Posts tagged science
Articles and news from the latest research reports.
Providing surgical robots with a new kind of machine intelligence that significantly extends their capabilities and makes them much easier and more intuitive for surgeons to operate is the goal of a major new grant announced as part of the National Robotics Initiative.
The five-year, $3.6 million project, titled Complementary Situational Awareness for Human-Robot Partnerships, is a close collaboration among research teams directed by Nabil Simaan, associate professor of mechanical engineering at Vanderbilt University; Howie Choset, professor of robotics at Carnegie Mellon University; and Russell Taylor, the John C. Malone Professor of Computer Science at Johns Hopkins University.
“Our goal is to establish a new concept called complementary situational awareness,” said Simaan. “Complementary situational awareness refers to the robot’s ability to gather sensory information as it works and to use this information to guide its actions.”
“I am delighted to be working with Nabil Simaan on a medical robotics project,” Choset said. “I believe him to be a thought leader in the field.” Taylor added, “This project advances our shared vision of human surgeons, computers and robots working together to make surgery safer, less invasive and more effective.”
One of the project’s objectives is to restore the type of awareness surgeons have during open surgery – where they can directly see and touch internal organs and tissue – which they have lost with the advent of minimally invasive surgery because they must work through small incisions in a patient’s skin. Minimally invasive surgery has become increasingly common because patients experience less pain, blood loss and trauma, recover more quickly and get fewer infections, and is less expensive than open surgery.
Surgeons have attempted to compensate for the loss of direct sensory feedback through pre-operative imaging, where they use techniques like MRI, X-ray imaging and ultrasound to map the internal structure of the body before they operate. They have employed miniaturized lights and cameras to provide them with visual images of the tissue immediately in front of surgical probes. They have also developed methods that track the position of the probe as they operate and plot its position on pre-operative maps.
Simaan, Choset and Taylor intend to take these efforts to the next level. They intend to create a system that acquires data from a number of different types of sensors as an operation is underway and integrates them with pre-operative information to produce dynamic, real time maps that precisely track the position of the robot probe and show how the tissue in its vicinity responds to its movements.
For example, adding pressure sensors to robot probes will provide real time information on how much force the probe is exerting against the tissue surrounding it. Not only does this make it easier to work without injuring the tissue but it can also be used to “palpate” tissue to search for hidden tumor edges, arteries and aneurisms. Such sensor data can also feed into computer simulations that predict how various body parts shift in response to the probe’s movements.
To acquire sensory data during surgery, the VU team lead by Simaan will develop methods that allow surgical snake-like robots explore the shapes and variations in stiffness of internal organs and tissues. The team will generate models that estimate locations of hidden anatomical features such as arteries and tumors and provide them to the JHU and CMU teams to create adaptive telemanipulation techniques that assist surgeons in carrying out various surgical procedures.
To create these dynamic, three-dimensional maps, the CMU team led by Choset will employ a technique called Simultaneous Localization and Mapping that allows mobile robots to navigate in unexplored areas. This class of algorithms was developed for navigating through rigid environments, such as buildings, landforms and streets, so the researchers must extend the technique so it will work in the flexible environment of the body. These maps will form the foundation of the Complementary Situation Awareness (CSA) framework.
Once they can create these maps, the collaborators intend to use them to begin semi-automating various surgical sub-tasks, such as tying off a suture, resecting a tumor or ablating tissue. For example, the resection sub-task would allow a surgeon to instruct his robot to resect tissue from point “a” to “b” to “c” to “d” to a depth of five millimeters and the robot would then cut out the tissue specified.
The researchers also intend to create what they call “virtual fixtures.” These are pre-programmed restrictions on the robot’s actions. For example, a robot might be instructed not to cut in an area where a major blood vessel has been identified. Not only would this prevent the robot from cutting a blood vessel when operating autonomously, but it would also prevent a surgeon from doing so accidently when operating the robot manually.
“We will design the robot to be aware of what it is touching and then use this information to assist the surgeon in carrying out surgical tasks safely,” Simaan said.
The Johns Hopkins team led by Taylor will develop the system infrastructure for the CSA framework, with special emphasis on the interfaces used by the surgeon. The software will be based on Johns Hopkins’ open-source “Surgical Assistant Workstation” toolkit, permitting researchers both within and outside the team to access the results of the research and adapt them for other projects.
The teams will be using several different experimental robots during this research, but all the systems will share a common surgeon interface based on mechanical components from early model da Vinci surgical robots donated by Intuitive Surgical (Sunnyvale, California) and interfaced to control electronics designed by Johns Hopkins.
