Dual Contrast Agent to Light Up Arterial Health Risks

WestAshtonTwo degrees plus two scan energies and one heavy metal equals a new way to detect dangerous plaques in the coronary arteries.

Potentially.

Jeffrey Ashton, a biomedical engineering graduate student in Duke University’s  MD-PhD program, has won an American Heart Association Fellowship to develop a new contrast agent for CT scans. Not only would the agent be able to detect plaque buildup in arteries, but also reveal how likely the plaque is to rupture and cause a heart attack or stroke.

The  prestigious fellowship, which comes with a two-year, $50,000 grant, is intended to help young researchers launch independent careers in cardiovascular and stroke research by obtaining significant scientific results under the supervision of a mentor.

Or in this case, two mentors. The research is made possible through a collaboration betweenJennifer West, the Fitzpatrick Family University Professor of Engineering at Duke University, andCristian Badea, a professor of radiology at Duke Medicine.

“CT scans are very effective for seeing where there’s a pathology and how big it is,” said Ashton. “But that information can’t accurately predict which plaques pose an imminent risk to the patient.”

A better predictor is the proteases secreted by advanced plaques. Previous research has shown that plaques nearing their tipping point pump out more of these specialized enzymes than typical tissue.

To find plaques and determine their chances of rupturing, the project will use a relatively new technology called dual-energy CT scanning. Aptly named, the technique conducts two scans simultaneously with x-rays of differing energies. This allows doctors to see multiple materials at the same time.

“If we see an atherosclerotic plaque with a normal CT scan, we could do a dual energy CT scan using this new contrast agent to determine the risk,” said Ashton.

The first material the dual energies will light up is iodine, a contrast agent commonly used in CT scans. The second is gold nanoparticles. But the two won’t be jumping into the pool alone; they’ll be joined at the hip.

Ashton plans to connect the two elements using peptides that are easily broken by the proteases secreted by advanced plaques. As the iodine builds up in the plaque, the attached gold nanoparticles will either stay put or break free. The former indicates the plaque is in no danger of rupturing; the latter indicates a need for intervention.

“Working with Cristian has been great because, while we have done a lot of work in contrast agents in the past, we have no expertise in CT scanning technology, and he is one of the world’s leading experts in multi-modal CT imaging,” said West. “By coming together, we’ve been able to translate some of the approaches we’ve used in the past from an optical imaging platform onto a CT platform, which enables many more types of clinical applications.”

For his part, Ashton couldn’t be happier with the situation.

“Even before I started my PhD, I knew I was interested in contrast agents, but I didn’t think anyone at Duke was working with them,” said Ashton. “But rotating through Professor West’s and Professor Badea’s labs, I found that both were interested in the intersection between CT imaging and nanoparticle contrast agent development. It’s been great. I was lucky to find two labs with a need that I could fill, which also happened to be exactly what I was interested in.”

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Watching Individual Neurons Respond to Magnetic Therapy

The light grey coil on the left is a conventional, commercially available TMS coil. The black coil on the right is the new, innovative version designed to fit a smaller non-human primate’s cranium and work with the neural monitoring device. Photo courtesy of Warren Grill.

The light grey coil on the left is a conventional, commercially available TMS coil. The black coil on the right is the new, innovative version designed to fit a smaller non-human primate’s cranium and work with the neural monitoring device. Photo courtesy of Warren Grill.

Engineers and neuroscientists at Duke University have developed a method to measure the response of an individual neuron to transcranial magnetic stimulation (TMS) of the brain. The advance will help researchers understand the underlying physiological effects of TMS — a procedure used to treat psychiatric disorders — and optimize its use as a therapeutic treatment.

TMS uses magnetic fields created by electric currents running through a wire coil to induce neural activity in the brain. With the flip of a switch, researchers can cause a hand to move or influence behavior. The technique has long been used in conjunction with other treatments in the hopes of improving treatment for conditions including depression and substance abuse.

