Platelet-like particles augment natural blood clotting for treating trauma

Associate Professor Tom Barker and Research Scientist Ashley Brown examine bacteria growing on a plate, part of a technique for evolving antibodies in their work on platelet-like particles.
Credit: Georgia Tech Photo

A new class of synthetic platelet-like particles could augment natural blood clotting for the emergency treatment of traumatic injuries -- and potentially offer doctors a new option for curbing surgical bleeding and addressing certain blood clotting disorders without the need for transfusions of natural platelets.

The clotting particles, which are based on soft and deformable hydrogel materials, are triggered by the same factor that initiates the body's own clotting processes. Testing done in animal models and in a simulated circulatory system suggest that the particles are effective at slowing bleeding and can safely circulate in the bloodstream. The particles have been tested with human blood, but have not undergone clinical trials in humans.

Supported by the National Institutes of Health, the U.S. Department of Defense, and the American Heart Association, the research will be reported September 7, 2014, in the journal Nature Materials. Researchers from the Georgia Institute of Technology, Emory University, Children's Healthcare of Atlanta and Arizona State University collaborated on the research.

"When used by emergency medical technicians in the civilian world or by medics in the military, we expect this technology could reduce the number of deaths from excessive bleeding," said Ashley Brown, a research scientist in the Georgia Tech School of Chemistry and Biochemistry and first author of the paper. "If EMTs and medics had particles like these that could be injected and then go specifically to the site of a serious injury, they could help decrease the number of deaths associated with serious injuries."

The bloodstream contains proteins known as fibrinogen that are the precursors for fibrin, the polymer that provides the basic structure for natural blood clots. When they receive the right signals from a protein known as thrombin, these precursors polymerize at the site of the bleeding. The synthetic platelet-like particles use the same trigger, and so are activated only when the body's natural clotting process is initiated.

To create that trigger, the researchers followed a process known as molecular evolution to develop an antibody that could be attached to the hydrogel particles to change their form when they encounter thrombin-activated fibrin. The resulting antibody has a high affinity for the polymerized form of fibrin and a low affinity for the precursor material.

"Fibrin production is on the back end of the clotting process, so we feel that it is a safer place to try to interact with it," said Tom Barker, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, and one of the paper's co-corresponding authors. "The specificity of this material provides a very important advantage in triggering clotting at just the right time."

The effectiveness of the platelet-like particles has been tested in an animal model and in a microfluidic chamber designed to simulate conditions within the body's circulatory system. In the chamber, tubes about the thickness of a human hair were lined with endothelial cells as in natural blood vessels.

The chamber was used to study normal human blood, as well as human blood that had been depleted of its natural platelets. In platelet-rich blood, clots formed as expected, and blood without platelets did not form clots. When the platelet-like particles were added to the platelet-depleted blood, it was able to clot.

The researchers also tested blood from infants that had undergone open heart surgery, which requires that their blood be diluted, reducing its clotting ability. When platelet-like particles were added to the dilute neonate blood, it was able to form clots.

Finally, safety testing was done on blood from hemophiliac patients. Because that blood lacks the triggers needed to cause fibrin formation, the particles had no effect. Before they can be used in humans, the particles will have to undergo human trials and receive clearance from the U.S. Food & Drug Administration (FDA).

About one micron in diameter, the particles were originally developed to be used on the battlefield by wounded soldiers, who might self-administer them using a device about the size of a smartphone. But the researchers believe the particles could also reduce the need for platelet transfusions in patients undergoing chemotherapy or bypass surgery, and in those with certain blood disorders.

"For a patient with insufficient platelets due to bleeding or an inherited disorder, physicians often have to resort to platelet transfusions, which can be difficult to obtain," said Dr. Wilbur Lam, another of the paper's co-authors and a physician in the Aflac Cancer and 
Blood Disorders Center at Children's Healthcare of Atlanta and the Department of Pediatrics at the Emory University School of Medicine. "These particles could potentially be a way to obviate the need for a transfusion. Though they don't have all the assets of natural platelets, a number of intriguing experiments have shown that the particles help augment the clotting process."

In addition to providing new treatment options, the particles could also cut costs by reducing costly natural transfusions, said Lam, who is also an assistant professor in the Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

What ultimately happens to the hydrogel particles circulating in the bloodstream will be the topic of future research, noted Brown. Particles of similar size and composition are normally eliminated from the body.

While the platelet-like particles lack many features of natural platelets, the researchers were surprised to find one property in common. Clots formed by natural platelets begin to contract over a period of hours, beginning the body's repair process. Clots formed from the synthetic particles also contract, but over a longer period of time, Brown noted.

Source: Georgia Institute of Technology

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New genetic clues found in fragile X syndrome

Research by Vitaly Klyachko, PhD, and colleagues has shed new light on brain dysfunctions associated with fragile X syndrome. Credit: Robert Boston

Scientists have gained new insight into fragile X syndrome -- the most common cause of inherited intellectual disability -- by studying the case of a person without the disorder, but with two of its classic symptoms.

In patients with fragile X, a key gene is completely disabled, eliminating a protein that regulates electrical signals in the brain and causing a host of behavioral, neurological and physical symptoms. This patient, in contrast, had only a single error in this gene and exhibited only two classic traits of fragile X -- intellectual disability and seizures -- allowing the researchers to parse out a previously unknown role for the gene.

"This individual case has allowed us to separate two independent functions of the fragile X protein in the brain," said co-senior author Vitaly A. Klyachko, PhD, associate professor of cell biology and physiology at Washington University School of Medicine in St. Louis. "By finding the mutation, even in just one patient, and linking it to a partial set of traits, we have identified a distinct function that this gene is responsible for and that is likely impaired in all people with fragile X."