Although these prototypes are not intended for use on human patients, the research results could eventually lead to advances in surgical care.
Although the development effort is focused on surgical robots, the CSA modeling and control framework could have a major impact in other applications as well.
According to Simaan, CSA could be used by a bomb squad robot to disarm a bomb or by a human user operating a robotic excavator to dig out the foundation of a new building without damaging the underground pipes or by rescue robots searching deep tunnels for injured miners.
“In the past we have used robots to augment specific manipulative skills,” said Simaan. “This project will be a major change because the robots will become partners not only in manipulation but in sensory information gathering and interpretation, creation of a sense of robot awareness and in using this robot awareness to complement the user’s own awareness of the task and the environment”
Lou Gehrig’s Disease: From Patient Stem Cells to Potential Treatment Strategy in One Study
Although the technology has existed for just a few years, scientists increasingly use “disease in a dish” models to study genetic, molecular and cellular defects. But a team of doctors and scientists led by researchers at the Cedars-Sinai Regenerative Medicine Institute went further in a study of Lou Gehrig’s disease, a fatal disorder that attacks muscle-controlling nerve cells in the brain and spinal cord.
After using an innovative stem cell technique to create neurons in a lab dish from skin scrapings of patients who have the disorder, the researchers inserted molecules made of small stretches of genetic material, blocking the damaging effects of a defective gene and, in the process, providing “proof of concept” for a new therapeutic strategy – an important step in moving research findings into clinical trials.
The study, published Oct. 23 in Science Translational Medicine, is believed to be one of the first in which a specific form of Lou Gehrig’s disease, or amyotrophic lateral sclerosis, was replicated in a dish, analyzed and “treated,” suggesting a potential future therapy all in a single study.
"In a sense, this represents the full spectrum of what we are trying to accomplish with patient-based stem cell modeling. It gives researchers the opportunity to conduct extensive studies of a disease’s genetic and molecular makeup and develop potential treatments in the laboratory before translating them into patient trials," said Robert H. Baloh, MD, PhD, director of Cedars-Sinai’s Neuromuscular Division in the Department of Neurology and director of the multidisciplinary ALS Program. He is the lead researcher and the article’s senior author.
Laboratory models of diseases have been made possible by a recently invented process using induced pluripotent stem cells – cells derived from a patient’s own skin samples and “sent back in time” through genetic manipulation to an embryonic state. From there, they can be made into any cell of the human body.
The cells used in the study were produced by the Induced Pluripotent Stem Cell Core Facility of Cedars-Sinai’s Regenerative Medicine Institute. Dhruv Sareen, PhD, director of the iPSC facility and a faculty research scientist with the Department of Biomedical Sciences, is the article’s first author and one of several institute researchers who participated in the study.
"In these studies, we turned skin cells of patients who have ALS into motor neurons that retained the genetic defects of the disease," Baloh said. "We focused on a gene, C9ORF72, that two years ago was found to be the most common cause of familial ALS and frontotemporal lobar degeneration, and even causes some cases of Alzheimer’s and Parkinson’s disease. What we needed to know, however, was how the defect triggered the disease so we could find a way to treat it."
Frontotemporal lobar degeneration is a brain disorder that typically leads to dementia and sometimes occurs in tandem with ALS.
The researchers found that the genetic defect of C9ORF72 may cause disease because it changes the structure of ribonucleic acid (RNA) coming from the gene, creating an abnormal buildup of a repeated set of nucleotides, the basic components of RNA.
"We think this buildup of thousands of copies of the repeated sequence GGGGCC in the nucleus of patients’ cells may become "toxic" by altering the normal behavior of other genes in motor neurons," Baloh said. "Because our studies supported the toxic RNA mechanism theory, we used two small segments of genetic material called antisense oligonucleotides – ASOs – to block the buildup and degrade the toxic RNA. One ASO knocked down overall C9ORF72 levels. The other knocked down the toxic RNA coming from the gene without suppressing overall gene expression levels. The absence of such potentially toxic RNA, and no evidence of detrimental effect on the motor neurons, provides a strong basis for using this strategy to treat patients suffering from these diseases."
Researchers from another institution recently led a phase one trial of a similar ASO strategy to treat ALS caused by a different genetic mutation and reportedly uncovered no safety issues.
