By Matt Wood

Each day people make decisions about how much effort they’re willing to put into various tasks. The decision about how much effort to invest in an activity is influenced by the reward for doing something and the probability of actually getting it. You might be willing to work hard at your job because the reward—a paycheck—is both valuable and fairly certain. But you might not be willing to try a complicated new recipe for dinner, even though it sounds delicious, because of the chance that it won’t turn out well.

Animal studies suggest that the neurotransmitter dopamine plays an important role in this type of decision-making, especially the decision to expend effort. In rats, dopamine levels influence tolerance for effort and probability costs. Rats with higher levels of dopamine are more willing to press levers and climb over barriers to reach better food, whereas those with lower levels will settle for food that’s less tasty but within easy reach.

Little is known about how dopamine affects effort-based decision-making processes in humans. But a new study published in The Journal of Neuroscience by Margaret Wardle, a post doctoral researcher in the Department of Psychiatry and Behavioral Neuroscience at the University of Chicago, her mentor Harriet de Wit, Professor and Director of the Human Behavioral Pharmacology Laboratory, and colleagues at Vanderbilt University shows for the first time that people behave in much the same way. Their research, sponsored by the National Institute on Drug Abuse, not only sheds light on how dopamine influences decision-making in humans, but also points toward possible treatment for psychiatric disorders like depression.

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By Rob Mitchum

A surgical procedure is a daunting experience for any patient, though thanks to general anesthesia, it’s not typically a memorable one. That’s not the case for patients who go through an awake craniotomy — a unique procedure that allows surgeons to react based on feedback from the patient during removal of a brain tumor.

“I remember them waking me up using a flashlight and talking to me,” Anna Litchfield, a 49-year-old patient who was operated on by Maciej Lesniak, MD, Professor of Surgery and Neurology, said in August. “I remember Dr. Lesniak saying ‘Anna, are you OK?’ and I remember saying ‘Great, Dr. L!’ out of nowhere. I never thought I’d call him Dr. L! In retrospect, I feel like my brain was thrilled that he was there operating.”

Awake craniotomies are unique, complex procedures typically used to remove tumors nestled close to functional areas of the brain. Though the macabre nature of the surgery might induce shudders, the benefits for the patient are great. As the tumor is carefully removed by the surgeon, a neurologist can continuously monitor the patient’s language, motor and sensory function to make sure critical parts of the brain suffer minimal damage.

“When tumors are in what we call eloquent, functional areas, the margin of error is a millimeter,” Lesniak said. “You have to ask yourself whether you feel comfortable with a patient being asleep, potentially missing that millimeter while taking out the tumor and having them wake up devastated, or minimizing that risk.”

Lesniak and his team at the University of Chicago Medical Center perform more awake craniotomies than any other group in the Chicago area — more than 30 each year. Each surgery utilizes a truly interdisciplinary and experienced team of neurosurgeons, neurologists, anesthesiologists and operating room nurses who must collaborate to ensure the unusual surgery’s success. Often, craniotomy candidates are referred to Lesniak from hospitals around the area and country, as the surgery can be performed only by individuals with significant expertise and experience.

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If you called someone a rat, they probably wouldn’t take it as a compliment. But in a clever new study published today in Science, a team of University of Chicago neurobiologists show that rodents could serve as role models for how humans should behave. Rats were given a difficult choice between heart and stomach: either open a container of chocolate chips and enjoy the feast, or free a companion and share the chocolate chip bounty. The results argue that humans aren’t the only species to feel empathy for the distress of another and act upon it, suggesting a deep evolutionary basis for helping your fellow creature.

When Inbal Ben-Ami Bartal was a master’s student in Israel researching immunosuppression after surgery, she noticed a strange phenomenon in her laboratory rats. When rats were brought to the room where she regularly conducted surgical procedures, they grew extremely agitated.

“It was very obvious that rats could sense what was going on with other rats,” Bartal said. “They freaked out and were affected by the emotional state of the other rats once they were removed from the cages.”

Other researchers had previously noticed this phenomenon in both humans and animals and gave it the name “emotional contagion,” describing when the distress or pain of one individual spreads to others. In 2006, Jeffrey Mogil of McGill University found evidence of this effect in mice, observing that when one mouse is given a mildly painful stimulus, a second mouse viewing the first mouse’s pain will exhibit increased sensitivity to pain. When that paper was published, it was considered by some to be the first evidence for empathy in a rodent. But Bartal, having started as a graduate student advised by Jean Decety, Irving B. Harris Professor of Psychology and Psychiatry at the University of Chicago, wanted to find more definite proof of rat compassion.

Collaborating with the laboratory of Peggy Mason, professor of neurobiology, Bartal designed a test to see whether emotional contagion could actually drive a rat to take action. Two rats who live together in the same cage were placed in a special arena, with one held in a transparent, tube-shaped restrainer and one allowed to roam free. The restrainer’s door could be opened by a nudge from the outside, though the free rat - at least initially - didn’t know that. But after several sessions where the free rat was visibly agitated by his trapped companion’s distress, he figured out how to pop open the restrainer. As you can see in this video from Science, once the free rat learned this trick, he would take action almost immediately upon being placed in the arena during subsequent sessions.