The research, appearing in the Proceedings of the National Academy of Sciences (PNAS) Online Early Edition in December and in the print issue Jan. 5, is by investigators at Washington University and Emory University School of Medicine in Atlanta.

In studying fragile X, researchers' focus long has been on the problems that occur when brain cells receive signals. Like radio transmitters and receivers, brain cells send and receive transmissions in fine tuned ways that separate the signals from the noise. Until recently, most fragile X research has focused on problems with overly sensitive receivers, those that allow in too much information. The new study suggests that fragile X likely also causes overactive transmitters that send out too much information.

"The mechanisms that researchers have long thought were the entirety of the problem with fragile X are obviously still very much in play," Klyachko said. "But this unique case has allowed us to see that something else is going on."

The finding also raises the possibility that drugs recently tested as treatments for fragile X may be ineffective, at least in part, because they only dialed down the brain's receivers, presumably leaving transmitters on overdrive.

Fragile X syndrome results from an inherited genetic error in a gene called FMR1. The error prevents the manufacture of a protein called FMRP. Loss of FMRP is known to affect how cells in the brain receive signals, dialing up the amount of information allowed in. The gene is on the X chromosome, so the syndrome affects males more often and more severely than females, who may be able to compensate for the genetic error if their second copy of FMR1 is normal.

Patients with fragile X have a range of symptoms. One of the mysteries of the syndrome is how loss of a single gene can lead to such a variety of effects in different patients. Some patients are profoundly intellectually disabled, unable to talk or communicate. Others are only mildly affected. Patients often experience seizures, anxiety and impulsive behavior. Typical physical symptoms include enlarged heads, flat feet and distinctive facial features. 

Almost one-third of patients with fragile X also show symptoms of autism spectrum disorders.

To gain insight into what else FMRP might do, the researchers plumbed genetic sequencing data from more than 900 males with intellectual disabilities but without classic fragile X syndrome. They looked for mutations in the FMR1 gene that might impair the protein but not eliminate it entirely. Even in this relatively large sample size, they only found one patient with abnormal FMRP, resulting from a change in a single letter of the gene's DNA code.

Importantly, although this individual has intellectual disability and seizures, his physical features are not typical of the syndrome, and he is not autistic.

To see what effect this mutation might have, geneticist Stephen T. Warren, PhD, and his team at Emory replicated it in mouse brain cells and tested it for the widely known functions of FMRP. To their surprise, this mutated FMRP appeared to work normally. In other words, the patient's brain cells had entirely normal receivers, which appeared to work in ways that were indistinguishable from those in healthy people.

"This single point mutation does not seem to affect the classical, well-known functions of FMRP," said Klyachko, also an associate professor of biomedical engineering. "This patient presents a case of partial fragile X syndrome associated with mutated, rather than absent, FMRP. As far as I know, this is the only known case of this. It's a unique opportunity to parse out the functions of FMRP. What does this mutation impair to cause only two symptoms of fragile X?"

To find out, Warren and his team replicated the mutation in fruit flies.

Surprisingly, according to the researchers, the fruit fly studies indicated that this single mutation increased the number of transmitters in brain cells, implicating a fundamental problem in which the brain's cells send out too many signals.

To verify this mechanism in mammals, they turned to Klyachko's lab at Washington University, which has expertise in understanding how brain cells regulate the sending of electrical signals. Indeed, in past work Klyachko showed that total loss of FMRP in mice disrupts the normal process by which brain cells send signals, causing transmitters to send out too much information. In the new study, they were able to verify the same effect from just the mutation and link it to human disease. This single mutation in FMRP has the same overactivating effect on transmissions as the total loss of the protein.

The researchers said they can't rule out the possibility that additional problems also are caused by this mutation and are present in fragile X. But this research specifies at least one additional dysfunction not previously recognized. Further studies of patients with different partial symptoms of fragile X and different mutations -- if any can be found -- might identify more.

Source: Washington University School of Medicine

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'Microlesions' in epilepsy discovered by novel technique

Clusters of differentially expressed genes predict cellular abnormalities. Credit: Jeffrey Loeb

Using an innovative technique combining genetic analysis and mathematical modeling with some basic sleuthing, researchers have identified previously undescribed microlesions in brain tissue from epileptic patients. The millimeter-sized abnormalities may explain why areas of the brain that appear normal can produce severe seizures in many children and adults with epilepsy.

The findings, by researchers at the University of Illinois at Chicago College of Medicine, Wayne State University and Montana State University, are reported in the journal Brain.

Epilepsy affects about 1 percent of people worldwide. Its hallmark is unpredictable seizures that occur when groups of neurons in the brain abnormally fire in unison. Sometimes epilepsy can be traced back to visible abnormalities in the brain where seizures start, but in many cases, there are no clear abnormalities or scaring that would account for the epileptic activity.

"Understanding what is wrong in human brain tissues that produce seizures is critical for the development of new treatments because roughly one third of patients with epilepsy don't respond to our currently available medications," said Dr. Jeffrey Loeb, professor and head of neurology and rehabilitation in the UIC College of Medicine and corresponding author on the study. "Knowing these microlesions exist is as huge step forward in our understanding of human epilepsy and present new targets for treating this disease."

Loeb and colleagues searched for cellular changes associated with epilepsy by analyzing thousands genes in tissues from 15 patients who underwent surgery to treat their epilepsy. They used a mathematical modeling technique called cluster analysis to sort through huge amounts of genetic data.

Using the model, they were able to predict and then confirm the presence of tiny regions of cellular abnormalities -- the microlesions -- in human brain tissue with high levels of epileptic electrical activity, or 'high-spiking' areas where seizures begin.