(Source: cedars-sinai.edu)
A Trace of Memory: Researchers Watch Neurons in the Brain During Learning and Memory Recall
A team of neurobiologists led by Simon Rumpel at the Research Institute of Molecular Pathology (IMP) in Vienna succeeded in tracking single neurons in the brain of mice over extended periods of time. Advanced imaging techniques allowed them to establish the processes during memory formation and recall. The results of their observations are published this week in PNAS Early Edition.
Most of our behavior – and thus our personality – is shaped by previous experience. To store the memory of these experiences and to be able to retrieve the information at will is therefore considered one of the most basic and important functions of the brain. The current model in neuroscience poses that memory is stored as long-lasting anatomical changes in synapses, the specialized structures by which nerve cells connect and signal to each other.
At the Research Institute of Molecular Pathology (IMP) in Vienna, Simon Rumpel and Kaja Moczulska used mice to study the effects of learning and memorizing on the architecture of synapses. They employed an advanced microscopic technique called in vivo two-photon imaging that allows the analysis of structures as small as a thousandth of a millimetre in the living brain.
Using this technology, the neurobiologists tracked individual neurons over the course of several weeks and analysed them repeatedly. They focussed their attention on dendritic spines that decorate the neuronal processes and correspond to excitatory synapses. The analyses were combined with behavioral experiments in which the animals underwent classic auditory conditioning. The results showed that the learning experience triggered the formation of new synaptic connections in the auditory cortex. Several of these new structures persisted over time, suggesting a long-lasting trace of memory and confirming an important prediction of the current model.
Apart from the changes during memory formation, the IMP-scientists were interested in the act of remembering. Earlier studies had shown that memory recall is associated with molecular processes similar to the initial formation of memory. These similarities have been suggested to reflect remodelling of memory traces during recall.
To test this hypothesis, previously trained mice were exposed to the auditory cue a week after conditioning while tracking dendritic spines in the auditory cortex. The results showed that although some molecular processes indeed resembled those during memory formation, the anatomical structure of the synapses did not change. These findings suggest that memory retrieval does not lead to a modification of the memory trace per se. Instead, the molecular processes triggered by memory formation and recall could reflect the stabilization of previously altered or recently retrieved synaptic connections.
The primary goal of elucidating the processes during memory formation and recall is to increase our basic knowledge. Insights gained from these studies might however help us to understand diseases of the nervous system that affect memory. They may also, in the future, provide the basis for treatments that offer relief to traumatized patients.
Yeast, human stem cells drive discovery of new Parkinson’s disease drug targets
Using a discovery platform whose components range from yeast cells to human stem cells, Whitehead Institute scientists have identified a novel Parkinson’s disease drug target and a compound capable of repairing neurons derived from Parkinson’s patients.
The platform—whose effectiveness is described in dual papers published online this week in the journal Science—could accelerate the discovery of drug candidates that address the underlying pathology of Parkinson’s and other neurodegenerative diseases. Today, no such drugs exist.
Parkinson’s disease (PD) and such neurodegenerative diseases as Huntington’s and Alzheimer’s are characterized by protein misfolding, resulting in toxic accumulations of proteins in the cells of the central nervous system. Cellular buildup of the protein alpha-synuclein, for example, has long been associated with PD, making this protein a seemingly appropriate target for therapeutic intervention.
In the search for compounds that might alter a protein’s behavior or function—such as that of alpha-synuclein—drug companies often rely on so-called target-based screens that test the effect large numbers of compounds have on the protein in question in rapid, automated fashion. Though efficient, such an approach is limited by the fact that it essentially occurs in a test tube. Seemingly promising compounds emerging from a target-based screen may act quite differently when they’re moved from the in vitro environment into a living setting.
To overcome this limitation, the lab of Whitehead Member Susan Lindquist has turned to phenotypic screens in which candidate compounds are studied within a living system. In Lindquist’s lab, yeast cells—which share the core cell biology of human cells —serve as living test tubes in which to study the problem of protein misfolding and to identify possible solutions. Yeast cells genetically modified to overproduce alpha-synuclein serve as robust models for the toxicity of this protein that underlies PD.
“Phenotypic screens are probably underutilized for identifying drug targets and potential compounds,” says Daniel Tardiff, a scientist in the Lindquist lab and lead author of one of the Science papers. “Here, we let the yeast tell us what is a good target. We let a living cell tell us what’s critical for reversing alpha-synuclein toxicity.”
