive hepatic fibrosis, or scarring of their liver, which can reduce its capacity to function, and sometimes lead to cancer,” said Donald Jump, a professor in the OSU College of Public Health and Human Sciences, principal investigator with the Linus Pauling Institute, and corresponding author on this research.

“There’s a lot of interest in finding ways to help the liver recover from this damage, but this research suggests that diets lower in fat and cholesterol, even if they help you lose weight, are not enough,” Jump said. “For more significant liver recovery, the intake of sugar has to come down, probably along with other improvements in diet and exercise.”

The issues are both serious and complex, the researchers said.

“Everyone recognizes this is a serious problem,” said Kelli Lytle, an OSU doctoral candidate and lead author on this study. “We’re trying to find out if some of the types of dietary manipulation that people use, such as weight loss based on a low fat diet, will help address it. However, a common concern is that many ‘low-fat’ food products have higher levels of sugar to help make them taste better.”

Weight loss does appear to help address some of the problems associated with the Western diet, the research shows. But according to this study, a diet with continued high levels of sugar will significantly slow recovery of liver damage that has already been done.

Complications related to liver inflammation, scarring and damage are projected to be the leading cause of liver transplants by 2020, the researchers noted in their study. Such scarring was once thought to be irreversible, but more recent research has shown it can be at least partially reversed with optimal diet and when the stimulus for liver injury is removed.

In this report, scientists studied two groups of laboratory mice that had been fed a “Western diet” and then switched to different, healthier diets, low in fat and cholesterol.

Both of the improved diets caused health improvements and weight loss. But one group that was fed a diet still fairly high in sugar – an amount of sugar comparable to the Western diet - had significantly higher levels of inflammation, oxidative stress and liver fibrosis.

More research is still needed to determine whether a comprehensive program of diet, weight maintenance, exercise and targeted drug therapies can fully resolve liver fibrosis, the study concluded.

This research was supported by the National Institutes of Health and the U.S. Department of Agriculture.

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Donald Jump, 541-737-4007

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Sugar intake too high

Thousands of landslides in Nepal earthquake raise parallels for Pacific Northwest

CORVALLIS, Ore. – Research teams have evaluated the major 7.8 magnitude subduction zone earthquake in Gorkha, Nepal, in April 2015, and identified some characteristics that may be of special relevance to the future of the Pacific Northwest.

Most striking was the enormous number and severity of landslides.

Many people understand the damage that can be caused to structures, roads, bridges and utilities by ground shaking in these long-lasting types of earthquakes, such as the one that’s anticipated on the Cascadia Subduction Zone between northern California and British Columbia.

But following the Nepal earthquake – even during the dry season when soils were the most stable – there were also tens of thousands of landslides in the region, according to reconnaissance team estimates. In their recent report published in Seismological Research Letters, experts said that these landslides caused pervasive damage as they buried towns and people, blocked rivers and closed roads.

Other estimates, based on the broader relationship between landslides and earthquake magnitude, suggest the Nepal earthquake might have caused between 25,000 and 60,000 landslides.

The subduction zone earthquake expected in the future of the Pacific Northwest is expected to be larger than the event in Nepal.

Ben Mason, a geotechnical engineer and assistant professor in the College of Engineering at Oregon State University, was a member of the Geotechnical Extreme Event Reconnaissance team that explored the Nepal terrain. He said that event made clear that structural damage is only one of the serious threats raised by subduction zone earthquakes.

“In the Coast Range and other hilly areas of Oregon and Washington, we should expect a huge number of landslides associated with the earthquake we face,” Mason said. “And in this region our soils are wet almost all year long, sometimes more than others. Each situation is different, but soils that are heavily saturated can have their strength cut in half.”

Wet soils will also increase the risk of soil liquefaction, Mason said, which could be pervasive in the Willamette Valley and many areas of Puget Sound, Seattle, Tacoma, and Portland, especially along the Columbia River.

Scientists have discovered that the last subduction zone earthquake to hit the Pacific Northwest was in January 1700, when – like now - soils probably would have been soggy from winter rains and most vulnerable to landslides.