"Using cluster analysis is like using a metal detector to find a needle in a haystack," said Loeb. The model, he said, revealed 11 gene clusters that "jumped right out at us" and were either up-regulated or down-regulated in tissue with high levels of epileptic electrical activity compared to tissue with less epileptic activity from the same patient.

When they matched the genes to the types of cells they came from, the results predicted that there would be reductions of certain types of neurons and increases in blood vessels and inflammatory cells in brain tissue with high epileptic activity.

When Fabien Dachet, an expert in bioinformatics research at UIC and first author of the study, went back to the tissue samples and stained for these cells, he found that all of the prediction were correct- there was a marked increase in blood vessels, inflammatory cells, and there were focal microlesions made up of neurons that had lost most of their normal connections that allow them to communicate with one another. "We think that these newly found microlesions lead to spontaneous, abnormal electrical currents in the brain that lead to epileptic seizures," said Loeb.

Loeb and his colleagues at UIC are using the same approach to look for the clusters of differentially expressed genes associated with ALS, a neurodegenerative disease, and in brain tumors. "We now have a way to predict cellular changes by simply measuring the genetic composition, with some fairly simple calculations, between more- and less-affected epileptic human tissues," explained Loeb.

"This technique gives us the ability to discover previously unknown cellular abnormalities in almost any disease where we have access to human tissues," Loeb said. He is currently developing at UIC a national 'neurorepository' of electrically mapped and genetically analyzed brain tissue for such studies.

Source: University of Illinois at Chicago

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'Darwinian' test uncovers an antidepressant's hidden toxicity

A University of Utah test detects hidden toxic effects by subjecting mice to competition for resources. Biology professor Wayne K. Potts and biologist Shannon M. Gaukler, who recently completed a doctoral degree at the U, stand in front of the test enclosure, illuminated in red light that mice perceive as nightfall. Credit: Andy Brimhall / University of Utah

Because of undetected toxicity problems, about a third of prescription drugs approved in the U.S. are withdrawn from the market or require added warning labels limiting their use. An exceptionally sensitive toxicity test invented at the University of Utah could make it possible to uncover more of these dangerous side effects early in pharmaceutical development so that fewer patients are given unsafe drugs.

To prove the point, the U researchers ran their test on Paxil, an antidepressant that thousands of pregnant women used in the years before it was linked to an increased risk of birth defects. The U.S. Food and Drug Administration now requires a warning about use in the first trimester of pregnancy. In the U study, mice exposed during development experienced multiple problems: males weighed less, had fewer offspring, dominated fewer territories and died at a higher rate. Females took longer to produce their first litters, had fewer pups and pups that were underweight. The drug doses were relatively close to those prescribed for people. In the conventional animal safety testing reported by the drug's manufacturer, no reproductive side effects emerged until rodents took doses multiple times higher than those given to treat depression.

"We are seeing effects at a dose that is close to human levels. And we are doing it exactly the way we need to determine if it presents a risk of harm to a developing fetus," says University of Utah biologist Shannon M. Gaukler, the study's lead author who recently completed a doctoral degree at the U. The study will be published in the January-February issue of Neurotoxicology and Teratology, which has posted a preprint online.

University of Utah biology professor Wayne K. Potts, the study's senior author, says that detecting toxicity problems early in preclinical testing would not only protect patients from exposure to unsafe drugs, but also help pharmaceutical companies avoid wasting billions of dollars bringing drugs to market only to have them fail.

"If we can find these health problems early on in preclinical testing, it has the potential of saving them a lot of money," Potts says.

Survival-of-the-fittest test

The key to the test's sensitivity is the way it uses untamed house mice -- rather than docile, inbred laboratory strains -- and subjects them to a relentless, Darwinian competition for food, shelter and mates much like they would face in the wild. Mice jostle and race for a place in a roughly 300-square-foot pen divided into six territories by wire fencing that individuals must climb to invade or flee neighboring turf. Four of the territories are prime real estate with multiple hidden nesting sites and direct access to feeders. Two territories are poor, offering only open nesting sites and indirect feeder access. The test is called the organismal performance assay, or OPA.

Potts first came up with the idea as a way to explore the impact of inbreeding. Those studies revealed harmful effects of cousin-level inbreeding that had gone unnoticed for decades of research on mouse genetics. Laboratory mice that are only slightly less healthy may not appear so when given ample food and living space. But if there is a defect in any physiological system, it is likely to stand out during intense competition.

"When they really have to compete directly, males are constantly testing each other and fighting over territories," Potts says. "If they don't win a territory, females won't consider them when it comes time to choose a mate."

In a study published last year, the performance assay revealed that doses of sugar that people regularly consume -- and deemed safe by regulators -- may in fact be toxic. When mice ate a diet of 25 percent extra sugar (the mouse equivalent of drinking three cans of soda daily) females died at twice the normal rate and males were a quarter less likely to hold territory and reproduce.

Testing Paxil

In the Paxil study, the researchers gave food laced with the antidepressant to 20 breeding pairs of mice for several weeks, until all had produced up to four litters. Doses were equivalent to about 1.8 times the level typically prescribed for people. The offspring also ate Paxil-laced chow until they reached breeding age. The researchers then released the exposed offspring into the competitive arena with the offspring of a control group of mice never exposed to Paxil. Groups consisted of eight males and 14 to 16 females, creating population densities comparable to those seen in the wild. The researchers started five such populations and kept them going for six months.

Males exposed to Paxil were about half as likely to control a territory. They also lagged behind control males in body weight throughout the weeks of competition and were more likely to die. Exposed males produced 44 percent fewer offspring. Exposed females showed no significant weight or mortality differences, but they produced half as many offspring as control females at the initial assessment. Their fecundity rebounded at later time points.