While studies have demonstrated the efficacy of TMS, the technique’s physiological mechanisms have long been lost in a “black box.” Researchers know what goes into the treatment and the results that come out, but do not understand what’s happening in between.

Part of the reason for this mystery lies in the difficulty of measuring neural responses during the procedure; the comparatively tiny activity of a single neuron is lost in the tidal wave of current being generated by TMS. But the new study demonstrates a way to remove the proverbial haystack.

The results were published online June 29 inNature Neuroscience.

“Nobody really knows what TMS is doing inside the brain, and given that lack of information, it has been very hard to interpret the outcomes of studies or to make therapies more effective,” saidWarren Grill, professor of biomedical engineering, electrical and computer engineering, and neurobiology at Duke. “We set out to try to understand what’s happening inside that black box by recording activity from single neurons during the delivery of TMS in a non-human primate. Conceptually, it was a very simple goal. But technically, it turned out to be very challenging.”

First, Grill and his colleagues in the Duke Institute for Brain Sciences (DIBS) engineered new hardware that could separate the TMS current from the neural response, which is thousands of times smaller. Once that was achieved, however, they discovered that their recording instrument was doing more than simply recording.

The TMS magnetic field was creating an electric current through the electrode measuring the neuron, raising the possibility that this current, instead of the TMS, was causing the neural response. The team had to characterize this current and make it small enough to ignore.

Finally, the researchers had to account for vibrations caused by the large current passing through the TMS device’s small coil of wire — a design problem in and of itself, because the typical TMS coil is too large for a non-human primate’s head. Because the coil is physically connected to the skull, the vibration was jostling the measurement electrode.

Michael Platt, director of the Duke Institute for Brain Sciences, Center for Cognitive Neuroscience; Warren Grill, professor of biomedical engineering, electrical and computer engineering, and neurobiology; Marc Sommer, associate professor of biomedical engineering and neurobiology; and Tobias Egner, assistant professor of psychology and neuroscience. Photo courtesy of Duke University.

Michael Platt, director of the Duke Institute for Brain Sciences, Center for Cognitive Neuroscience; Warren Grill, professor of biomedical engineering, electrical and computer engineering, and neurobiology; Marc Sommer, associate professor of biomedical engineering and neurobiology; and Tobias Egner, assistant professor of psychology and neuroscience. Photo courtesy of Duke University.

The researchers were able to compensate for each artifact, however, and see for the first time into the black box of TMS. They successfully recorded the action potentials of an individual neuron moments after TMS pulses and observed changes in its activity that significantly differed from activity following placebo treatments.

Grill worked with Angel Peterchev, assistant professor in psychiatry and behavioral science, biomedical engineering, and electrical and computer engineering, on the design of the coil. The team also included Michael Platt, director of DIBS and professor of neurobiology, and Mark Sommer, a professor of biomedical engineering.

They demonstrated that the technique could be recreated in different labs. “So, any modern lab working with non-human primates and electrophysiology can use this same approach in their studies,” said Grill.

The researchers hope that many others will take their method and use it to reveal the effects TMS has on neurons. Once a basic understanding is gained of how TMS interacts with neurons on an individual scale, its effects could be amplified and the therapeutic benefits of TMS increased.

“Studies with TMS have all been empirical,” said Grill. “You could look at the effects and change the coil, frequency, duration or many other variables. Now we can begin to understand the physiological effects of TMS and carefully craft protocols rather than relying on trial and error. I think that is where the real power of this research is going to come from.”

This research was supported by a Research Incubator Award from the Duke Institute for Brain Sciences and by a grant from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (grant R21 NS078687).

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“Optimization Of Transcranial Magnetic Stimulation And Single Neuron Recording Methods For Combined Application In Alert Non-Human Primates.” Mueller, J.K., Grigsby, E.M., Prevosto, V., Petraglia III, F.W., Rao, H., Deng, Z., Peterchev, A.V., Sommer, M.A., Egner, T., Platt, M.L., Grill, W.M. Nature Neuroscience, June 29, 2014. DOI:10.1038/nn.3751

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Big Ten Still Big in Research and Development

It’s time once again to revisit why the hell I’d choose the Big Ten as the conference to follow for science and research stories. Besides the obvious reasons that I’m from Ohio, went to Ohio State and Indiana, and worked for Michigan State, there’s also the small fact that its the best conference for research.