“We are not training these rats in any way,” Bartal said. “These rats are learning because they are motivated by something internal. We’re not showing them how to open the door, they don’t get any previous exposure on opening the door, and it’s hard to open the door. But they keep trying and trying, and it eventually works.”

Proving that the free rat’s actions were motivated by empathy required more experimental conditions. When the restrainer was left empty, or when researchers put a stuffed toy rat in the tube, the free rat showed no interest in opening the restrainer door. He did, however, when the arena was rigged so that opening the restrainer released the trapped rat into a separate compartment from the free rat, showing that the free rat was not motivated by the “reward” of social interaction. The experiments left behavior motivated by empathy as the simplest explanation for the rats’ behavior.

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Brain surgery remains one of the more complex procedures in the clinical arsenal, an intervention any doctor would like to avoid if possible. But many conditions - a growing brain tumor, a bleeding hemorrhage - require the surgeon to go in, opening the skull, dodging blood vessels, and preserving healthy tissue to correct the problem. If these maladies were somehow preventable or treatable with a medication, it could cut down on the complications and cost of neurosurgery. Even so, you might be surprised to find a surgeon doing the research that could someday reduce his own workload.

That’s the case with Issam Awad, professor of surgery at the University of Chicago Medical Center, and the latest paper in his project studying an abnormality of the brain’s blood vessels. Cerebral cavernous malformation (CCM), alternatively known as cavernous angioma, occurs when the small blood vessels of the brain grow abnormally large. These malformations can occasionally form a dangerous lesion, leading to headaches, bleeding in the brain, or stroke. But it wasn’t until the routine use of MRI technology until clinicians discovered just how commonly CCM can be found - 1 in 500 people - even though it is often non-symptomatic.

The presence of non-symptomatic CCM complicates the matter further for neurosurgeons, who must decide whether to perform surgery to correct the lesion or wait to see if it worsens. This dilemma is especially difficult in patients with a family history of CCM, which makes up about one-third of the cases. Waiting to see if the angioma is going to become problematic enough to require surgery can be a frustrating experience.

“There is currently no treatment in clinical use to either prevent the formation or the maturation of these lesions,” Awad said. “The way we deal with them now is we wait until a lesion gets bad or does something bad, and then we take it out.”

Awad and colleagues Douglas Marchuk from Duke University and Mark Ginsberg at the University of California, San Diego have used those familial CCM cases to find the cause of the condition, focusing on a gene called KRIT1 (or CCM1 for its clinical significance). By knocking down KRIT1, they could create a mouse model that formed CCM lesions, and study the cellular signals that accompany the condition. It turned out that reducing the activity of KRIT1 increased the activity of a signal called ROCK, which made CCM lesions leakier and more severe. CCM lesions removed surgically from human subjects by Awad also tested for high levels of ROCK, suggesting that the mechanism was the same across species.

So the obvious hypothesis to test was whether an inhibitor of ROCK could block the formation of CCM lesions. For a paper published yesterday in Stroke, researchers from the three laboratories performed the experiments in their mouse model of CCM, treating the mice for four months with a ROCK inhibitor drug called fasudil. When they compared the brains of these drug-treated animals to the brains of animals treated with a placebo, they found fewer lesions, smaller lesions, and a reduction in inflammation and hemorrhage after fasudil.

“This animal model and humans have lesions that are aggressive and symptomatic: They leak blood, they show inflammatory properties, and endothelial cells multiply or proliferate,” Awad said. “None of these features were present in the fasudil-treated mice. It was like the lesion was chilled down and shrunk.”

Though promising, this early experiment was performed in only a small number of mice. More extensive testing in animals - and if everything goes well, in human clinical trials - will be required before the drug can be deployed in the neurology practice. Fasudil is also not yet approved for use in the United States, though it is used in Japan for a different neurological condition and has been “clinically well tolerated” there, Awad said.

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Finding the cause and the cure for a deadly disease is a little bit like investigating a murder. Clinicians collect clues from their patients, bring them back to the lab, and try to reconstruct the crime and identify the killer. For amyotrophic lateral sclerosis (aka ALS or Lou Gehrig’s Disease), this investigation has lasted over a hundred years - since neurologist Jean-Marie Charcot first described the disease in 1874. But it’s only in the last two decades that ALS researchers have started to find major breaks in the case, revealing genetic clues to the origin of this deadly neurodegenerative disease. At a special ALS gathering at the University of Chicago, Medical Center neurologist Raymond Roos told nearly 200 patients and caregivers that the case may finally be cracked soon.

“I think the field is on fire now,” said Roos, the Marjorie and Robert E. Straus Professor of Neurology. “I think it’s astounding and exciting what’s going on with respect to neurodegenerative diseases and absolutely ALS. We have all these things piling up now and we are continuing [to look]. Should we be optimistic about the future? Yes.”

Wednesday’s gathering, put together by the Greater Chicago Chapter of the ALS Assocation, was a unique two-part event featuring both a symposium for researchers of the disease and a luncheon/health expo for the patients and their families. In one room of historic Ida Noyes Hall, 14 Chicago scientists studying the origins of ALS and developing new treatments for what is currently an incurable disease shared their latest results. Meanwhile, patients and their families learned about medical devices and advocacy opportunities, and shared stories of how they cope with their disorder.