The scientific study of slope stability is still a work in progress, Mason said, and often easier to explain after a landslide event has occurred than before it happens. But continued research on earthquake events such as those in Nepal may help improve the ability to identify areas most vulnerable to landslides, he said. Models can be improved and projections made more accurate.

“If you look just at the terrain in some parts of Nepal and remove the buildings and people, you could think you were looking at the Willamette Valley,” Mason said. “There’s a lot we can learn there.”

In Nepal, the damage was devastating.

Landslides triggered by ground shaking were the dominant geotechnical effect of the April earthquake, the researchers wrote in their report, as slopes weakened and finally gave way. Landslides caused by the main shock or aftershocks blocked roads, dammed rivers, damaged or destroyed villages, and caused hundreds of fatalities.

The largest and most destructive event, the Langtang debris avalanche, began as a snow and ice avalanche and gathered debris that became an airborne landslide surging off a 500-meter-tall cliff. An air blast from the event flattened the forest in the valley below, moved 2 million cubic meters of material and killed about 200 people.

Surveying the damages after the event, Mason said one of his most compelling impressions was the way people helped each other.

“Nepal is one of the poorest places, in terms of gross domestic product, that I’ve ever visited,” he said. “People are used to adversity, but they are culturally rich. After this event it was amazing how their communities bounced back, people helped treat each other’s injuries and saved lives. As we make our disaster plans in the Pacific Northwest, there are things we could learn from them, both about the needs for individual initiative and community response.”

Aside from landslides, many lives were lost in collapsing structures in Nepal, often in homes constructed of rock, brick or concrete, and frequently built without adequate enforcement of building codes, the report suggested. Overall, thousands of structures were destroyed. There are estimates that about 9,000 people died, and more than 23,000 were injured. The earthquake even triggered an avalanche on Mount Everest that killed at least 19 people.

The reconnaissance effort in Nepal was made possible by support from the National Science Foundation, the U.S. Geological Survey, the U.S. Agency for International Development, the OSU College of Engineering, and other agencies and universities around the world.

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Ben Mason, 541-737-2014

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Nepal landslide
Nepal landslide

New approach to medication counseling shown to be highly effective

CORVALLIS, Ore. – It takes about one minute longer, but pharmacists who employ an unconventional, interactive patient counseling technique can more than double the chance that people will understand key issues on how to take, understand and manage their use of prescription drugs.

A new study just published in the Journal of the American Pharmacists Association provides compelling evidence that this technique could significantly improve the understanding of drug use and storage, possible side effects, what to expect from a medication and what to do if something isn’t working.

“This approach to prescription drug counseling has now been shown to be a dramatic improvement over conventional methods,” said Robert Boyce, director of pharmacy services in the Student Health Center Pharmacy at Oregon State University, and corresponding author on the study. “This is the first real analysis to prove that it works, and that the approach could be extremely important for health care in America.”

Historically, pharmacists who provided patients with information about their prescription medications – when that was done at all – most often used what was called a “lecture format,” essentially a one-way form of communication that was often referred to as reading off the label. The efficacy of this system varied widely, and gave little assurance that patients had heard and understood a range of details about the drug they were preparing to take.

By contrast, Boyce co-developed an alternative approach during a 21-year career with the Public Health Service pharmacy program of the Indian Health Service, a federal health program for American Indians and Alaskan natives. It emphasizes a questioning of patients on their understanding of the drug they have been prescribed, and answers questions about whatever they don’t understand.  It’s a discussion, not a presentation.

The concept, Boyce said, was released in 1991 to every school and college of pharmacy, and is now gaining much wider acceptance across the nation. This study, which included a survey of 500 participants at four community pharmacies in Oregon, is the first of its type to confirm the value of the new approach. A lead author was Naomi Lam, a pharmacy resident at the OSU Student Health Center Pharmacy at the time of the research.

In this approach, patients are asked three basic, open-ended questions, relating to the name and purpose of the medication; how to use and store it; and what possible side effects there might be, and what to do if they occur.

The new study found that 71 percent of patients using the new counseling approach could answer all three questions correctly, compared to 33 percent of patients who were instructed with the conventional system.

