Implant Bacteria, Beware: Researchers Create Nano-sized Assassins

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ScienceDaily (June 28, 2009) — Staphylococcus epidermidis is quite an opportunist. Commonly found on human skin, the bacteria pose little danger. But S. epidermidis is a leading cause of infections in hospitals. From catheters to prosthetics, the bacteria are known to hitch a ride on a range of medical devices implanted into patients.

Inside the body, the bacteria multiply on the implant's surface and then build a slimy, protective film to shield the colony from antibiotics. According to a study in the journal Clinical Infectious Diseases, up to 2.5 percent of hip and knee implants alone in the United States become infected, affecting thousands of patients, sometimes fatally.
More ominously, there is no effective antidote for infected implants. The only way to get rid of the bacteria is to remove the implant. "There is no [easy] solution," said Thomas Webster, a biomedical engineer at Brown University.
Now, Webster and Brown graduate student Erik Taylor have created a nano-sized headhunter that zeroes in on the implant, penetrates S. epidermidis's defensive wall and kills the bacteria. The finding, published in the International Journal of Nanomedicine, is the first time iron-oxide nanoparticles have been shown to eliminate a bacterial infection on an implanted prosthetic device.
In lab tests, Taylor, the lead author, and Webster, associate professor of engineering and orthopaedics, noted that up to 28 percent of the bacteria on an implant had been eliminated after 48 hours by injecting 10 micrograms of the nanoparticle agents. The same dosage repeated three times over six days destroyed essentially all the bacteria, the experiments showed.
The tests show "there will be a continual killing of the bacteria until the film is gone," said Webster, who is editor-in-chief of the peer-reviewed journal in which the paper appears.
A surprising added benefit, the scientists learned, is the nanoparticles' magnetic properties appear to promote natural bone cell growth on the implant's surface, although this observation needs to be tested further.
To carry out the study, the researchers created iron-oxide particles (they call them "superparamagnetic") with an average diameter of eight nanometers. They chose iron oxide because the metallic properties mean the particles can be guided by a magnetic field to the implant, while its journey can be tracked using a simple magnetic technique, such as magnetic resonance imaging (MRI). Moreover, previous experiments showed that iron seemed to cause S. epidermidis to die, although researchers are unsure why. (Webster said it may be due to iron overload in the bacteria's cell.)
Once the nanoparticles arrive at the implant, they begin to penetrate the bacterial shield. The researchers are studying why this happens, but they believe it's due to magnetic horsepower. In the tests, the researchers positioned a magnet below the implant, producing a strong enough field to force the nanoparticles above to filter through the film and proceed to the implant, Webster explained.
The particles then penetrate the bacterial cells because of their super-small size. A micron-sized particle, a thousand times larger than a nanoparticle, would be too large to penetrate the bacterial cell wall.
The researchers plan to test the iron-oxide nanoparticles on other bacteria and then move on to evaluating the results on implants in animals. The research was funded by the private Hermann Foundation Inc. In addition, Taylor's tuition and stipend are funded through the National Science Foundation GK-12 program.
Adapted from materials provided by Brown University.

Deep in the Red: Using Infrared to Watch What Goes On in a Living Body

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An infrared version of the Nobel Prize-winning green fluorescent protein could make the technique even more powerful.