Danger signals

The test can provide an early warning of possible toxic effects, but it does not identify causal pathways. In the case of Paxil, the test might have alerted the drug's developers to the risk of birth defects when taken during pregnancy at prescribed doses, not just at the high levels used in conventional safety testing. Other selective serotonin reuptake inhibitors, or SSRIs, don't appear to pose the same level of risk as Paxil, but their safety for use during pregnancy remains unclear.

"It's unknown how Paxil causes birth defects and why Paxil has a stronger correlation with birth defects than other SSRIs," Gaukler says. "We think most of our results are driven by endocrine disruption."

Previous studies have shown that Paxil can lower the level of several reproductive hormones in female rats. In male rats, doses comparable to those prescribed for people can lower testosterone and boost estradiol. Other animal studies have shown that Paxil can lower sperm count and degrade sperm quality.

Potts says the performance assay may be even more important for identifying the toxic effects of agricultural chemicals, industrial pollutants, and other manufactured chemicals released into the environment.

"We don't really have a sensitive, broad toxicity assessment system," Potts says. "That's why these things slip through the cracks and we often don't discover harmful effects until after 10 or 20 years of epidemiology studies using the public as the experimental guinea pigs."

Source:  University of Utah

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Alcohol interferes with body's ability to regulate sleep

At right: Mahesh Thakkar, PhD, associate professor and director of research in the MU School of Medicine’s Department of Neurology, and Pradeep Sahota, MD, chair of the MU School of Medicine’s Department of Neurology, have studied alcohol’s effects on sleep for more than five years. Their study found that drinking interferes with the brain’s built-in system for regulating a person’s need for sleep. Credit: Image courtesy of University of Missouri-Columbia

Researchers from the University of Missouri School of Medicine have found that drinking alcohol to fall asleep interferes with sleep homeostasis, the body's sleep-regulating mechanism.

Alcohol is known to be a powerful somnogen, or sleep inducer, and approximately 20 percent of the U.S. adult population drinks alcohol to help fall asleep. The researchers, led by Mahesh Thakkar, PhD, associate professor and director of research in the MU School of Medicine's Department of Neurology, have studied alcohol's effects on sleep for more than five years. They found that alcohol interferes with the brain's built-in system for regulating a person's need for sleep.

"The prevailing thought was that alcohol promotes sleep by changing a person's circadian rhythm -- the body's built-in 24-hour clock," Thakkar said. "However, we discovered that alcohol actually promotes sleep by affecting a person's sleep homeostasis -- the brain's built-in mechanism that regulates your sleepiness and wakefulness."

Sleep homeostasis balances the body's need for sleep in relation to how long a person has been awake. If an individual loses sleep, the body produces adenosine, a naturally occurring sleep-regulating substance that increases a person's need for sleep. When a person goes to sleep early, sleep homeostasis is shifted and he or she may wake up in the middle of the night or early morning. The researchers found that alcohol alters the sleep homeostatic mechanism and puts pressure on an individual to sleep. When this happens, the sleep period is shifted, and a person may experience disrupted sleep.

"Based on our results, it's clear that alcohol should not be used as a sleep aid," said Pradeep Sahota, MD, chair of the MU School of Medicine's Department of Neurology and an author of the study. "Alcohol disrupts sleep and the quality of sleep is diminished. Additionally, alcohol is a diuretic, which increases your need to go the bathroom and causes you to wake up earlier in the morning."

In addition to studying alcohol's impact on sleep homeostasis, the researchers explored how alcohol withdrawal affects sleep. The investigators found that after extended periods of frequent drinking, subjects would fall asleep as expected, but would wake within a few hours and would be unable to fall back asleep. When the subjects were not given alcohol, the researchers found that subjects showed symptomatic insomnia.

"During acute alcohol withdrawal, subjects displayed a significant increase in wakefulness with a reduction in rapid eye movement and non-rapid eye movement sleep," Thakkar said. "This caused insomnia-like symptoms and suggests an impaired sleep homeostasis."

The researchers hope to use these findings to explore other effects of alcohol consumption.

"Sleep is an immense area of study," Thakkar said. "Approximately one-third of our life is spent sleeping. Coupled with statistics that show 20 percent of people drink alcohol to sleep, it's vital that we understand how the two interact. If you are experiencing difficulty sleeping, don't use alcohol. Talk to your doctor or a sleep medicine physician to determine what factors are keeping you from sleeping. These factors can then be addressed with individualized treatments."

The study, "Alcohol Disrupts Sleep Homeostasis," is an invited article published in the international biomedical journal Alcohol.

Source:  University of Missouri-Columbia

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An end to needle phobia: Device could make painless injections possible

"As many as 1 in 10 people experience needle phobia, which may have negative consequences, such as decreasing the rate of vaccinations and blood donation," said William McKay, M.D., lead author of the study. Credit: © uwimages / Fotolia

Imagine no tears during infant vaccines and no fear of the needle for those old enough to know what's coming. Such painless injections could be possible with a device that applies pressure and vibration while the needle is inserted in the skin, according to a study presented at the ANESTHESIOLOGY™ 2014 annual meeting.

"As many as 1 in 10 people experience needle phobia, which may have negative consequences, such as decreasing the rate of vaccinations and blood donation," said William McKay, M.D., lead author of the study and a professor of anesthesiology in perioperative medicine and pain management at the University of Saskatchewan, Saskatoon, Canada. 

"Our early research suggests that using a device that applies pressure and vibration before the needle stick could help significantly decrease painful sensations by closing the 'gate' that sends pain signals to the brain."