With either approach, most people understood what medication they were taking and what it was for. However, with the new system, four times as many people understood how and when to take their medication, and also could answer basic questions about adverse effects.

According to this study, the average time it took pharmacists to use the new counseling system was a little over two minutes, compared to 75 seconds for conventional counseling.

“For a busy pharmacist, some might suggest this is a significant additional amount of time,” Boyce said. “But when you compare that to the risks of something not going right when a patient does not understand what the specific directions are, or what to expect from their medication, the additional effort seems minimal.”

Patient counseling about medications, Boyce said, is still an evolving aspect of health care. Prior to federal legislation that became law in January, 1993, which mandated pharmacist counseling for Medicare patients receiving new prescriptions, pharmacist counseling was quite variable, and often not done at all.

Since that time, all but three states in the country have enacted laws that require patient counseling on medication, or an offer to counsel, be made available. As a result, the activity of counseling is far more common. The alternative system being proposed, however, has the ability to take such counseling and make it far more effective, Boyce said.

“This approach to counseling can find out what a patient does and doesn’t understand,” Boyce said. “It’s especially important when it comes to drug efficacy and side effects. If a medication isn’t working properly, patients learn what actions to take. If they experience side effects, they know better how to handle it and when to contact their doctor or pharmacist.”

The conversational, interactive approach also becomes highly favored by patients once it is implemented, Boyce said. People better remember what they heard and discussed, feel as if they are being listened to, and they appreciate the attention, he said. Gaps in understanding are addressed during the conversation and before moving on to the next question.

Some common sense concerns can also be immediately identified with this format, which may be less obvious in conventional counseling. A patient may have hearing problems; language barriers; or cognitive circumstances that must be considered. An immediate understanding of that can significantly improve the level of communication.

Previous research has shown that when people do not understand the proper use of their medications, adherence rates plummet. Also, studies show that patients are most interested in information on adverse effects, but that this topic historically was one of those least discussed by both doctors and pharmacists.

The study suggested that additional research with more groups be done to verify the value of the new system. It also outlined stages of improvement as pharmacists adapt to the new approach, become more comfortable with it and increase both their speed and communication effectiveness.

 

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Robert Boyce, 541-231-7323

Research identifies key genetic link in the biology of aging

CORVALLIS, Ore. – New research at Oregon State University suggests it may be possible to slow age-related disease with new types of treatments.

Scientists have tracked the syndromes associated with aging to their biochemical roots, and identified a breakdown in genetic communication as part of the problem. The findings imply that aging happens for a reason, and that while aspects of it may be inevitable, there could be ways to slow down disease development.

The newest study relate to a protein, Nrf2, that helps regulate gene expression and the body’s reaction to various types of stressors. The research was published in Free Radical Biology and Medicine, in work supported by the National Institutes of Health and the Medical Research Foundation of Oregon.

“We’re very excited about the potential of this area of research,” said Tory Hagen, corresponding author on this study, and the Helen P. Rumbel Professor for Health Aging Research in the Linus Pauling Institute and the OSU Department of Biochemistry and Biophysics in the College of Science.

“At least one important part of what we call aging appears to be a breakdown in genetic communication, in which a regulator of stress resistance declines with age,” Hagen said. “As people age and their metabolic problems increase, the levels of this regulator, Nrf2, should be increasing, but in fact they are declining.”

Nrf2 is both a monitor and a messenger, OSU researchers say. It’s constantly on the lookout for problems with cells that may be caused by the many metabolic insults of life – oxidative stress, toxins, pollutants, and other metabolic dysfunction.

When it finds a problem, Nrf2 essentially goes back to the cellular nucleus and rings the alarm bell, where it can “turn on” up to 200 genes that are responsible for cell repair, detoxification of carcinogens, protein and lipid metabolism, antioxidant protection and other actions. In their report, the scientists called it a “longevity-assurance” factor.

Nrf2 is so important that it’s found in many life forms, not just humans, and it’s constantly manufactured by cells throughout the body. About half of it is used up every 20 minutes as it performs its life-protective functions. Metabolic insults routinely increase with age, and if things were working properly, the amount of Nrf2 that goes back into the nucleus should also increase to help deal with those insults.