The day’s scientific component demonstrated both why the ALS investigation has taken so long, and why Roos thinks there is cause for optimism. The central mystery of ALS is why it selectively targets the motor neurons of the nervous system, the extremely long cells that deliver instructions from the brain to the muscles of the body. As the motor neurons die off, the patient experiences a progressive paralysis, losing the ability to maintain balance, walk, and eventually, breathe. Figuring out what causes this specific population of neurons to perish will point the way to treatments that slow or even reverse the progression of the disease.

For suspects, scientists have looked to genes. Roughly 10 percent of ALS cases are inherited through generations of families, indicating a genetic cause. While this population might be only a small minority of cases compared to the more common “sporadic” cases, they could be a foothold along the path to understanding both types of ALS.

“Those are very important even though they make up this small group, because they open a window,” Roos said. “If we can identify the gene that’s mutated, we can figure out what the function of that gene is. The hope and assumption and, I think, the reality, is that information will guide us into understanding the non-inherited, sporadic form.”

In 1993, scientists discovered the first ALS-associated gene/suspect, called SOD1. Though mutations of this gene explain only 20 percent of the familial 10 percent, they have been an important clue into exactly what goes wrong inside a motor neuron during the disease’s tragic march. The morning’s sessions zoomed in on these details, describing how a faulty SOD1 can kill off a cell through to the aggregation of cellular proteins, the interruption of the cell’s highway-like transport system (presented by UIC’s Gerardo Morfini and Scott Brady), and the creation of a “toxic channel” (as told by UCMC’s Michael Allen). The damage caused by SOD1 mutants might not even be limited to the motor neurons themselves, as Roos presented research demonstrating its toxic activity in the cells surrounding those neuronal types.

The path from what goes wrong to the creation of new potential therapies for ALS was explained by Richard Silverman, a chemist from Northwestern University. By screening for compounds that prevent the type of protein aggregations observed in the motor neurons of ALS patients, chemists hope to design new drugs that will slow the damage and hopefully, the physical symptoms they produce. Silverman detailed the incremental design of two new compounds in his laboratory that, in animal studies, produce an extension of life that is two to three times longer than seen with the only drug currently approved for use in ALS, riluzole.

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What made the human brain? According to Stanley Kubrick and Arthur C. Clarke, it was a giant obsidian monolith inspiring primates to use tools and weapons. Scientists have taken a more nuanced approach, looking for the biology behind the complex structures and enhanced function of the human brain. But merely comparing the genes expressed in adult human brains to those of other animals yielded few promising differences, leading scientists to focus on changes in the regulation of old genes rather than the arrival of new genes. After all, the construction of a structure as important as the brain cannot rely on unpredictable, novel genes with new functions, right?

However, those young genes are recently taking on a higher profile. In a 2010 paper, the University of Chicago laboratory of Manyuan Long demonstrated that new genes exclusive to a given species can be just as critical to an organism’s survival as the old, conserved genes it shares with other species. The implication at the time was that what makes us uniquely human could lie in those “young” genes that only appeared in our genome relatively recently.

“Animal models have proven to be very useful and important for dissecting human disease,” said Sidi Chen in 2010 about that study. “But if our intuition is correct, some important health information for humans will reside in the unique parts of the human genome.”

A new study from Long’s lab appearing yesterday in PLoS Biology identifies one important place where those new genes may play role: the human brain. By merging a database of gene age with gene transcription data from humans and mice, researchers looked for where young genes specific to each species were expressed.They found that a higher percentage of primate-specific young genes were expressed in the brain compared to mouse-specific young genes. Human-specific young genes also were more likely to be expressed in uniquely human brain structures, such as the neocortex and prefrontal cortex.

“Newer genes are found in newer parts of the human brain,” said Yong Zhang, PhD, postdoctoral researcher and first author on the study. “We know the brain is the most remarkable difference between humans and other mammals and primates. These new genes are a candidate for future studies, as they are more likely to underlie this difference.”

Another intriguing finding in the gene age data was inspired by Zhang’s visit to the obstetrician with his pregnant wife. While viewing an ultrasound of his unborn child, Zhang said he realized that much of human development takes place during fetal stages - suggesting those early months should be a critical time for gene expression. As predicted, young human-specific genes in the brain were more likely to be turned on during fetal or infant development.The early activity of these genes suggests scientists should be looking at earlier developmental stages for genetic activity that ultimately shapes the complexity of the human brain.

“What’s really surprising is that the evolutionary newest genes on the block act early,” said co-author Patrick Landback, a graduate student in Long’s laboratory. “The primate-specific genes act before birth, even when a human embryo doesn’t look very different from a mouse embryo. But the actual differences are laid out early.”

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Biology used to be the scientific discipline where data was at a premium, a rare resource painstakingly collected in the field or the laboratory. But today’s biologists are confronted with a flood of data, a fire-hose torrent of genetic and clinical information that only builds with the spread of fast sequencing and electronic medical records. But as these databases fill terabyte after terabyte of computer storage, the successful transformation of that data into practical information about human biology and disease has lagged behind. Genome-wide association studies (GWAS) have  explained only a small percentage of disease heritability, clinical records remain largely unstudied on a large scale, and the complications created by environmental influences and multi-gene disorders have frustrated scientists.