Researchers studied the use of pressure, vibration, and cooling or warming in 21 adults poked in the shoulder by a plastic needle that doesn't break the skin but produces needle-like pain. They tested different levels of pressure, vibration and temperature to determine the amount that provided the most benefit. The perception of pain was significantly decreased when a specific amount of pressure and vibration was applied to the site for 20 seconds prior to using the plastic needle. The addition of heat added a small benefit, but it wasn't significant. The study should be repeated in children, who may experience pain differently, said Dr. McKay. The addition of heat or cold might be more beneficial, he said.

While commercial devices that include some of these features are available, they could be improved by incorporating the additional features tested in this and other studies, he said. They could be used to prevent pain prior to providing intravenous (I.V.) treatment, the drawing or donating of blood, or administering vaccinations.

The concept likely works by distraction as well as employing the gate-control theory of pain, in which these sensations (pressure, vibration and potentially temperature) close the gate that allows the brain to register pain.

Source: American Society of Anesthesiologists (ASA)

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Back pain killing your sex life? Study reveals best positions to save your spine

Contrary to popular belief, spooning is not always the best sex position for those with a bad back, according to new research from the University of Waterloo. For the first time ever, scientists have successfully documented the way the spine moves during sex and discovered exactly why certain positions are better than others when it comes to avoiding back pain. The pioneering study combined infrared and electromagnetic motion capture systems to track how ten couples' spines moved when attempting five common sex positions. The findings were used to create an atlas, or set of guidelines, that recommends different sex positions and thrusting techniques based on what movements trigger a patient's pain. Pictured: Professor Stuart McGill demonstrates the motion of the spine during sex.  
Credit: University of Waterloo

Contrary to popular belief, spooning is not always the best sex position for those with a bad back, according to new research from the University of Waterloo.

For the first time ever, scientists have successfully documented the way the spine moves during sex and discovered exactly why certain positions are better than others when it comes to avoiding back pain.

"Any family doctor will tell you that couples often ask them how to manage their back pain during and after sex. Many couples will remain celibate because one night of love-making can lead to months of back agony," said Professor Stuart McGill, of Waterloo's Faculty of Applied Health Sciences. "Until now, doctors have never had any hard science to base their recommendations upon."

The pioneering study combined infrared and electromagnetic motion capture systems -- like those used in the creation of video games -- to track how 10 couples' spines moved when attempting five common sex positions. The findings were used to create an atlas, or set of guidelines, that recommends different sex positions and thrusting techniques based on what movements trigger a patient's pain.

"Before now, spooning was often recommended by physicians as the one position that fit all. But as we've discovered, that is not the case," said Natalie Sidorkewicz, a PhD candidate at Waterloo and lead author on the paper. "Sex positions that are suitable for one type of back pain aren't appropriate for another kind of pain."

The atlas recommends that men who are flexion-intolerant -- meaning those whose back pain is made worse by touching their toes or sitting for long periods of time, for example -- replace spooning with doggy-style sex. The guide recommends that these men use a hip-hinging motion rather than thrusting with their spines.

"For the first time ever, we now have very solid science to guide clinicians on their recommendations for patients who suffer debilitating back pain, but still want to be intimate," said Sidorkewicz. "This has the potential to improve quality of life -- and love-life -- for many couples."

According to Statistics Canada, four of every five people will experience at least one episode of disabling low back pain in their lifetime. Up to 84 per cent of men with low back pain and 73 per cent of women report a significant decrease in the frequency of intercourse when suffering back pain.

The study also shed light for the first time on the mechanics of the male orgasm. Electrodes hooked up to the male participants' muscles revealed that it is abdominal and buttock, not back muscles, that are most active during orgasm. Spine motion, on the other hand, varied with the individual. For some males, a drastic increase in flexion or extension was seen, while for others spine motion did not change much at all.

"Many of the back pain patients that we see have told us that they experience elevated levels of pain during orgasm, to the point where they will avoid having one during sex with their partner," said Sidorkewicz. "These initial findings help us to begin to understand what might be provoking their pain during the moment of climax."

A paper documenting male spine movement was published in the journal Spine. Female findings are expected to be published in the coming months. The next phase of the study will involve recruiting patients with hip pain and additional categories of back pain to further develop the guidelines.

Source: University of Waterloo

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New technology may identify tiny strains in body tissues before injuries occur

The top image shows how the new algorithm is able to identify an area (in red) where stress has created a weak spot in a small piece of plastic wrap. The older method (shown in the bottom half of the picture) is unable to pinpoint the place where the plastic wrap is weakening.
Credit: John Boyle, © The Royal Society (used with permission)

Researchers at Washington University in St. Louis have developed algorithms to identify weak spots in tendons, muscles and bones prone to tearing or breaking. The technology, which needs to be refined before it is used in patients, one day may help pinpoint minor strains and tiny injuries in the body's tissues long before bigger problems occur.

The research is available online Aug. 27 in the Journal of the Royal Society Interface, which publishes research at the nexus of the physical and life sciences.

"Tendons are constantly stretching as muscles pull on them, and bones also bend or compress as we carry out everyday activities," said senior investigator Stavros Thomopoulos, PhD, professor of orthopaedic surgery. "Small cracks or tears can result from these loads and lead to major injuries. Understanding how these tears and cracks develop over time therefore is important for diagnosing and tracking injuries."

To that end, Thomopoulos and his colleagues developed a way to visualize and even predict spots where tissues are weakened. To accomplish this, they stretched tissues and tracked what happened as their shapes changed or became distorted.

The paper's first author, John J. Boyle, a graduate student in biomedical engineering, combined mechanical engineering fundamentals with image-analysis techniques to create the algorithms, which were tested in different materials and in animal models.

"If you imagine stretching Silly Putty or a swimming cap with a picture on it, as you pull, the picture becomes distorted," Boyle said. "This allows us to track how the material responds to an external force."

In one of the experiments described in the paper, Boyle sprayed a pattern of dots on plastic wrap, stretched it and tracked the dots.