Instead, the level of nuclear Nrf2 declines, and the OSU scientists say they have discovered why.

“The levels of Nrf2, and the functions associated with it, are routinely about 30-40 percent lower in older laboratory animals,” said Kate Shay, director of the Healthy Aging Core Laboratory at OSU and co-author on this study. “We’ve been able to show for the first time what we believe is the cause.”

The reason for this decline, the scientists said, is increasing levels of a micro-RNA called miRNA-146a.

Micro-RNAs have been one of the most profound scientific discoveries of the past 20 years. They were once thought to be “junk DNA” because researchers could see them but they had no apparent biological role. They are now understood to be anything but junk – they help play a major role in genetic signaling, controlling what genes are “expressed,” or turned on and off to perform their function.

In humans, miRNA-146a plays a significant role. It can turn on the inflammation processes that, in something like a wound, help prevent infection and begin the healing process. But with aging, this study now shows that miRNA-146a expression doesn’t shut down properly, and it can significantly reduce the levels of Nrf2.

This can cause part of the chronic, low-grade inflammation that is associated with the degenerative diseases that now kill most people in the developed world, including heart disease, cancer, diabetes and neurological disease.

“The action of miRNA-146a in older people appears to turn from a good to a bad influence,” Shay said. “It may be causing our detoxification processes to decline just when we need them the most.”

Some of the things found to be healthy for individuals, in diet or lifestyle, may be so because they help to conserve the proper balance between the actions of miRNA-146a and Nrf2, the OSU researchers said. Alternatively, it may be possible to reduce excessive levels of miRNA-146a with compounds that interfere with its function. There may also be other micro-RNAs associated with this process, they said, that need further research.

“Overall, these results provide novel insights for the age-related decline in Nrf2 and identify new targets to maintain Nrf2-dependent detoxification with age,” the researchers wrote in their conclusion.

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Tory Hagen, 541-737-5083

Tooth fillings of the future may incorporate bioactive glass

CORVALLIS, Ore. – A few years from now millions of people around the world might be walking around with an unusual kind of glass in their mouth, and using it every time they eat.

Engineers at Oregon State University have made some promising findings about the ability of “bioactive” glass to help reduce the ability of bacteria to attack composite tooth fillings – and perhaps even provide some of the minerals needed to replace those lost to tooth decay.

Prolonging the life of composite tooth fillings could be an important step forward for dental treatment, the researchers say, since more than 122 million composite tooth restorations are made in the United States every year. An average person uses their teeth for more than 600,000 “chews” a year, and some studies suggest the average lifetime of a posterior dental composite is only six years.

The new research was just published in the journal Dental Materials, in work supported by the National Institutes of Health.

“Bioactive glass, which is a type of crushed glass that is able to interact with the body, has been used in some types of bone healing for decades,” said Jamie Kruzic, a professor and expert in advanced structural and biomaterials in the OSU College of Engineering.

“This type of glass is only beginning to see use in dentistry, and our research shows it may be very promising for tooth fillings,” he said. “The bacteria in the mouth that help cause cavities don’t seem to like this type of glass and are less likely to colonize on fillings that incorporate it. This could have a significant impact on the future of dentistry.”

Bioactive glass is made with compounds such as silicon oxide, calcium oxide and phosphorus oxide, and looks like powdered glass. It’s called “bioactive” because the body notices it is there and can react to it, as opposed to other biomedical products that are inert. Bioactive glass is very hard and stiff, and it can replace some of the inert glass fillers that are currently mixed with polymers to make modern composite tooth fillings.

“Almost all fillings will eventually fail,” Kruzic said. “New tooth decay often begins at the interface of a filling and the tooth, and is called secondary tooth decay. The tooth is literally being eroded and demineralized at that interface.”

Bioactive glass may help prolong the life of fillings, researchers say, because the new study showed that the depth of bacterial penetration into the interface with bioactive glass-containing fillings was significantly smaller than for composites lacking the glass.

Fillings made with bioactive glass should slow secondary tooth decay, and also provide some minerals that could help replace those being lost, researchers say. The combination of these two forces should result in a tooth filling that works just as well, but lasts longer.