Into this impasse comes a new multi-institutional project based at the University of Chicago: the Silvio O. Conte Center, funded by a nearly $14 million combination of grants from the National Institute of Mental Health and the Chicago Biomedical Consortium. Led by Andrey Rzhetsky, professor of medicine and human genetics at the Medical Center, the collaboration of 15 scientists from 7 institutions will apply the power of advanced computation and data-mining to the growing tide of data collected about neuropsychiatric disorders. The trick will be to not just focus on one database, be it genetics or environmental factors or clinical outcomes, but all of them at once, creating a higher-resolution image of what goes awry in the brain to cause mental disease.

“A great deal of data already exists, yet nobody is already looking at it the way we plan to do and we have very smart people on this team,” said Rzhetsky, who is also a senior fellow of the Computation Institute at the University of Chicago and Institute for Genomics and Systems Biology. “When you have multiple communities that partially study the same subject you can get a kind of three-dimensional picture of a phenomenon.”

Rzhetsky has previously demonstrated the promise of data-mining - the discovery of patterns and information in large pools of data - using clinical records and scientific literature. In a 2007 study, his team examined 1.5 million patient records and found significant overlap between mental disorders such as schizophrenia, bipolar disorder, and autism, suggesting a similar overlap of the genetic factors that cause these conditions. Two years later, Rzhetsky and colleagues applied text-mining computation to the scientific literature database PubMed, creating a network of genes and biological interactions associated with cerebellar conditions such as ataxia and degeneration.

Beyond demonstrating the potential of data-mining, those studies also shed light on the hazy borders separating different psychiatric disorders. While the overlaps could complicate psychiatric diagnosis in the clinic, they might also make the disorders susceptible to the multi-faceted approach proposed by the Conte Center.

“Most studies are done one disorder at a time, and that’s like studying the trunk or the hoof or the tail of an elephant; you might miss the big picture,” said Benjamin Lahey, Irving B. Harris Professor of epidemiology at the University of Chicago and a co-investigator at the Conte Center. “This project will enable us to look at things in a way that has never been done before, at a scale that dwarfs anything that’s ever been done.”

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A visit to any casino will quickly demonstrate how vices clump together. At any hour of the day or night, many of the customers sitting intently in front of a slot machine will also be smoking cigarettes or drinking a cocktail. Sadly, addictions to these pursuits also tend to go hand in hand, with higher rates of compulsive gambling observed in people addicted to drugs such as cocaine and alcohol. Furthermore, when people perform gambling-like tasks while their brain is scanned by an MRI machine, the games activate areas of the brain also stimulated by drugs of abuse - perhaps accounting for the addiction-like behavior of gamblers.

“If you’ve ever been to a casino, and you watch people using slot machines, you’ll surely have noticed the sense of compulsion to put the next coin in, even though you get no money back most of the time,” said Paul Vezina, professor of psychiatry and behavioral neuroscience at the University of Chicago.

But does one bad habit truly lead to the other? In a recent paper for the journal Behavioural Brain Research, a team from Vezina’s laboratory offers evidence that the unpredictability crucial to gambling’s appeal can cross over to enhance the effects of abused drugs. By adapting self-administration, a common tool used to model drug-taking in animal research, to partially replicate the random pay-off of a slot machine, graduate student Bryan Singer was able to test whether gambling-like behavior influences a rat’s subsequent response to the drug amphetamine. The result suggests that gambling may have properties similar to a “gateway drug,” as an activity that can increase the abusive potential of drugs.

First of all, how do you simulate the casino experience for a rat? Self-administration - where the animal presses a lever to receive a food or drug reward - is fairly similar to a slot machine to begin with. In a self-administration protocol, the researcher sets the number of lever presses required before the reward is given. A “fixed ratio” of 5 means that the rat would have to hit the lever five times before receiving a food pellet or rewarding hit of cocaine. But with a “variable ratio” setup, unpredictability is introduced into the process. If the variable ratio is set to an average of 5, anywhere from 1 to 10 presses might be required to produce reward, a figure that changes every time like the random number generator of a slot machine. So while the rat does not have anything at stake other than the physical work it takes to hit the lever, it never knows when it will hit the “jackpot.”

“One of the main differences is that for a slot machine there’s a good chance you’re going to lose money, but here there’s little negative aspect,” Singer said. “It’s like a very loose slot machine.”

In this experiment, Singer and co-author John Scott-Railton used the non-caloric sweetener saccharine as a reward - a sweet treat that rats will work to acquire without ever getting full or intoxicated. For 55 days, half of the rats worked for saccharine under fixed ratio conditions and half worked under the variable ratio setup. Then, after a two week break, each rat was given a small dose of amphetamine, and researchers measured their activity as the dosed rats ran around their cage.

Even though the rats in each group received the same amount of saccharine and did the same amount of work during their lever-pressing careers, those exposed to the random rules of the variable ratio exhibited a stronger response to amphetamine. The result suggests that unpredictable rewards may prime the same brain areas hijacked by drugs of abuse, producing a stronger behavioral response - known in the field as sensitization - even upon first exposure to a stimulant drug.

“What this paper is showing is that unpredictable conditions may cause sensitization,” Vezina said. “There are activities that may play just as important a gateway role as drugs, and gambling may be one of them.”