Don’t believe me? Just ask the National Science Foundation and their annual report on how much money is being spent on research at each and every school in the country. True, just spending a lot of money doesn’t necessarily mean that the research is awesome, but just name me one example of a company that spends a ton of cash and also sucks at what it does.

In any case, as you might expect with the Federal government all tied up in knots, overall spending across the board was flat between 2011 and 2012 (yup, it takes a while to get all of these statistics in). And yet, most Big Ten schools saw a small increase in their annual R&D expenditures.

Let’s take a look at their standings:

  • #2 – University of Michigan, Ann Arbor – $1.322 billion
  •  #3 – University of Wisconsin, Madison – $1.169 billion
  • #14 – University of Minnesota, Twin Cities – $826 million
  • $18 – Pennsylvania State University – $797 million
  • #19 – Ohio State University – $766 million
  • #28 – Northwestern University – $631 million
  • #32 – Purdue University – $602 million
  • #33 – University of Illinois, Urbana-Champaign – $583 million
  • #36 – Michigan State University – $507 million
  • #42 – University of Iowa – $446 million
  • #51 – University of Chicago – $419 million

Not too shabby, eh? Besides having two schools in the top three and five in the top 25, the Big Ten just barely misses out on having all of its schools ranked in the top 50. And if you’re wondering why the University of Chicago is on the list, check out my “Why the Big Ten” page listed up there on the blog’s header.

Some of you smart folks out there might have noted that I left out the University of Nebraska. Yes, they’re now a part of the Big Ten and yes, they have a good football team. But are they up to snuff when it comes to science?

  • #83 – University of Nebraska, Lincoln – $253 million

In a word, nope.

What about next year’s class, with Rutgers and the University of Maryland bringing up the Big Ten to a weird total of 14?

  • #45 – Rutgers University – $434 million
  • #47 – University of Maryland – $433 million

Not too shabby. That’ll do.

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Watch Out for Hurricane Daphne, Not Hurricane Manslaughter

hurricane-ivan_200_600x450When I first saw the line, “Female Hurricanes are Deadlier Than Male Hurricanes,” my initial reaction was, “Well, that must be bullshit.” How does our arbitrary naming of meteorological phenomena impact the strength and severity of said storms?

Naturally, it doesn’t. But it just might impact our perceptions of said storms.

Suppose you’re at a bar and you accidentally knock over a random bottle of Colt 45 and the person next to you says, “Uh oh, you better scram. That was Daphne’s beer.” Despite the fact that you’re at a hole-in-the-wall southern biker bar and the person giving you the warning looks like Hafthor Bjornsson, you might take his advice less seriously than if he’d said, “Uh oh, you better scram. That was Manslaughter’s beer.”

Okay, so the chances of somebody actually naming their kid Manslaughter is pretty slim. But the logic holds true. A more masculine name evokes a slightly different set of expectations in our brains than a feminine one.

That’s the theory behind the University of Illinois’ hypothesis as well. When folks hear that Hurricane Dolly is coming, they don’t take it as seriously as if Hurricane Victor is coming. And it’s not that they’re dumb enough to think the names have anything to do with the storm’s strength, it’s just a subconscious influence that people tend to have.

But is there data to back up the theory?

According to doctoral student Kiju Jung and his colleagues, there is. The research team dug through the statistics of the number of casualties caused by male-named and female-named hurricanes since 1950. And those statistics clearly show that the malefemale-named hurricanes cause more fatalities than their femalemale-named counterparts (thanks for the correction of the blatant mistake, Blaire!), even after disposing of hurricanes Katrina and Audrey, which were ridiculously deadly.