In a screen of nearly 200,000 compounds, Tardiff and collaborators identified one chemical entity that not only reversed alpha-synuclein toxicity in yeast cells, but also partially rescued neurons in the model nematode C. elegans and in rat neurons. Significantly, cellular pathologies including impaired cellular trafficking and an increase in oxidative stress, were reduced by treatment with the identified compound. Enabled by the chemistry provided by Nate Jui in the Buchwald lab at MIT, Tardiff found that the compound was working by restoring functions mediated by a cellular protein critical for trafficking that was previously thought to be “undruggable.”
But would these findings apply in human cells? To answer that question, husband-and-wife team Chee-Yeun Chung and Vikram Khurana led the second study published in Science to examine neurons derived from induced pluripotent stem (iPS) cells generated from Parkinson’s patients. The cells and differentiated neurons (of a type damaged by the disease) were derived from patients that carried alpha-synuclein mutations and develop aggressive forms of the disease. To ensure that any pathology developed in the cultured neurons could be attributed solely to the genetic defect, the researchers also derived control neurons from iPS cells in which the mutation had been corrected.
Chung and Khurana used the wealth of data from the yeast alpha-synuclein toxicity model to clue them in on key cellular processes that became perturbed as patient neurons aged in the dish. Strikingly, exposure to the compound identified via yeast screens in Tardiff’s study reversed the damage in these neurons.
“It was remarkable that the compound rescued yeast cells and patient neurons in similar ways and through the same target—a target we would not have identified without yeast genetics to guide us,” says Khurana, a postdoctoral scientist in the Lindquist lab and a neurologist at Massachusetts General Hospital who recruited patients for participation in this research. Khurana believes that the abnormalities discovered occur in the early stages of disease. If so, successful manipulation of the targets identified here might help slow or even prevent disease progression.
For the researchers involved, these findings are a bit of surprise. Because neurodegenerative disorders like PD are largely diseases of aging, modeling them in a culture dish using neurons grown from iPS cells has been thought to be exceedingly difficult, if not impossible.
“Many, ourselves included, were skeptical that we could find any important pathologies for a neurodegenerative disorder by reprogramming patient cells,” says Chung, a Senior Research Scientist in the Lindquist lab. “Critically, we also validated these pathologies in post-mortem brains, so we’re quite confident these are relevant for the disease.”
Next steps for these scientists include chemically optimizing the compound identified and testing it in animal models. Moreover, they are convinced that this yeast-human stem cell discovery platform could be applied to other neurodegenerative diseases for which yeast models have been developed.
“Using yeast genetics to identify a compound and its mechanism of action against the fundamental pathology of a disease illustrates the power of the system we’ve built,” says Lindquist, who is also professor of biology at MIT and a Howard Hughes Medical Institute investigator. “It’s critical that we continue to leverage this power because as we reduce the rate at which people are dying from cancer and heart disease, the burden of these dreaded neurodegenerative diseases is going to rise. It’s inevitable.”
Genetic analysis reveals insights into the genetic architecture of OCD, Tourette syndrome
An international research consortium led by investigators at Massachusetts General Hospital (MGH) and the University of Chicago has answered several questions about the genetic background of obsessive-compulsive disorder (OCD) and Tourette syndrome (TS), providing the first direct confirmation that both are highly heritable and also revealing major differences between the underlying genetic makeup of the disorders. Their report is being published in the October issue of the open-access journal PLOS Genetics.
"Both TS and OCD appear to have a genetic architecture of many different genes – perhaps hundreds in each person – acting in concert to cause disease,” says Jeremiah Scharf, MD, PhD, of the Psychiatric and Neurodevelopmental Genetics Unit in the MGH Departments of Psychiatry and Neurology, senior corresponding author of the report. “By directly comparing and contrasting both disorders, we found that OCD heritability appears to be concentrated in particular chromosomes – particularly chromosome 15 – while TS heritability is spread across many different chromosomes.”
An anxiety disorder characterized by obsessions and compulsions that disrupt the lives of patients, OCD is the fourth most common psychiatric illness. TS is a chronic disorder characterized by motor and vocal tics that usually begins in childhood and is often accompanied by conditions like OCD or attention-deficit hyperactivity disorder. Both conditions have been considered to be heritable, since they are known to often recur in close relatives of affected individuals, but identifying specific genes that confer risk has been challenging.
Two reports published last year in the journal Molecular Psychiatry (1, 2), with leadership from Scharf and several co-authors of the current study, described genome-wide association studies (GWAS) of thousands of affected individuals and controls. While those studies identified several gene variants that appeared to increase the risk of each disorder, none of the associations were strong enough to meet the strict standards of genome-wide significance. Since the GWAS approach is designed to identify relatively common gene variants and it has been proposed that OCD and TS might be influenced by a number of rare variants, the research team adopted a different method. Called genome-wide complex trait analysis (GCTA), the approach allows simultaneous comparision of genetic variation across the entire genome, rather than the GWAS method of testing sites one at a time, as well as estimating the proportion of disease heritability caused by rare and common variants.