"As you pull and stretch the plastic wrap, eventually tears begin to emerge," he explained. 

"The new algorithm allowed us to find the places where the tears were beginning to form and to track them as they extended. Older algorithms are not as good at finding and tracking localized strains as the material stretches."

In fact, one of the two new algorithms is 1,000 times more accurate than older methods at quantifying very large stretches near tiny cracks and tears, the research showed. And a second algorithm has the ability to predict where cracks and failures are likely to form.

"This extra accuracy is critical for quantifying large strains," said Guy Genin, PhD, professor of mechanical engineering and co-senior investigator on the study. "Commercial algorithms that estimate strain often are much less sensitive, and they are prone to detecting noise that can arise from the algorithm itself rather than from the material being examined. The new algorithms can distinguish the noise from true regions of large strains."

Thomopoulos, who also is a professor of biomedical engineering and of mechanical engineering, works with Genin to study the shoulder's rotator cuff, a group of tendons and muscles that connect the upper arm to the shoulder blade. They want to learn why some surgeries to repair rotator cuff injuries ultimately fail. Their goal is to increase the odds that the tissue in the shoulder will heal following surgery, and they believe the new algorithms could help them get closer to that goal.

How soon the new algorithms could be used in patients depends on getting better images of the body's tissues. Current imaging techniques, such as MRI and ultrasound, lack the required clarity and resolution.

Genin also explained that although the goal of the current study is to better understand how forces at work on human tissue cause injury and stress, the algorithms also could help engineers identify vulnerable parts of buildings and other structures. Our muscles and bones, he said, are influenced by the same strains that affect those structures.

"Whether it's a bridge or a tendon, it's vital to understand the ways that physical forces cause structures and tissues to deform so that we can identify the onset of failures and eventually predict them," he said.

In the long run, they want to use the algorithms to prevent additional injuries following surgery to repair knees, shoulders and other tissues. They also said it may be possible some day to predict problems before they occur.

The group, which applied for a provisional patent earlier this year, hopes the algorithms will be useful to researchers in the medical and engineering fields.

As a piece of plastic wrap is stretched, the new algorithms identify the location (in red) where it is weakening, which is where the material eventually breaks.

Source: Washington University in St. Louis

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Neck manipulation may be associated with stroke

Vertebral artery as it passes through the neck vertebrae of the spine and enters the skull base. Arrows indicate head movement during lateral rotation and lateral flexion, motions that may be performed as part of a neck manipulation. Credit: © 2013 Trial FX.

Manipulating the neck has been associated with cervical dissection, a type of arterial tear that can lead to stroke. Although a direct cause-and-effect link has not been established between neck manipulation and the risk of stroke, healthcare providers should inform patients of the association before they undergo neck manipulation.

Treatments involving neck manipulation may be associated with stroke, though it cannot be said with certainty that neck manipulation causes strokes, according to a new scientific statement published in the American Heart Association's journal Stroke.

Cervical artery dissection (CD) is a small tear in the layers of artery walls in the neck. It can result in ischemic stroke if a blood clot forms after a trivial or major trauma in the neck and later causes blockage of a blood vessel in the brain. Cervical artery dissection is an important cause of stroke in young and middle-aged adults.

"Most dissections involve some trauma, stretch or mechanical stress," said José Biller, M.D., lead statement author and professor and chair of neurology at the Loyola University Chicago Stritch School of Medicine. "Sudden movements that can hyperextend or rotate the neck -- such as whiplash, certain sports movements, or even violent coughing or vomiting -- can result in CD, even if they are deemed inconsequential by the patient."

Although techniques for cervical manipulative therapy vary, some maneuvers used as therapy by health practitioners also extend and rotate the neck and sometimes involve a forceful thrust.

There are four arteries that supply blood to the brain: the two carotid arteries on each side of the neck, and the two vertebral arteries on the back of the neck. The influence of neck manipulation seems more important in vertebral artery dissection than in internal carotid artery dissection.

"Although a cause-and-effect relationship between these therapies and CD has not been established and the risk is probably low, CD can result in serious neurological injury," Biller said. "Patients should be informed of this association before undergoing neck manipulation."

The association between cervical artery dissection and cervical manipulative therapies was identified in case control studies, which aren't designed to prove cause and effect. An association means that there appears to be a relationship between two things, i.e., manipulative therapy of the neck and a greater incidence of cervical dissection/stroke. 

However, it's not clear whether other factors could account for the apparent relationship.

The relationship between neck manipulation and cervical artery dissection is difficult to evaluate because patients who already are beginning to have a cervical artery dissection may seek treatment to relieve neck pain, a common symptom of cervical artery dissection that can precede symptoms of stroke by several days.

You should seek emergency medical evaluation if you develop neurological symptoms after neck manipulation or trauma, such as:

• Pain in the back of your neck or in your head;
• Dizziness/vertigo;
• Double vision;
• Unsteadiness when walking;
• Slurred speech;
• Nausea and vomiting;
• Jerky eye movements.

"Tell the physician if you have recently had a neck trauma or neck manipulation," Biller said. 

"Some symptoms, such as dizziness or vertigo, are very common and can be due to minor conditions rather than stroke, but giving the information about recent neck manipulation can raise a red flag that you may have a CD rather than a less serious problem, particularly in the presence of neck pain."

Source: American Heart Association

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Correct seat belt use saves children's lives

Nine out of ten children are seriously or fatally injured in traffic accidents because they are incorrectly restrained or because of loose objects in cars. Credit: Marianne Skjerven-Martinsen, NIPH

Nine out of ten children are seriously or fatally injured in traffic accidents because they are incorrectly restrained or because of loose objects in cars. Correct use of safety equipment will save more lives, according to a new study from the Norwegian Institute of Public Health (NIPH).