Fluorescent proteins, which are compounds that can absorb and then emit light, have become a powerful instrument in the cell biologist's toolkit—so powerful, in fact, that the discovery and development of green fluorescent proteins from jellyfish earned the 2008 Nobel Prize in Chemistry. (Here's a Q&A with one of the winners, Columbia University's Martin Chalfie, about his work.) These proteins have limitations, however: They need to be excited with the blue to orange part of the visible spectrum, at wavelengths of 495 to 570 nanometers. These wavelengths of light are too short to penetrate tissue very well, and so green fluorescent proteins are mainly used in test tube studies to watch cell division or to label certain cell types.
But one of the 2008 Nobelists, Roger Y. Tsien of the University of California, San Diego, and his U.C.S.D. colleagues report in today's issue of Science that they have developed a new fluorescent protein that could enable scientists to tag and visualize cellular activity as it happens inside a live animal. The protein, after absorbing light from the far-red part of the spectrum, shines in the near-infrared, at wavelengths of around 700 nanometers.
These longer wavelengths can penetrate mammalian tissue and even pass through bone. "Say you label a tumor with a green fluorescent protein, and if this labeled tumor is buried inside the animal, then you barely can get green fluorescence out," says lead researcher Xiaokun Shu. "But if you label this deeply buried tumor by infrared fluorescent proteins, you will get a stronger signal because infrared penetrates tissue more efficiently."
Tsien's group derived the infrared fluorescent protein from a hardy bacterium called Deinococcus radiodurans, famous for its ability to survive extreme environments. Bacteria do not actually use this class of proteins, called bacteriophytochromes, to emit light. "They use these bacteriophytochromes to control gene expression,” Shu says—the proteins convert absorbed light into energy to signal certain genes to turn on or off.
The initial challenge for researchers was to re-engineer the protein so that absorbed light would be re-emitted instead of being used as a source of power. They accomplished the feat by deleting the part of the protein that converts the absorbed light into chemical energy; as a result, this truncated and mutant form gave up its absorbed energy as an infrared glow. The scientists incorporated the engineered bacterial protein into mammalian cells—specifically, into the liver of a live mouse, which lit up with infrared light.
The finding paves the way for in vivo visualization of a wide range of biochemical processes and internal organs in animals. (Its use in humans is unlikely, as it would require gene therapy and the ethically dubious transplantation of bacterial genes into humans.)
“This is so important," comments David James, a cell biologist from Australia's Garvan Institute in Sydney, "because a lot of knowledge at the moment is confined to individual cells grown on a glass coverslip," leaving open the question of whether that knowledge "is transferable to an animal." The infrared version could also solve the problem of naturally occuring fluorescence from other biological molecules, which tend to glow at wavelengths similar to conventional fluorescent protein markers and thereby create a lot of “background noise," James says.

But even greater potential lies in harnessing the bacteriophytochrome's original function, namely, powering gene expression. It should be feasible, Tsien thinks, to put back in the signal-controlling properties of the phytochrome. Then it could be possible with animals to “switch on genes and control biochemistry" with light, he says.
For example, you want to explore the effects on mouse behavior of switching on a particular gene that controls some aspect of brain function, but, thankfully for the mouse, you do not want to open up its skull or stick a needle in its brain. "If the infrared fluorescent protein can be made to turn back into an infrared phytochrome, you could have the switch all ready and just waiting for enough infrared light," Tsien speculates. Because infrared light can penetrate the skull, it can reach the phytochrome and remotely switch the gene on, resulting in observable changes in the mouse's behavior.
It's the next evolutionary step for fluorescent proteins, remarks Tsien, who believes that phytochromes represent a class of proteins with enormous potential. If he's correct, then in the coming years, expect more scientists to see the (infrared) light.

By Bianca Nogrady

Neural Activity Connected To Blood Flow In New Brain Stimulation Technique

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http://www.sciencedaily.com/releases/2007/10/071009080049.htm

Science Daily — euroscientists at the University of California, Berkeley, have for the first time measured the electrical activity of nerve cells and correlated it to changes in blood flow in response to transcranial magnetic stimulation (TMS), a noninvasive method to stimulate neurons in the brain.

Their findings, reported in the Sept. 28 issue of the journal Science, could substantially improve the effectiveness of brain stimulation as a therapeutic and research tool.
With technological advances over the past decade, TMS has emerged as a promising new tool in neuroscience to treat various clinical disorders, including depression, and to help researchers better understand how the brain functions and is organized.
TMS works by generating magnetic pulses via a wire coil placed on top of the scalp. The pulses pass harmlessly through the skull and induce short, weak electrical currents that alter neural activity. Yet the relative scarcity of data describing the basic effects of TMS, and the uncertainty in how the method achieves its effects, prompted the researchers to conduct their own study.
"There are potentially limitless applications in both the treatment of clinical disorders as well as in fundamental research in neuroscience," said Elena Allen, a graduate student at UC Berkeley's Helen Wills Neuroscience Institute (HWNI) and co-lead author of the study. "For example, TMS could be used to help determine what parts of the brain are used in object recognition or speech comprehension. However, to develop effective applications of TMS, it is first necessary to determine basic information about how the technique works."
Other techniques for studying neural activity in humans, such as functional magnetic resonance imaging (fMRI) or electroencephalogram (EEG), only measure ongoing activity. TMS, on the other hand, offers the opportunity to non-invasively and reversibly manipulate neural activity in a specific brain area.
In a set of experiments, the researchers used TMS to generate weak, electrical currents in the brain with quick 2- to 4-second bursts of magnetic pulses to the visual cortex of cats. Direct measurements of the electrical discharge of nerve cells in the region in response to the pulses revealed that TMS predictably caused an initial flurry of neural activity, significantly increasing cell firing rates. This increased activity lasted 30 to 60 seconds, followed by a relatively lengthy 5 to 10 minutes of decreased activity.
What the researchers were able to determine for the first time was that the neural response to TMS correlated directly to changes in blood flow to the region. Using oxygen sensors and optical imaging, the researchers found that an initial increase in blood flow was followed by a longer period of decreased activity after the magnetic pulses were applied.
"This long-lasting suppression of activity was surprising," said Brian Pasley, a graduate student at HWNI and co-lead author of the study. "We're still trying to understand the physiological mechanisms underlying this effect, but it has implications for how TMS could be used in clinical applications."
The critical confirmation of the connection between blood flow and neural activity means that researchers can use TMS to alter neural activity, and then use fMRI, which tracks blood flow changes, to assess how the nerve cells respond over time.
"One of the most exciting applications of TMS is the ability to non-invasively modify neural activity in specific ways," said Pasley. "The brain is malleable, so brain stimulation may be used to alter and promote specific functions, like learning and memory, or suppress abnormal activity that underlies neurological disorders. If we can figure out the right ways to stimulate the brain, TMS will likely be useful in attempts to improve neural function."
The researchers noted that one of the difficulties in using TMS for specific applications is the fact that its effects vary in different brain regions and individuals.
"Using TMS is inherently challenging because its neural effects can be so variable," said Ralph Freeman, UC Berkeley professor of vision science and optometry and principal investigator of the study. "Fortunately, we can determine empirically what the end result is by making measurements with fMRI. This should be valuable to clinicians who must evaluate the effectiveness of a stimulation treatment. In turn, fMRI may serve as a guide to determine adjustments in treatment parameters."
The study was also co-authored by Thang Duong, a UC Berkeley graduate student in vision science. The National Eye Institute of the National Institutes of Health and the National Science Foundation helped support this research.
Note: This story has been adapted from material provided by University of california - Berkeley.