"Trying to find a single causative gene for diseases with a complex genetic background is like looking for the proverbial needle in a haystack,” says Lea Davis, PhD, of the section of Genetic Medicine at the University of Chicago, co-corresponding author of the PLOS Genetics report. “With this approach, we aren’t looking for individual genes. By examining the properties of all genes that could contribute to TS or OCD at once, we’re actually testing the whole haystack and asking where we’re more likely to find the needles.”
Using GCTA, the researchers analyzed the same genetic datasets screened in the Molecular Psychiatry reports – almost 1,500 individuals affected with OCD compared with more than 5,500 controls, and nearly TS 1,500 patients compared with more than 5,200 controls. To minimize variations that might result from slight difference in experimental techniques, all genotyping was done by collaborators at the Broad Institute of Harvard and MIT, who generated the data at the same time using the same equipment. Davis was able to analyze the resulting data on a chromosome-by-chromosome basis, along with the frequency of the identified variants and the function of variants associated with each condition.
The results found that the degree of heritability for both disorders captured by GWAS variants is actually quite close to what previously was predicted based on studies of families impacted by the disorders. “This is a crucial point for genetic researchers, as there has been a lot of controversy in human genetics about what is called ‘missing heritability’,” explains Scharf. “For many diseases, definitive genome-wide significant variants account for only a minute fraction of overall heritability, raising questions about the validity of the approach. Our findings demonstrate that the vast majority of genetic susceptibility to TS and OCD can be discovered using GWAS methods. In fact, the degree of heritability captured by GWAS variants is higher for TS and OCD than for any other complex trait studied to date.”
Nancy Cox, PhD, section chief of Genetic Medicine at the University of Chicago and co-senior author of the PLOS Genetics report, adds, “Despite the fact that we confirm there is shared genetic liability between these two disorders, we also show there are notable differences in the types of genetic variants that contribute to risk. TS appears to derive about 20 percent of genetic susceptibility from rare variants, while OCD appears to derive all of its susceptibility from variants that are quite common, which is something that has not been seen before.”
In terms of the potential impact of the risk-associated variants, about half the risk for both disorders appears to be accounted for by variants already known to influence the expression of genes in the brain. Further investigation of those findings could lead to identification of the affected genes and how the expression changes contribute to the development of TS and OCD. Additional studies in even larger patient populations, some of which are in the planning stages, could identify the biologic pathways disrupted in the disorder, potentially leading to new therapeutic approaches.
(Source: medicalxpress.com)
Grasshopper Mice Are Numb to the Pain of the Bark Scorpion Sting
The painful, potentially deadly stings of bark scorpions are nothing more than a slight nuisance to grasshopper mice, which voraciously kill and consume their prey with ease. When stung, the mice briefly lick their paws and move in again for the kill.
The grasshopper mice are essentially numb to the pain, scientists have found, because the scorpion toxin acts as an analgesic rather than a pain stimulant.
The scientists published their research this week in Science.
Ashlee Rowe, lead author of the paper, previously discovered that grasshopper mice, which are native to the southwestern United States, are generally resistant to the bark scorpion toxin, which can kill other animals.
It is still unknown why the toxin is not lethal to the mice.
“This venom kills other mammals of similar size,” said Rowe, Michigan State University assistant professor of neuroscience and zoology. “The grasshopper mouse has developed the evolutionary equivalent of martial arts to use the scorpions’ greatest strength against them.”
Rowe, who conducted the research while at The University of Texas at Austin, and her colleagues ventured into the desert and collected scorpions and mice for their experiments.
To test whether the grasshopper mice felt pain from the toxin, the scientists injected small amounts of scorpion venom or nontoxic saline solution in the mice’s paws. Surprisingly, the mice licked their paws (a typical toxin response) much less when injected with the scorpion toxin than when injected with a nontoxic saline solution.
“This seemed completely ridiculous,” said Harold Zakon, professor of neuroscience at The University of Texas at Austin. “One would think that the venom would at least cause a little more pain than the saline solution. This would mean that perhaps the toxin plays a role as an analgesic. This seemed very far out, but we wanted to test it anyway.”
Rowe and Zakon discovered that the bark scorpion toxin acts as an analgesic by binding to sodium channels in the mouse pain neurons, and this blocks the neuron from firing a pain signal to the brain.