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How do you know an animal model of a disease is really working? Researchers can create diseases such as cancer in a rat or mouse, but a tumor in a rodent may not behave the same way as a tumor in a human being. The challenge is even more difficult when scientists try to model psychiatric conditions, which in humans rely upon interviews and nuanced diagnosis. It’s hard to get a rat to stay on a therapist’s couch, much less ask whether they are feeling depressed or anxious.

So psychiatrists interested in using an animal model to probe the underlying biology of a mental condition are forced to be careful, clever and realistic. For a new model of obsessive-compulsive disorder (OCD) published last week by a team of scientists from the University of Chicago, the validity of the model was based on both the symptoms they observed in their animals and how those symptoms were treated.

More than 2 million people in the United States have been diagnosed with OCD, a condition marked by severe anxiety, repetitive behaviors, and intrusive thoughts. Yet only one drug has been found to help alleviate these symptoms - fluoxetine, a serotonin reuptake inhibitor originally developed for the treatment of depression - and the drug is only effective in roughly half of all OCD patients. Finding and testing better treatments for OCD will require animal models of the disease.

“Treatment for these people is greatly needed, and there really are very few highly valid animal models of the disorder,” said Nancy Shanahan, a postdoctoral researcher and lead author of the study in the journal Biological Psychiatry. “Having one that seems to mimic the disorder so well, especially in terms of the time course of treatments that work in humans, is potentially very useful for researching novel therapeutics.”

That’s easier said than done. The compulsive hand-washing, switch-flicking, or counting habits of human OCD sufferers would seem to be impossible symptoms to replicate in a rat, but some characteristics such as perseveration (repetitive movements or actions) and movement in an open field (a marker of a rodent’s comfort or anxiety in a strange environment) have been used by scientists as proxies for the debilitating effects of OCD. Some groups have created these behaviors by deleting genes, but for the new OCD model the UChicago team started with the unusual side effect of a migraine medication.

When the drug sumatriptan is given to people with OCD, it amplifies their symptoms, producing more intrusive thoughts and rituals. Shanahan gave her mice a similar drug that, like sumatriptan, activates a sub-class of receptors for the neurotransmitter serotonin called 1b receptors. In response, the mice showed behaviors that could be interpreted as OCD-like. Instead of exploring the entirety of their cage, they stayed close to the walls (as seen in the paths above) - a marker of high anxiety. Another test called prepulse inhibition that tests the animals’ startle response (thought to measure the brain’s ability to filter out intrusive thoughts), also revealed OCD-like behavior after the serotonin 1b drug was given.

Yet it’s still subjective to say that a mouse that paces around the walls of its cage is suffering from the same underlying biological issues as a human whose anxiety keeps them from leaving the house. More evidence was needed to prove the model’s “predictive validity” - how closely it resembles the human disease.

“A model should be evaluated on its ability to predict, not based on how much it looks like OCD,” explained Stephanie Dulawa, assistant professor in the Department of Psychiatry and Behavioral Neuroscience and senior author of the study. “The best way to do that is to evaluate manipulations with known effects in OCD.”

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By John Easton

Let’s start with a statistic: almost 2,000 citations a year. One paper by Paul Meier, the Ralph and Mary Otis Isham Distinguished Service Professor emeritus of statistics, pharmacological and physiological sciences, medicine, and the college, has been cited more often, by a wide margin, than any other paper in the field. At last count it was the fifth most cited research paper of all time, in any field. With about 34,000 citations to date, Kaplan, E. L., and Meier, P. (1958), “Nonparametric Estimation from Incomplete Observations,” has been cited by another scientific publication about once, on average, for every day of Meier’s long life—he was born in 1924—and still counting.

Sadly, however, that ratio can only increase. Citation counting will continue, but the numbering of days stopped on Sunday, August 7th, when Professor Meier, a world-class statistician who made “extraordinary contributions to statistics and to society,” according to Columbia University - and everyone else - passed away peacefully at his Manhattan home.

The Kaplan-Meier estimator is used ubiquitously in medical studies to estimate and depict the fraction of patients living for a certain amount of time after treatment. This is not as simple as it sounds. Survival curves are complicated by the uncooperative way in which research subjects often behave. Some leave a study part of the way through. Others elect not to die before the study ends. These are known as “censored observations.” The Kaplan-Meier estimate is a simple way to compute the survival curve despite such troublesome behavior.

There was almost a Kaplan estimator and a Meier estimator. Each had submitted a separate manuscript to the Journal of the American Statistical Association, but the editor recommended that their papers be combined into one. It took them four years. “At one place he solved a problem that I couldn’t solve,” Meier later recalled in an interview [pdf]. “Other places I solved problems he couldn’t.” Finally published in 1958, it was only cited 25 times over the next ten years. Then, boosted by statisticians’ increased computing power, it caught on. It has since been applied to data from clinical trials of therapies for every disease from cancer to cardiology to concussion.

Friends and colleagues point out that this was only one of Meier’s fundamental contributions. He published many more studies, was a persistent and outspoken advocate for randomization in clinical studies, helped design some of the 20th Century’s most important clinical trials and trained many of the leaders in the field.

“Paul was a friend and colleague as well as one of the most influential statisticians of an important era,” recalled Stephen Stigler, the current chair of statistics at the University of Chicago. “He left an indelible mark on us, and through his research on the world’s clinic analytical practice. He will be missed and cannot be replaced.”