Fausto Intilla

www.oloscience.com

Brain Network Related To Intelligence Identified

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http://www.sciencedaily.com/releases/2007/09/070911092117.htm

Science Daily — A primary mystery puzzling neuroscientists – where in the brain lies intelligence? – just may have a unified answer.

In a review of 37 imaging studies related to intelligence, including their own, Richard Haier of the University of California, Irvine and Rex Jung of the University of New Mexico have uncovered evidence of a distinct neurobiology of human intelligence. Their Parieto-Frontal Integration Theory (P-FIT) identifies a brain network related to intelligence, one that primarily involves areas in the frontal and the parietal lobes.
“Recent neuroscience studies suggest that intelligence is related to how well information travels throughout the brain,” said Haier, a professor of psychology in the School of Medicine and longtime human intelligence researcher. “Our review of imaging studies identifies the stations along the routes intelligent information processing takes. Once we know where the stations are, we can study how they relate to intelligence.”
The data suggest that some of the brain areas related to intelligence are the same areas related to attention and memory and to more complex functions like language. Haier and Jung say this possible integration of cognitive functions suggests that intelligence levels might be based on how efficient the frontal-parietal networks process information.
Brain imaging studies of intelligence are relatively new, with Haier doing some of the first ones only 20 years ago. Although there is still discussion about how to define and measure intelligence, Haier and Jung found surprising consistency in the studies they reviewed despite the fact the studies represented a variety of approaches.
A detailed report on this research including peer commentary from 19 researchers appears online in the journal Behavioral and Brain Sciences.
In his peer commentary, University of Washington psychologist Earl Hunt writes: “The Jung & Haier P-FIT model shows how far we have progressed toward understanding the biological basis of intelligence. Twenty-five years ago researchers in the field were engaged in an unedifying discussion of the relation between skull sizes and intelligence test scores. By taking advantage of the huge advances in measurement of the brain that have occurred in the past quarter century, [Jung and Haier] can take the far more sophisticated view that individual differences in intelligence depend, in part, upon individual differences in specific areas of the brain and in the connections between them.”
Haier and Jung have made some of the seminal findings in intelligence studies. In a 2004 study, they found that regions related to general intelligence are located throughout the brain and that a single “intelligence center,” such as the frontal lobe, is unlikely. And in a 2005 study, they found that while there are essentially no disparities in general intelligence between the sexes, women have more white matter and men more gray matter related to intelligence test scores, suggesting that no single neuroanatomical structure determines general intelligence and that different types of brain designs can produce equivalent intellectual performance.
“Genetic research has demonstrated that intelligence levels can be inherited, and since genes work through biology, there must be a biological basis for intelligence,” Haier said. “We have a long way to go before we understand the details, but our P-FIT model provides a framework for testing new hypotheses in future experiments.”
Note: This story has been adapted from a news release issued by University of California - Irvine.

Fausto Intilla

www.oloscience.com