Pain neurons have a couple of different sodium channels, called 1.7 and 1.8, and research has shown that when toxins bind to 1.7 channels, the channels open, sodium flows in and the pain neuron fires.
By sequencing the genes for both the 1.7 and 1.8 sodium channels, the scientists discovered that channel 1.8 in the grasshopper mice has amino acids different from mammals that are sensitive to bark scorpion stings, such as house mice, rats and humans. They then found that the scorpion toxin binds to one of these amino acids to block the activation of channel 1.8 and thus inhibit the pain response.
“Incredibly, there is one amino acid substitution that can totally alter the behavior of the toxin and block the channel,” said Zakon.
The riddle hasn’t been completely solved just yet, though, Rowe said.
“We know the region of the channel where this is taking place and the amino acids involved,” she said. “But there’s something else that’s playing a role, and that’s what I’m focusing on next.”
Some resistance to prey toxins in mammals has been found in other species. The mongoose, for example, is resistant to the cobra. And naked mole rats’ eyes do not burn in pain when carbon dioxide builds up in their underground tunnels.
This study, however, is the first to find that an amino acid substitution in sodium channel 1.8 can have an analgesic effect.
Rowe said studies such as this could someday help researchers target these sodium channels for the development of analgesic medications for humans.
NIH funds development of novel robots to assist people with disabilities, aid doctors
Three projects have been awarded funding by the National Institutes of Health to develop innovative robots that work cooperatively with people and adapt to changing environments to improve human capabilities and enhance medical procedures. Funding for these projects totals approximately $2.4 million over the next five years, subject to the availability of funds.
The awards mark the second year of NIH’s participation in the National Robotics Initiative (NRI), a commitment among multiple federal agencies to support the development of a new generation of robots that work cooperatively with people, known as co-robots.
“These projects have the potential to transform common medical aids into sophisticated robotic devices that enhance mobility for individuals with visual and physical impairments in ways only dreamed of before,” said NIH Director Francis S. Collins, M.D., Ph.D. “In addition, as we continue to rely on robots to carry out complex medical procedures, it will become increasingly important for these robots to be able to sense and react to changing and unpredictable environments within the body. By supporting projects that develop these capabilities, we hope to increase the accuracy and safety of current and future medical robots.”
NIH is participating in the NRI with the National Science Foundation, the National Aeronautics and Space Administration, and the U.S. Department of Agriculture. NIH has funded three projects to help develop co-robots that can assist researchers, patients, and clinicians.
A Co-Robotic Navigation Aid for the Visually Impaired: The goal is to develop a co-robotic cane for the visually impaired that has enhanced navigation capabilities and that can relay critical information about the environment to its user. Using computer vision, the proposed cane will be able to recognize indoor structures such as stairways and doors, as well as detect potential obstacles. Using an intuitive human-device interaction mechanism, the cane will then convey the appropriate travel direction to the user. In addition to increasing mobility for the visually impaired and thus quality of life, methods developed in the creation of this technology could lead to general improvements in the autonomy of small robots and portable robotics that have many applications in military surveillance, law enforcement, and search and rescue efforts. Cang Ye, Ph.D., University of Arkansas at Little Rock (co-funded by the National Institute of Biomedical Imaging and Bioengineering [NIBIB] and the National Eye Institute).
MRI-Guided Co-Robotic Active Catheter: Atrial fibrillation is an irregular heartbeat that can increase the risk of stroke and heart disease. By purposefully ablating (destroying) specific areas of the heart in a controlled fashion, the propagation of irregular heart activity can be prevented. This is generally achieved by threading a catheter with an electrode at its tip through a vein in the groin until it reaches the patient’s heart. However, the constant movement of the heart as well as unpredictable changes in blood flow can make it difficult to maintain consistent contact with the heart during the ablation procedure, occasionally resulting in too large or too small of a lesion. The aim is to develop a co-robotic catheter that uses novel robotic planning strategies to compensate for physiological movements of the heart and blood and that can be used while a patient undergoes MRI — an imaging method used to take pictures of soft tissues in the body such as the heart. By combining state-of-the art robotics with high-resolution, real-time imaging, the co-robotic catheter could significantly increase the accuracy and repeatability of atrial fibrillation ablation procedures. M. Cenk Cavusoglu, Ph.D., Case Western Reserve University, Cleveland (funded by NIBIB).