Why are some children seriously or fatally injured in traffic accidents while other children in the same vehicle walk away without physical injury? This is one of the main questions Dr Marianne Skjerven-Martinsen at the NIPH studied as part of her doctoral dissertation.

The study is part of the research project 'Barn i bil' (Eng: Children in cars), a collaboration between the NIPH and Oslo University Hospital. As part of the project, a roadside study of normal traffic on Norwegian high-speed roads also took place which showed that every third child was incorrectly restrained.

Correct seat belt use is crucial

By investigating traffic accidents in Norway, Skjerven-Martinsen and her colleagues documented that incorrect restraint and loose objects in cars play a significant role in the number of deaths and injuries among children.

The results show that:

• Accidents where children are seriously injured mainly occur on high speed roads, in weekend traffic and most often follow frontal collisions on roads without crash barriers between carriageways.
• More than 9 out of 10 children who were seriously or fatally injured in traffic accidents were incorrectly restrained or were hit by loose objects in the car.
• The most common error is that the seatbelt is misplaced, with the shoulder belt under the arm or behind the back, or the lap belt is placed too high on the abdomen.
• Loose objects also cause damage to passengers, often indirectly when heavy luggage shifts, displacing the rear seat where the child is sitting.
• Correctly secured children have a low risk of injury, even in a heavy collision.

Children over 4 years are injured most frequently and the most common injuries are to the head, face, chest and abdomen.

For younger children, the most common errors are loose or misplaced straps.

Learn from experience

"We see that adults want to protect their children but they may lack knowledge of what can happen if the equipment is not used properly. The aim of this study was to evaluate the incorrect usage of child restraint in the vehicle, related to the child's height, age and type of equipment. In this way, we can give advice to parents, authorities and particularly the motor industry," says Skjerven-Martinsen.

In her thesis, she also described how children of different ages should be secured to prevent serious injury in car accidents. The findings provide a scientific basis for targeted prevention.

Source: Norwegian Institute of Public Health

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'Darting' mice may hold clues to ADHD, autism, bipolar disorder

Mice inserted with a rare human genetic variation in the dopamine transporter could lead to improvements in the diagnosis and treatment of brain disorders. Credit: Image courtesy of Vanderbilt University Medical Center

A darting mouse may hold an important clue in the development of Attention Deficit Hyperactivity Disorder (ADHD), autism and bipolar disorder, according to a study by a Vanderbilt University-led research team recently published in the Proceedings of the National Academy of Sciences.

The transgenic mouse, into which was inserted a rare human genetic variation in the dopamine transporter (DAT), could lead to improvements in the diagnosis and treatment of these all-too-common brain disorders, said Randy Blakely, Ph.D., the report's senior author.
The mutation, which has been found in people with ADHD, autism and bipolar disorder, affects the function of DAT, a protein that regulates the brain's supply of the neurotransmitter by removing excess dopamine from the synapse, or the space between nerve cells.

The DAT mutation causes the transporter to become "leaky" and spew out dopamine like "a vacuum cleaner in reverse," said Blakely, Allan D. Bass Professor of Pharmacology.

While mice with leaky DAT proteins have too much dopamine hanging around their synapses, surprisingly they aren't particularly hyperactive, possibly because DAT can still remove some of the dopamine.

But the mice exhibit an unusual "darting behavior." While their wild-type littermates are docile and quite unresponsive when researchers pick them up, those with the mutation "take off."

"Early on," Blakely said, "we could tell which ones carried the mutation by observing this response." Heightened anxiety does not appear to be the cause.

Blakely and his colleagues wonder whether this behavior is a form of "impulsivity." Rather than acting on their memories of being picked up a lot, the mice are opting for an inappropriate escape strategy.

Normal mice also stand up a lot to explore their cage. This "rearing" behavior is exacerbated by stimulant drugs. But not in these mice.

"We wonder whether this may be a sign that their behavior is driven less by searching for clues to appropriate behavior versus acting on innate impulses," Blakely said.

Other, better tests of impulsivity that evaluate premature decision-making can be applied in rodents and humans. "These tests are next on our docket," he said.

The actions of amphetamine and methylphenidate (Ritalin) are also affected by the mutation. In normal animals and people without ADHD, the stimulants flood the synapse with dopamine, eliciting hyperactivity.

But when given to the mutant animals, the drug demonstrates a "blunted" effect on both dopamine release and on locomotor activation compared to normal animals.

Blakely wonders whether stimulants like Adderall and Ritalin quell hyperactive and impulsive behaviors in some children with ADHD by reducing inappropriate dopamine leak. 
"These mice may give us much better clues as to how these drugs are acting," he said.
To that end, Blakely recently received a five-year, $2-million grant from the National Institutes of Health (NIH grant number MH109054) to pursue explorations of these mice.

"Dopamine has classically been implicated in reward and the ability to detect novelty and to respond to pleasure and to engage in effective social interactions," he continued. The darting mice thus might shed light on a much broader spectrum of behaviors.

"We've got a lot to do," he said, "a lot of needy people (to help)."

Source: Vanderbilt University Medical Center

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ADHD: Brains not recognizing angry expressions

These two faces were presented to children. Credit: © National Institutes of Natural Sciences

Inattention, hyperactivity, and impulsive behavior in children with ADHD can result in social problems and they tend to be excluded from peer activities. They have been found to have impaired recognition of emotional expression from other faces.

The research group of Professor Ryusuke Kakigi of the National Institute for Physiological Sciences, National Institutes of Natural Sciences, in collaboration with Professor Masami K. 