“I have been so fortunate and privileged to know this truly great, wonderful, helpful, kind man who was always so generous with his skills and wise advice,” said toxoplasmosis expert Rima McLeod, professor of ophthalmology and visual sciences at the University. “He is one of the founding fathers and giants of statistics in the past century. He was at the same time simply a modest, helpful, supportive and warm colleague who only let you know how special he was by the quality and content of what he said and wrote.”

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To prepare for the grueling 2,200 miles of the Tour de France, cyclists train their muscles at both low and high altitudes. Riding at elevation does more than prepare them for the infamous mountain stages in the Alps, it has a biological effect, increasing the capacity of red blood cells to carry oxygen and improving how their muscles use energy. Though it may seem counter-intuitive, training in the low oxygen conditions found at high altitude is actually beneficial to an athlete’s muscular performance long-term. Could the same be said for another important muscle - the one located inside your skull?

That’s one implication of a new study from University of Chicago researchers on the relationship between the sleep disorder sleep apnea and strokes. Patients with sleep apnea suffer from repeated breathing “pauses” during the night, moments where their brain is briefly deprived of oxygen (known scientifically as “hypoxia”). One or two of these hypoxic episodes may not be dangerous by themselves, but cumulatively, they can be very harmful - sleep apnea has been associated with cognitive impairment, behavioral effects, and cardiovascular disease.

Indeed, sleep apnea increases the danger twice over for one especially serious vascular problem: stroke. Research indicates that patients with the disorder are more likely to suffer a stroke, and if a stroke occurs, it is more likely to cause severe brain damage than in people without sleep apnea. Both sides of this connection have been targeted by investigators from the Department of Pediatrics sleep research group at the University of Chicago Medical Center. In one recent study, led by David Gozal, chair and professor of pediatrics, and Richard Li, assistant professor of pediatrics, the researchers found a mechanism for why putting rats through “intermittent hypoxia” during sleep (an animal model of sleep apnea) can increase the risk of atherosclerosis, the hardening of the arteries involved in many cardiovascular conditions.

But another study, published last month in The Journal of Neuroscience, focused on stroke’s aftermath, testing whether the extra brain damage from a stroke in sleep apnea patients was due to the low-oxygen episodes or an associated risk factor such as obesity. A team led by Yang Wang, associate professor of pediatrics and director of basic research for the sleep medicine laboratory, again simulated sleep apnea in otherwise normal rats with intermittent hypoxia (IH), comparing them with rats that slept in normal oxygen conditions. When a controlled stroke was induced in each of these groups, the resulting damage was very different - the IH rats suffered more damage than controls, indicating a direct effect of hypoxic episodes upon recovery after stroke.

“It seems that something very bad is happening that affects the ability of the cells to survive or to recover after stroke,” Gozal said.

The researchers then focused on a possible mechanism for why intermittent hypoxia leads to more severe strokes, choosing energy metabolism as their primary suspect. When the brain is active - or trying to recover from damage - it needs a lot of fuel. As with the rest of the body, glucose is the first option for providing energy. But like muscles, a healthy brain can also use lactate as an alternative energy source in times of high demand. The gas pump for getting lactate into neurons is a protein called monocarboxylate transporter 2, or MCT2. Wang and colleagues looked at how intermittent hypoxia affected levels of MCT2 and how MCT2 levels affected the severity of stroke.

The pathway fell into place - exposing rats to IH decreased the expression of the MCT2 gene, while decreasing MCT2 activity through various methods increased brain damage after stroke. A transgenic mouse with elevated MCT2 was even created, and found to be protected against a stroke’s damaging effects. Thus, repeated hypoxia events during sleep could disrupt MCT2 and impair the brain’s ability to use lactate for energy - perhaps by “crying wolf” too many times. Gozal used the metaphor of a night watchman repeatedly running up the stairs for minor smoke alarms, only to be too tired to respond when the big fire starts.

“I think we have dissected in a very careful way, with a lot of work, the mechanisms that may explain why patients with sleep apnea are not only at increased risk of stroke, but also why when that stroke hits, they have a risk of not really recovering,” Gozal said.

The study also raised an intriguing idea about how to prevent this elevated sensitivity to stroke in sleep apnea patients.

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Countless campaigns have been launched to steer schoolchildren toward healthy habits, and yet rates of childhood obesity and diabetes continue to soar. Celebrity endorsements, catchy catchphrases, and food pyramid redesigns have struggled to combat the allure of fast food and television in the battle for child health in the United States. But with childhood obesity rates tripling in the last 30 years and type 2 diabetes showing up earlier in life, there’s an urgent need for more effective programs to promote nutrition and exercise in kids. One strategy is to create more relevant programs, locally focused and tailored to the culture of the children the program is trying to help.

That approach inspired not one but two child diabetes prevention programs created by Medical Center researchers and tested with our neighbors on Chicago’s South Side. The two programs - called Reach-Out and Power-Up - are siblings, with similar designs, goals, and measures, but in slightly different populations and venues. The pilot studies, both published in recent months, demonstrate the challenges faced by researchers in creating effective, reproducible programs with a local focus…and also offer hope that a successful intervention is possible.