Their findings were further supported when they asked random participants to rate the level of fear imposed by a series of mock hurricane reports. As expected, people tend to rate storms with tougher-sounding names as more fear-inducing.

But others aren’t so sure that the numbers bear the conclusions out.

Every hurricane was originally given a female name because of their unpredictability and tendency to wreak havoc. Until, that is, the late 1970s when people realized that was incredibly sexist and started alternating male and female names.

But our country’s infrastructure wasn’t quite what it is today back in the 1950s and 1960s. Perhaps the statistics show a slant toward female hurricanes’ deaths because people just died more often from storms back in the day?

Not so fast, says Jung and his colleagues. Their study didn’t just look at male vs female names, it also looked at the impact of masculinity within the genders; Hurricane Victoria might sound more tough and dangerous than Hurricane Delilah.

So what do you think? Are the names we give hurricanes subconsciously affecting how much people feel threatened by them, causing them to take fewer precautions and wind up on the autopsy table? Or did the researchers just discover something that was already widely known—that society has created a subconscious bias between masculinity and femininity?

The paper, “Female Hurricanes are Deadlier Than Male Hurricanes,” was published in the Proceedings of the National Academy of Sciences by Jung and his colleagues Sharon Shavitt and Madhu Viswanathan at the University of Illinois as well as Joseph Hilbe from Arizona State University.

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Forget Fracking, Let’s Blow Shit Up

still-gaslandThe Environmental Protection Agency and President Obama are making headlines today with the announcement of an initiative to slash coal pollution. The aim is to get each state to individually cut its current carbon dioxide emissions by 30 percent, with each state choosing how best to go about its business. You can be sure, though, that at least part of the cut would have to come from the coal-fired electrical plants that dot the black eyes of the American landscape.

You can also be sure that the whole thing will end up in court for several years and that the next President and congress could very likely repeal it before it sees the light of day. After all, no news is American news. But that’s neither here nor there.

With the coal industry once again in the news—as well as Canadian oil’s route through Nebraska in hot debate—it seems that hydraulic fracking isn’t getting nearly the amount of time on the 24-hour “news” channels that it should. I mean, I’ve almost gone consecutive bowel movements without hearing the term fracking, and America just can’t stand for that.

So I’m here to balance the equation and point out a recent study from Northwestern University that suggests we’re going about fracturing shale all wrong. We shouldn’t be using pressurized water. Oh no. Instead we should be blowing it up with an electric pulse arc.

An arc is basically what happens when a shit-ton of electricity jumps out of one wire and enters its nearby neighbor. The heat and electricity ionizes the gas between, creating a small space of plasma. Electric arcs get used in welding a lot, but on a much smaller scale than what would be needed to blow apart solid shale.

The ability of an electric pulse arc to blow apart shale sounds shaky to me, but I’m no expert. Zdenek P. Bazant sure sounds like a name that knows what its talking about when it comes to science, though, so I will defer to the physics outlined in the paper he wrote.

The idea is to use the kinetic energy of high-rate shearing generated by an underground explosion caused by an electric pulse arc to reduce the rock to small fragments. Since there’s no water being pumped underground, there’s little risk of contamination issues. But would it work?

Bazant has already shown that the basic idea works well in the laboratory with exploding concrete instead of shale. And he claims that the mathematics between the concrete and shale is similar, indicating that it’s at least a viable thought. But would it really work?

“This theory is not proven for fracturing shale—we don’t know whether it would work—but it is an idea that is worth investigating,” Bažant said. “An oil company or a national laboratory would need to conduct experiments and learn how to handle the practical issues.”

My money would be on a national laboratory. I’m pretty sure oil companies are far too busy spending their billions of dollars on lobbyists to keep the status quo and their money flowing in rather than looking for ways to fundamentally change everything they do in the name of the environment.

But I for one sure would like to see somebody do some follow up studies.