Recently extracted human molars were used in this research to produce simulated tooth restoration samples for laboratory experiments. OSU has developed a laboratory that’s one of the first in the world to test simulated tooth fillings in conditions that mimic the mouth.

If this laboratory result is confirmed by clinical research, it should be very easy to incorporate bioactive glass into existing formulations for composite tooth fillings, Kruzic said.

The antimicrobial effect of bioactive glass is attributed, in part, to the release of ions such as those from calcium and phosphate that have a toxic effect on oral bacteria and tend to neutralize the local acidic environment.

“My collaborators and I have already shown in previous studies that composites containing up to 15 percent bioactive glass, by weight, can have mechanical properties comparable, or superior to commercial composites now being used,” Kruzic said.

This work was done in collaboration with researchers from the School of Dentistry at the Oregon Health & Science University and the College of Dental Medicine at Midwestern University.

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Jamie Kruzic, 541-737-7027

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Harbor seal deaths show presence of bacterial infection

CORVALLIS, Ore. – A study by microbiologists at Oregon State University has concluded that an unsuspected bacterial infection, rather than a viral disease, was associated with the stranding and death of seven harbor seals on the California coast in 2009.

The research, made with a powerful investigative method called “meta-transcriptomics,” found a high incidence of infection in the seals with the bacterial pathogen Burkholderia, and provides the first report in the Americas of this bacteria in a wild harbor seal.

The bacteria probably did not directly cause the death of the seals, researchers say, but this provides  further evidence of the increase in emerging marine pathogens, and the need for improved monitoring and study of zoonotic diseases that could affect both human and wildlife populations.

In light of these findings, OSU researchers also remind the public that they should not touch stranded or dead marine mammals.

The research was recently published in PLOS ONE, in work supported by the Oregon Sea Grant program and the National Science Foundation.

“We now have improved tools to better identify new diseases as they emerge from natural reservoirs, and can record and track these events,” said Rebecca Vega-Thurber, an assistant professor of microbiology in the OSU College of Science. “It’s becoming clear there are more pathogens than we knew of in the past, and that some of them can move into human populations.

“This is why it’s increasingly important that we accurately pinpoint the cause of these diseases, and understand the full range of causes that may factor into these deaths.”

Cases such as this, the researchers said, point out that it’s not always a single pathogen that causes death, but a combination of pathogens, changing environmental influences, weakened hosts and other forces. In this seal-stranding event, the scientists also found evidence of Coxiella burnettii, another bacterial pathogen, at high levels in one animal.

Advances in this type of monitoring are being made with the comparatively new field of meta-transcriptomics, which has been referred to as a way to eavesdrop on the viral and microbial world, to catalogue and compare sequences from suspected pathogens. It’s just now being applied to marine systems, which are often reservoirs for pathogens that can emerge into terrestrial populations.

This phenomenon seems to be picking up speed, the researchers noted in their study.

About 61 percent of emerging human diseases arise from zoonotic pathogens, and about 70 percent of these originate from wildlife. The recent Ebola outbreak in Africa was one example; the bacterial pathogen that causes tuberculosis was introduced to the Americas from pinnipeds; and influenza has been shown to be transmitted from seals to humans.  In recent years, viral disease has been implicated in the deaths of tens of thousands of harbor seals.

Almost half of marine mammals die from unknown causes, the researchers said, but the use of new high-speed, analytic tools could offer ways to change that. The techniques don’t require prior information about the viruses and bacterial infections that may be affecting wildlife.

In the case of the stranded harbor seals in this study, it was initially suspected that viruses were the cause. This study largely ruled that out, but identified bacterial infection in the animals’ brains. The final cause of death is still unknown and research on that issue is continuing.

“These analytic tools should be increasingly useful in the future, and show us just what genes the pathogens may be using during an infection,” said Stephanie Rosales, a doctoral student in the OSU College of Science, and lead author on this study.  “A lot of new environmental changes and stresses are taking place that may lead to new emerging diseases, and we should be tracking them as they evolve.”

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Rebecca Vega-Thurber, 541-737-1851