Before the programs could be designed, the first step was to listen. The research team, led by Deborah Burnet, professor of medicine and pediatrics, organized focus groups with overweight children and their parents to learn about their specific obstacles to improving health and gather ideas about the types of physical activity and classes that would appeal to them. For example, the African-American children said they would like to try martial arts and yoga, so instructors for those activities were recruited. The conversations laid the groundwork for programs that would take the unique circumstances of families on the South Side of Chicago into account.

“Nutrition and exercise are both behaviors we do in a social context; in a place, in a neighborhood, in the context of certain social mores and expectations and cultural factors,” Burnet said. “Food, especially - who cooks, where we learn how to cook, how do our tastes get shaped in what we like to eat - those occur in social and cultural contexts.”

While both programs were designed to improve the health and behavior of children, the targets were both the kids and their parents. In Reach-Out, families gathered at a local YMCA for 14 weeks, splitting into separate parent and child groups for the first part of each session and then reconvening for a combined activity. Sessions included grocery store tours, exercise training, cooking classes, and even a family basketball game. Scavenger hunts, relay races, and Family Feud-style review quizzes were used to keep the kids and their parents engaged. But addressing the family’s cooking and eating habits could also be a sensitive topic.

“Feeding is all bound up with caring and love, so it’s very complicated - if you tell grandma she’s not cooking for her grandchildren right, her feelings get hurt,” Burnet said. “So how do you do that in a constructive way so that grandma is valued, but also moves in this healthy direction?”

At the end of the Reach-Out pilot study, published in the Journal of the National Medical Association, the program earned glowing reviews from participants, who said that it helped reduce food intake, steered them toward new fruits and vegetables, and encouraged increased physical activity. However, the clinical improvements were modest, including slight dips in BMI z-score (which scales the measure to child age) and glucose-to-insulin ratio. The incremental changes might mean that very heavy kids need more help to get back to healthy habits, Burnet said: “Kids who are this big probably need a more intensive treatment and intervention than a weekly community-based program.”

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Around the pediatric cancer wards at Comer Children’s Hospital, he was known by the rhyming nickname of “Doc Nach” and for delighting patients with his Mickey Mouse watch. On a ward where a smiling face goes a long way, Dr. James Nachman was always happy to provide a cheerful presence. Behind the scenes, he was also a dogged researcher, developing new protocols for children who didn’t respond to the standard treatment for acute lymphoblastic leukemia (ALL) and working to save the limbs of children diagnosed with sarcoma, a cancer of the bones.

Sadly, Nachman passed away last week at the age of 62, while on a rafting trip in the Grand Canyon. This week, Medical Center colleagues remembered “Doc Nach” for his skill with patients and scientific expertise.

“Jim was an outstanding clinician, teacher, and clinical researcher,” said John Cunningham, professor of pediatrics and chief of pediatric oncology. “He made seminal observations in leukemia and lymphoma that have impacted the lives of many children and adults with these diseases. He was an outstanding doctor, beloved by his patients, their families, and his colleagues. He was an irreplaceable member of our cancer team. We will miss him deeply.”

Patients’ families also were quick to pay tribute to Nachman. At the ChicagoNow blog “Ay Mama,” Laura Lutarewych wrote a moving post about her encounters with Nachman during the treatment of her 2-year-old daughter, Atia.

He’d walk into a room with a smile asking, “How’s my favorite girl?” It didn’t matter who the patient was - they were all his favorite, so it was fitting and each child wore their title proudly.

Without exception, he’d hold out his wrist and ask, “Who’s on my watch?” Atia especially loved that part, because she knew the script; she didn’t even have to look at the watch. With a huge smile, she’d point at it and exclaim, “Mickey Mouse!”

Earlier this year, we shot a video with Nachman for a series of informational segments on pediatric cancer topics that you can view below. Even in answering technical questions about how ALL is diagnosed and treated, you can see the good cheer and optimism in Nachman’s demeanor that was so comforting to his patients. For all of the people he touched during his life, that positive attitude will be missed.

“He was an optimistic, sunny person,” his brother Robert Nachman said in the Chicago Tribune obituary, “and his eyes lit up whenever he was talking about children.”

Elsewhere…

Linkage was off last week, so we didn’t have a chance to post this excellent front-page Chicago Tribune article about the neuroprosthetics research program here at the University of Chicago. Reporter Cynthia Dizikes also penned an online supplement that explains the link between assistant professor Sliman Bensmaia’s favorite Star Wars scene and his research on the neural mechanisms of touch.

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By John Easton

Are we flushing away cures? In the last few years, physicians have developed a new respect for what used to be considered waste. Led by a maverick Australian physician, many US doctors have begun to test the curative capacity, when appropriately acquired, prepared and administered, of human excrement.

For once, it’s not the fiber that interests these digestive specialists; it’s the creatures that live in it, the intestinal flora. These indwelling microbes, when compared cell-to-cell, outnumber their hosts by about 10 to one. More than 1,000 different strains of bacteria co-exist peacefully in the typical healthy bowel. But when the delicate balance is altered by antibiotics or other causes, a few strains can become dominant, leading to severe diarrhea, inflammation, tissue damage, even death.