The paper published in the Proceedings of the National Academy of Sciences is titled “Comminution of solids caused by kinetic energy of high shear strain rate, with implications for impact, shock, and shale fracturing.” Bažant and Ferhun C. Caner are co-authors of the paper. -

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Screening for Autism: There’s an App for That

autismscreeningMost schools across the United States provide simple vision tests to their students–not to prescribe glasses, but to identify potential problems and recommend a trip to the optometrist. Researchers are now on the cusp of providing the same kind of service for autism.

Researchers at Duke University have developed software that tracks and records infants’ activity during videotaped autism screening tests. Their results show that the program is as good at spotting behavioral markers of autism as experts giving the test themselves, and better than non-expert medical clinicians and students in training.

The results appear online in the journal Autism Research and Treatment.

“We’re not trying to replace the experts,” said Jordan Hashemi, a graduate student in computer and electrical engineering at Duke. “We’re trying to transfer the knowledge of the relatively few autism experts available into classrooms and homes across the country. We want to give people tools they don’t currently have, because research has shown that early intervention can greatly impact the severity of the symptoms common in autism spectrum disorders.”

The study focused on three behavioral tests that can help identify autism in very young children.

In one test, an infant’s attention is drawn to a toy being shaken on the left side and then redirected to a toy being shaken on the right side. Clinicians count how long it takes for the child’s attention to shift in response to the changing stimulus. The second test passes a toy across the infant’s field of view and looks for any delay in the child tracking its motion. In the last test, a clinician rolls a ball to a child and looks for eye contact afterward — a sign of the child’s engagement with their play partner.

In all of the tests, the person administering them isn’t just controlling the stimulus, he or she is also counting how long it takes for the child to react — an imprecise science at best. The new program allows testers to forget about taking measurements while also providing more accuracy, recording reaction times down to tenths of a second.

“The great benefit of the video and software is for general practitioners who do not have the trained eye to look for subtle early warning signs of autism,” said Amy Esler, an assistant professor of pediatrics and autism researcher at the University of Minnesota, who participated in some of the trials highlighted in the paper.

Guillermo Sapiro

Guillermo Sapiro

“The software has the potential to automatically analyze a child’s eye gaze, walking patterns or motor behaviors for signs that are distinct from typical development,” Esler said. “These signs would signal to doctors that they need to refer a family to a specialist for a more detailed evaluation.”

According to Hashemi and his adviser, Guillermo Sapiro, professor of electrical and computer engineering at Duke, because the program is non-invasive, it could be useful immediately in homes and clinics. Neither, however, expects it to become widely used — not because clinicians, teachers and parents aren’t willing, but because the researchers are working on an even more practical solution.

Later this year, the Duke team (which includes students and faculty from engineering and psychiatry) plans to test a new tablet application that could do away with the need for a person to administer any tests at all. The program would watch for physical and facial responses to visual cues played on the screen, analyze the data and automatically report any potential red flags. Any parent, teacher or clinician would simply need to download the app and sit their child down in front of it for a few minutes.

The efforts are part of the Information Initiative at Duke, which connects researchers from disparate fields to experts in computer programming to help analyze large data sets.

“We’re currently working with autism experts at Duke Medicine to determine what sorts of easy tests could be used on just a computer or tablet screen to spot any potential concerns,” said Sapiro. “The goal is to mimic the same sorts of social interactions that the tests with the toys and balls measure, but without the toys and balls. The research has shown that the earlier autism can be spotted, the more beneficial intervention can be. And we want to provide everyone in the world with the ability to spot those signs as early as possible.”

This research was supported by the National Science Foundation (1039741, 1028076), CAPES (BEX 1018/11-6), and FAPESP (2011/01434-9) Ph.D. scholarships from Brazil and the U.S. Department of Defense.

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“Computer vision tools for low-cost and non-invasive measurement of autism-related behaviors in infants,” Hashemi, J.; Tepper, M.; Spina, T.V.; Esler, A.; Morellas, V.; Papanikolopoulos, N.; Egger, H.; Dawson, G.; Sapiro, G. Autism Research and Treatment, 2014.