Novel Platform for Rapid Exploration of Robotic Ankle Exoskeleton Control: Wearable robots, such as powered braces for the lower extremities, can improve mobility for individuals with impaired strength and coordination due to aging, spinal cord injury, cerebral palsy, or stroke. However, methods for determining the optimal design of an assistive device for use within a specific patient population are lacking. This project proposes to create an experimental platform for an assistive ankle robot to be used in patients recovering from stroke. The platform will allow investigators to systematically test various robotic control methods and to compare them based on measurable physiological outcomes. Results from these tests will provide evidence for making more effective, less expensive, and more manageable assistive technologies. Stephen G. Sawicki, Ph.D., North Carolina State University, Raleigh; Steven Collins, Ph.D., Carnegie Mellon University, Pittsburgh (co-funded by the National Institute of Nursing Research and NSF).
These projects are supported by the grants EB018117-01; EB018108-01; NR014756-01; from the National Institute of Biomedical Imaging and Bioengineering (NIBIB), the National Eye Institute (NEI), and the National Institute of Nursing Research (NINR) and by award #1355716 from the National Science Foundation.
(Source: nih.gov)
Experimental drug reduces brain damage in rodents
An experimental drug called 3K3A-APC appears to reduce brain damage, eliminate brain hemorrhaging and improve motor skills in older stroke-afflicted mice and stroke-afflicted rats with comorbid conditions such as hypertension, according to a new study from Keck Medicine of USC.
The report, which appears online in the journal Stroke, provides additional evidence that 3K3A-APC may be used as a therapy for stroke in humans, either alone or in combination with the Food and Drug Administration (FDA)-approved clot-busting drug therapy known as tissue plasminogen activator (tPA). Clinical trials to test the drug’s efficacy in people experiencing acute ischemic stroke are expected to begin recruiting patients across the United States next year.
“Currently, tPA is the best treatment for stroke caused by a blocked artery, but it must be administered within three hours after stroke onset to be effective,” said Berislav Zlokovic, director of the Zilkha Neurogenetic Institute (ZNI) at the Keck School of Medicine of USC and the study’s lead investigator. “Because of this limited window, only a small fraction of those who suffer a stroke reach the hospital in time to be considered for tPA. Our studies show that 3K3A-APC extends tPA’s therapeutic window and counteracts tPA’s tendency to induce bleeding in the brains of animals having a stroke.”
Zlokovic is the scientific founder of ZZ Biotech, a Houston-based biotechnology company he co-founded with USC benefactor Selim Zilkha to develop biological treatments for stroke and other neurological ailments.
ZZ Biotech’s 3K3A-APC is a genetically engineered variant of the naturally occurring activated protein C (APC), which plays a role in the regulation of blood clotting and inflammation. 3K3A-APC has been shown to have a protective effect on the lining of blood vessels in rodent brains, which appears to help prevent bleeding caused by tPA.
In collaboration with Cedars-Sinai Medical Center and The Scripps Research Institute, Zlokovic and his team gave tPA — alone and in combination with 3K3A-APC — to mature female mice and male hypertensive rats four hours after stroke. They also gave 3K3A-APC in regular intervals up to seven days after stroke. The researchers measured the amount of brain damage, bleeding and motor ability of the rodents up to four weeks after stroke.
The researchers found that, under those conditions, tPA therapy alone caused bleeding in the brain and did not reduce brain damage or improve motor ability when compared to the control. The combination of tPA and 3K3A-APC, however, reduced brain damage by more than half, eliminated tPA-induced bleeding and significantly improved motor ability.
“Scientists all around the globe are studying potential stroke therapies, but very few have the robust preclinical data package that 3K3A-APC has,” said Kent Pryor, ZZ Biotech’s chief operating officer. “The results from Dr. Zlokovic’s studies have been very promising.”
Zlokovic’s team previously reported similar results in young, healthy male rodents. A Phase 1 trial testing the safety of 3K3A-APC in healthy human volunteers, led by study co-author Patrick D. Lyden of Cedars-Sinai concluded in February.
“We now have opened an investigational new drug application at the FDA to conduct a Phase 2 clinical trial of 3K3A-APC in patients experiencing acute ischemic stroke,” said Joe Romano, CEO and president of ZZ Biotech. “We are excited to see 3K3A-APC move from healthy volunteers to real patients suffering from this terrible disease.”
Brainpower applied to understanding of neural stem cells
How do humans and other mammals get so brainy? USC researcher Wange Lu and his colleagues shed new light on this question in a paper published in the journal Cell Reports on Oct. 24.