Yamaguchi and Assistant Professor Hiroko Ichikawa of Chuo University first identified the characteristics of facial expression recognition of children with ADHD by measuring hemodynamic response in the brain and showed the possibility that the neural basis for the recognition of facial expression is different from that of typically developing children.

The findings are discussed in Neuropsychologia.

The research group showed images of a happy expression or an angry expression to 13 children with ADHD and 13 typically developing children and identified the location of the brain activated at that time. They used non-invasive near-infrared spectroscopy to measure brain activity. Near-infrared light, which is likely to go through the body, was projected through the skull and the absorbed or scattered light was measured. The strength of the light depends on the concentration in "oxyhemoglobin" which gives the oxygen to the nerve cells working actively. The result was that typically developing children showed significant hemodynamic response to both the happy expression and angry expression in the right hemisphere of the brain.

On the other hand, children with ADHD showed significant hemodynamic response only to the happy expression but brain activity specific for the angry expression was not observed. 

This difference in the neural basis for the recognition of facial expression might be responsible for impairment in social recognition and the establishment of peer-relationships.

Source: National Institutes of Natural Sciences

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Slow to mature, quick to distract: ADHD brain study finds slower development of key connections

By examining hundreds of fMRI brain scans of children with ADHD and those without, the researchers identified key connections between brain networks that matured more slowly in ADHD brains.
Credit: Sripada lab, University of Michigan

A peek inside the brains of more than 750 children and teens reveals a key difference in brain architecture between those with attention deficit hyperactivity disorder and those without.

Kids and teens with ADHD, a new study finds, lag behind others of the same age in how quickly their brains form connections within, and between, key brain networks.

The result: less-mature connections between a brain network that controls internally-directed thought (such as daydreaming) and networks that allow a person to focus on externally-directed tasks. That lag in connection development may help explain why people with ADHD get easily distracted or struggle to stay focused.

What's more, the new findings, and the methods used to make them, may one day allow doctors to use brain scans to diagnose ADHD -- and track how well someone responds to treatment. This kind of neuroimaging "biomarker" doesn't yet exist for ADHD, or any psychiatric condition for that matter.

The new findings come from a team in the University of Michigan Medical School's Department of Psychiatry. They used highly advanced computing techniques to analyze a large pool of detailed brain scans that were publicly shared for scientists to study. Their results are published in the Proceedings of the National Academy of Sciences.

Lead author Chandra Sripada, M.D., Ph.D., and colleagues looked at the brain scans of 275 kids and teens with ADHD, and 481others without it, using "connectomic" methods that can map interconnectivity between networks in the brain.

The scans, made using function magnetic resonance imaging (fMRI) scanners, show brain activity during a resting state. This allows researchers to see how a number of different brain networks, each specialized for certain types of functions, were "talking" within and amongst themselves.

The researchers found lags in development of connection within the internally-focused network, called the default mode network or DMN, and in development of connections between DMN and two networks that process externally-focused tasks, often called task-positive networks, or TPNs. They could even see that the lags in connection development with the two task-related networks -- the frontoparietal and ventral attention networks -- were located primarily in two specific areas of the brain.

The new findings mesh well with what other researchers have found by examining the physical structure of the brains of people with and without ADHD in other ways.
Such research has already shown alterations in regions within DMN and TPNs. So, the new findings build on that understanding and add to it.

The findings are also relevant to thinking about the longitudinal course of ADHD from childhood to adulthood. For instance, some children and teens "grow out" of the disorder, while for others the disorder persists throughout adulthood. Future studies of brain network maturation in ADHD could shed light into the neural basis for this difference.

"We and others are interested in understanding the neural mechanisms of ADHD in hopes that we can contribute to better diagnosis and treatment," says Sripada, an assistant professor and psychiatrist who holds a joint appointment in the U-M Philosophy department and is a member of the U-M Center for Computational Medicine and Bioinformatics. "But without the database of fMRI images, and the spirit of collaboration that allowed them to be compiled and shared, we would never have reached this point."

Sripada explains that in the last decade, functional medical imaging has revealed that the human brain is functionally organized into large-scale connectivity networks. These networks, and the connections between them, mature throughout early childhood all the way to young adulthood. "It is particularly noteworthy that the networks we found to have lagging maturation in ADHD are linked to the very behaviors that are the symptoms of ADHD," he says.

Studying the vast array of connections in the brain, a field called connectomics, requires scientists to be able to parse through not just the one-to-one communications between two specific brain regions, but the patterns of communication among thousands of nodes within the brain. This requires major computing power and access to massive amounts of data -- which makes the open sharing of fMRI images so important.

"The results of this study set the stage for the next phase of this research, which is to examine individual components of the networks that have the maturational lag," he says. 

"This study provides a coarse-grained understanding, and now we want to examine this phenomenon in a more fine-grained way that might lead us to a true biological marker, or neuromarker, for ADHD."

Sripada also notes that connectomics could be used to examine other disorders with roots in brain connectivity -- including autism, which some evidence has suggested stems from over-maturation of some brain networks, and schizophrenia, which may arise from abnormal connections. Pooling more fMRI data from people with these conditions, and depression, anxiety, bipolar disorder and more could boost connectomics studies in those fields.
Volunteers needed for research:

To develop such a neuromarker, Sripada has embarked on follow-up research. One study is enrolling children between the ages of 7 and 17 who have ADHD and a comparison group of those without it; information is at http://umhealth.me/adhdchild. Another study is enrolling adults between the ages of 18 and 35 who have ADHD and a comparison group of those without it; information is at http://umhealth.me/adhdadult. Of note, fMRI scans do not expose a person to radiation. Anyone interested in these studies can email Psych-study@med.umich.edu or call (734) 232-0353; for the study of children, parents should make the contact and consent to research on behalf of their children.

Source: University of Michigan Health System

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