Bacterial aggregates derived from fecal matter have been used sporadically to treat digestive disease for more than 50 years. These were often last-ditch efforts aimed at restoring microbial balance for patients with raging intestinal infections. Fecal microbiota transplantation (FMT) - also known as fecal bacteriotherapy, among other names - is designed to calm a troubled bowel by reintroducing the vast diversity of collaborative bowel inhabitants after the usual, collegial mix has been disturbed.

The first FMT cases, dating back to 1958, were used to treat life-threatening infections caused by aggressive bacteria that had overwhelmed the bowel and eradicated the competition. When antibiotics were unable to control the infection, physicians were able to restore balance by collecting fecal matter from a healthy donor and injecting it into the patient’s colon. It was like a massive dose of probiotics, but delivered bottom up, rather than top down.

More recently, the approach has produced lasting remissions for a small number of patients with a common disease: ulcerative colitis. In 2003, a team led by the Australian physician, Thomas Borody, published a report [pdf] on successful treatment with this approach of six patients who had longstanding ulcerative colitis (UC). “Complete reversal of UC was achieved in all 6 patients following the infusion of human fecal flora,” the authors reported. “These 6 cases document for the first time the total disappearance of chronic UC without the need for maintenance treatment.”

After interviewing Borody, the Freakonomics podcast summarized the expanding medical role of human feces like this: “To paint it with a very broad brush: it could be that many maladies - from intestinal problems to obesity to disorders like multiple sclerosis and Parkinson’s and Alzheimer’s and perhaps even cancer - are related to damaged or missing gut bacteria; the solution therefore may lie in transplanting healthy bacteria into a sick person.”

“This is a fascinating idea, and the early studies show great promise,” said University of Chicago gastroenterologist David Rubin, associate professor of medicine. The notion has also made headway among patients. “We are getting at least one phone call a week from patients asking about the treatment and when we are going to start treating patients,” said colleague Stacy Kahn, instructor of pediatrics at the University of Chicago.

Although fewer than a dozen case reports involving ulcerative colitis have been published, Rubin and Kahn realized that many more patients were getting treated, largely without supervision or medical oversight, a development they called “alarming.” Several websites now provide guidance, almost like recipes, on how to perform this relatively simple procedure.

“This morning I decided to try a fecal transplant,” begins the saga of “Lucky Lindy,” posted on HealingWell.com. “I’ve been reading about it for months, and figured I might as well try … and while the process was a little gross it was easier than I anticipated. For anyone who is interested (and not grossed out), below is the process I used.” He goes on to list his entire protocol, with daily progress updates and cost-cutting tips, such as using a fork to stir the broth instead of a difficult-to-clean blender. read more

Anyone with a video game console at home can simulate  a variety of occupations: airplane pilot, race car driver, baseball player, Old West zombie hunter. As technology improves, the experience that can be created for these tasks grows ever more accurate and immersive, causing some experts to wonder whether simulation can be used for actual education as well as vicarious thrills. In the aeronautics field, this is old news - pilots have been trained on flight simulators for decades, gaining experience on high-risk, low-frequency tasks such as landing a damaged plane on a river. But in medicine, the use of simulation has only started picking up speed in the last decade, employing a mix of high-tech and low-tech to prepare doctors and nurses for both the usual and unusual.

In their Department of Medicine Grand Rounds presentation last week, Ernest Wang and Morris Kharasch from our partners at NorthShore University HealthSystem described the current state of simulation in medicine on the eve of their state-of-the-art simulation center’s grand opening. But while the idea might sound modern, it’s actually been around for more than 40 years, as Wang illustrated using a clip from the 1972 film Future Shock, narrated by Orson Welles.

Welles’ portentous warnings were a bit premature, it turned out. Never mind the leap from medical simulation dummy to humanoid robot, a generation would pass from when the first dummies were engineered in the late 1960’s before the broader field would accept simulators as a valid training tool for doctors.

“It looked pretty much what our current high-fidelity simulators look like, but didn’t have traction,” said Wang, a clinical associate professor at NorthShore. “There’s a Chinese saying: ‘When the student is ready the teacher will appear,’ and clearly they were too far ahead of their time and the conditions weren’t right.”

However, since 2000 the use of simulation in medicine has gathered momentum. A wide range of technologies are currently used for teaching sessions, from complex simulation environments that fully recreate the experience of being in an operating room to computer programs and table-top gadgets that rehearse medical decision-making and the performance of specific tasks. Medical simulation has grown to the point where a new specialty - the simulationist - may need to be created, Wang said.

“This would be a practitioner of simulation, who takes a recipe of clinically important cases, lessons learned from other industries, computer-driven full body simulators, realistic task trainers, and a dash of theater, to create a memorable learning experience that can be transferred directly to patient care,” Wang said. “In the end, that’s what this is about: education and patient care.”

Winning acceptance for medical simulation involves proving its success and determining its most effective uses. At the NorthShore center, educators have focused on designing simulation courses around “high-liability, low-frequency” events, said Kharasch, clinical director of the Center for Simulation Technology & Academic Research. The students in these courses might be residents encountering these situations for the first time, or older doctors who need a refresher on tasks they haven’t performed in many years before serving as an attending on the wards or in the emergency room.

“We’ve learned that as the years go on after you come out of residency, you are less able to do things that you once did as residents,” Kharasch said. “We spend a lot of time training on simple tasks that can be life-saving.”

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