The researchers donned their thinking caps to explain how neural stem and progenitor cells differentiate into neurons and related cells called glia. Neurons transmit information through electrical and chemical signals; glia surround, support and protect neurons in the brain and throughout the nervous system. Glia do everything from holding neurons in place to supplying them with nutrients and oxygen to protect them from pathogens.
By studying the embryo neural stem cells of mice in a petri dish, Lu and his colleagues discovered that a protein called SMEK1 promotes the differentiation of neural stem and progenitor cells. At the same time, SMEK1 keeps these cells in check by suppressing their uncontrolled proliferation.
The researchers also determined that SMEK1 doesn’t act alone: It works in concert with Protein Phosphatase 4 to suppress the activity of PAR3, a third protein that discourages neurogenesis — the birth of new neurons. With PAR3 out of the picture, neural stem cells and progenitors are free to differentiate into new neurons and glia.
“These studies reveal the mechanisms of how the brain keeps the balance of stem cells and neurons when the brain is formed,” said Wange Lu, associate professor of biochemistry and molecular biology at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC. “If this process goes wrong, it leads to cancer or mental retardation or other neurological diseases.”
Neural stem and progenitor cells offer tremendous promise as a future treatment for neurodegenerative disorders, and understanding their differentiation is the first step toward harnessing the cells’ therapeutic potential. This could offer new hope for patients with Alzheimer’s, Parkinson’s and many other currently incurable diseases.
Child neurologist finds potential route to better treatments for Fragile X, autism
When you experience something, neurons in the brain send chemical signals called neurotransmitters across synapses to receptors on other neurons. How well that process unfolds determines how you comprehend the experience and what behaviors might follow. In people with Fragile X syndrome, a third of whom are eventually diagnosed with Autism Spectrum Disorder, that process is severely hindered, leading to intellectual impairments and abnormal behaviors.
In a study published in the online journal PLoS One, a team of UNC School of Medicine researchers led by pharmacologist C.J. Malanga, MD, PhD, describes a major reason why current medications only moderately alleviate Fragile X symptoms. Using mouse models, Malanga discovered that three specific drugs affect three different kinds of neurotransmitter receptors that all seem to play roles in Fragile X. As a result, current Fragile X drugs have limited benefit because most of them only affect one receptor.
Nearly one million people in the United States have Fragile X Syndrome, which is the result of a single mutated gene called FMR1. In people without Fragile X, the gene produces a protein that helps maintain the proper strength of synaptic communication between neurons. In people with Fragile X, FMR1 doesn’t produce the protein, the synaptic connection weakens, and there’s a decrease in synaptic input, leading to mild to severe learning disabilities and behavioral issues, such as hyperactivity, anxiety, and sensitivity to sensory stimulation, especially touch and noise.
More than two decades ago, researchers discovered that – in people with mental and behavior problems – a receptor called mGluR5 could not properly regulate the effect of the neurotransmitter, glutamate. Since then, pharmaceutical companies have been trying to develop drugs that target glutamate receptors. “It’s been a challenging goal,” Malanga said. “No one so far has made it work very well, and kids with Fragile X have been illustrative of this.”
But there are other receptors that regulate other neurotransmitters in similar ways to mGluR5. And there are drugs already available for human use that act on those receptors. So Malanga’s team checked how those drugs might affect mice in which the Fragile X gene has been knocked out.
By electrically stimulating specific brain circuits, Malanga’s team first learned how the mice perceived reward. The mice learned very quickly that if they press a lever, they get rewarded via a mild electrical stimulation. Then his team provided a drug molecule that acts on the same reward circuitry to see how the drugs affect the response patterns and other behaviors in the mice.
His team studied one drug that blocked dopamine receptors, another drug that blocked mGluR5 receptors, and another drug that blocked mAChR1, or M1, receptors. Three different types of neurotransmitters – dopamine, glutamate, and acetylcholine – act on those receptors. And there were big differences in how sensitive the mice were to each drug.
“Turns out, based on our study and a previous study we did with my UNC colleague Ben Philpot, that Fragile X mice and Angelman Syndrome mice are very different,” Malanga said. “And how the same pharmaceuticals act in these mouse models of Autism Spectrum Disorder is very different.”
Malanga’s finding suggests that not all people with Fragile X share the same biological hurdles. The same is likely true, he said, for people with other autism-related disorders, such as Rett syndrome and Angelman syndrome.
“Fragile X kids likely have very different sensitivities to prescribed drugs than do other kids with different biological causes of autism,” Malanga said.
(Source: news.unchealthcare.org)