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Microchip-Like Technology Allows Single-Cell Analysis

lgthumb_singlecellassayA U.S. and Korean research team has developed a chip-like device that could be scaled up to sort and store hundreds of thousands of individual living cells in a matter of minutes. The system is similar to a random access memory chip, but it moves cells, rather than electrons.

Researchers at Duke University and Daegu Gyeongbuk Institute of Science and Technology (DGIST) in the Republic of Korea hope the cell-sorting system will revolutionize research by allowing the fast, efficient control and separation of individual cells that could then be studied in vast numbers.

“Most experiments grind up a bunch of cells and analyze genetic activity by averaging the population of an entire tissue rather than looking at the differences between single cells within that population,” said Benjamin Yellen, an associate professor of mechanical engineering and materials science at Duke’s Pratt School of Engineering. “That’s like taking the eye color of everyone in a room and finding that the average color is grey, when not a single person in the room has grey eyes. You need to be able to study individual cells to understand and appreciate small but significant differences in a similar population.”

The study appears May 14 online in Nature Communications.

Yellen and his collaborator, Cheol Gi Kim of DGIST, printed thin electromagnetic components onto a slide akin to those found on microchips. These patterns create magnetic tracks and elements like switches, transistors and diodes that guide magnetic beads and single cells tagged with magnetic nanoparticles through a thin liquid film.

Like a series of small conveyer belts, localized rotating magnetic fields move the beads and cells along specific directions etched into a track, while built-in switches direct traffic to storage sites on the chip. The result is an integrated circuit that controls small magnetic objects much like the way electrons are controlled on computer chips.

In the study, the engineers demonstrate a three-by-three grid of compartments that allow magnetic beads to enter but not leave. By tagging cells with magnetic particles and directing them to different compartments, the cells can be separated, sorted, stored, studied and retrieved.

Benjamin Yellen

Benjamin Yellen

In a random access memory chip, similar logic circuits manipulate electrons on a nanometer scale, controlling billions of compartments in a square inch. But cells are much larger than electrons, which would limit the new devices to hundreds of thousands of storage spaces per square inch.

But Yellen and Kim say that’s still plenty small for their purposes.

“You need to analyze thousands of cells to get the statistics necessary to understand which genes are being turned on and off in response to pharmaceuticals or other stimuli,” said Yellen. “And if you’re looking for cells exhibiting rare behavior, which might be one cell out of a thousand, then you need arrays that can control hundreds of thousands of cells.”

As an example, Yellen points to cells afflicted by HIV or cancer. In both diseases, most afflicted cells are active and can be targeted by therapeutics. A few rare cells, however, remain dormant, biding their time and avoiding destruction before activating and bringing the disease out of remission. With the new technology, the researchers hope to watch millions of individual cells, pick out the few that become dormant, quickly retrieve them and analyze their genetic activity.

“Maybe then we could find a way to target the dormant cells,” said Yellen.

Kim added, “Our technology can offer new tools to improve our basic understanding of cancer metastasis at the single cell level, how cancer cells respond to chemical and physical stimuli, and to test new concepts for gene delivery and metabolite transfer during cell division and growth.”

The researchers now plan to demonstrate a larger grid of 8×8 or 16×16 compartments with cells, and then to scale it up to hundreds of thousands of compartments. If successful, their technology would lend itself well to manufacturing, giving scientists around the world access to single-cell experimentation.

“Our idea is a simple one,” said Kim. “Because it is a system similar to electronics and is based on the same technology, it would be easy to fabricate. That makes the system relevant to commercialization.”

“There’s another technique paper we need to do as a follow-up before we get to actual biological applications,” added Yellen. “But they’re on their way.”

“Magnetophoretic circuits for digital control of single particles and cells,” Byeonghwa Lim, Venu Reddy, XingHao Hu, KunWoo Kim, Mital Jadhav, Roozbeh Abedini-Nassab, Young-Woock Noh, Yong Taik Lim, Benjamin B. Yellen, CheolGi Kim. Nature Communications, 2014. DOI: 10.1038/ncomms4846

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