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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Over the year-long discussion of health disparities in the MacLean Center for Clinical Medical Ethics seminar series, the health gaps presented between American whites and blacks have been predominantly a one-way street. On nearly every health measure - from infant mortality to diabetes to cardiovascular disease - higher rates are observed for African-Americans. But there’s one health gap where the racial positions are surprisingly flipped, said James Jackson of the University of Michigan in his visit to the series in early May. Over the course of a provocative talk, Jackson demonstrated how this strange reverse disparity in mental health could be hiding a model explaining the physical health gaps that continue to resist reduction efforts.

In a 2007 study, a survey project led by Jackson measured the lifetime prevalence of major depressive disorder in African-Americans, Caribbean blacks, and white Americans. An almost complete reversal from the normal health disparity was observed, with roughly 18% of whites diagnosed with major depression at some point in their lives, compared to only 10.4% of African-Americans. The data, though replicated several times, was initially greeted with skepticism by observers who were mostly familiar with biased data based on hospital admissions, Jackson said.

“When people noticed this, they really began to contort  the data,” said Jackson, a psychologist and director of the Institute for Social Research at the U. of M. “The argument was that there must be something wrong with the way it was assessed, because everybody knows that African-Americans have to have higher rates of psychiatric disorders than whites.”

But now that the reverse disparity has been verified in many different populations, Jackson has started to ask why these differences exist. His working theory hinges on two other observations: the delayed appearance of physical health disparities over the course of life, and cultural differences in the way people cope with stress. When well-known health disparities on measures such as diabetes or hypertension are broken down by age, there is not a consistent gap between blacks and whites, but a gap that emerges and rapidly grows in middle age (45-64 years old). Putting aside differences in infant mortality rates, some evidence actually suggests that black children are healthier than white children on many measures, Jackson said.

The growing gap in health measures over the life course is paralleled by another growing gap - in the frequency of poor health behaviors. In white populations, smoking rates peak in young adulthood and then decline, while the rate in black populations accelerates with age. The same pattern holds true for heavy alcohol use and drug use, Jackson said, while frequency of vigorous physical activity declines with age faster for black females than white females. Obesity is more complex - it is the only black-white difference observed early in life, at least for females - but this gap also widens over life course, regardless of socioeconomic status.

The core of Jackson’s theory was to cast those physically unhealthy behaviors not as mere vices, but as methods people use to self-medicate themselves against the stress of daily living.

“If you’re having a bad day…you know it. At the end of the day, your stomach is upset, you have a headache. There are palpable things that are present with regard to the stress reaction to the circumstances,” Jackson said. “But if you are growing a tumor for cancer, you don’t know it, until it reaches a certain stage.”

“If you know you’re having these stress-related kinds of problems, this awareness motivates you to action - you are motivated to do something about the physiological and psychological consequences of stressors in your life. And what do you want to do? People eat comfort food to reduce stress, the activity in the chronic stress response network,” Jackson said. “If I’m stressed, a Twinkie makes me feel better.”

Self-regulating stress can also go beyond junk food, Jackson said, to severe drug and alcohol use. All of these coping strategies may help dampen the stress response and protect mental health, but only at the cost of exacerbating physical health problems.

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[Cartoon from the University of Washington "Neuroscience for Kids" page.]

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In neuroscience, the neurons hog all the attention. Most research is focused on the 100 billion neurons of the brain, the elongated cells that fire electric action potentials and release chemical transmitters to communicate with each other. But the neurons are a minority in the brain, outnumbered 10 to 50 times over by their neglected stepbrothers, the glia. Traditionally, scientists think of glia as the mere support staff to the more fashionable neurons, playing the role of repairmen (microglia), wallpaper installers (oligodendrocytes), or janitors (astrocytes). When scientists go looking for the source of human behavior or disease in the brain, they tend to overlook the glia and go straight for the neurons.

But at the 2011 Chicago Symposium on Translational Neuroscience, held on campus last Friday, it was the glia who had their chance in the spotlight. Subtitled “Glia in Neuronal Health and Disease,” the day-long event steered away from the “glamour cells of the nervous system,” as the program described neurons. Instead, the focus was on mounting evidence concerning how glia play critical roles in sleep, depression, brain development, Lou Gehrig’s disease, and other notable neurological disorders. In a conference dedicated to transferring scientific discovery from the laboratory to the clinic, the talks described several possible new glial targets for treating some of the most common brain disorders.

Appropriately, the morning began with a talk about adenosine, a neurotransmitter known best by its very popular blocker, caffeine. As the audience sipped from cups of adenosine antagonist (coffee), Philip Hayden of the Tufts University School of Medicine described how this small nucleoside, made from ATP released by glial astrocytes, can have a big impact on an organism’s wakefulness and health. Most of Hayden’s discoveries were made using a special genetically-modified mouse, where the astrocyte release machinery was disrupted to reduce adenosine levels in the brain.

In normal mice (and humans), the amount of adenosine in the brain builds up over the course of the day, increasing drowsiness. When someone pulls an all-nighter, the elevated adenosine levels are responsible for the miserable feeling of the next day and the extra-long “catch-up” sleep most people need to recover. But in the mice with disrupted adenosine, there were no effects of sleep deprivation on their subsequent sleep, a sign of reduced “sleep pressure.”

“This is an awesome party pill,” Hayden joked. “You can stay up late at night, and wake up on time the next morning. You’re not getting the homeostatic response to sleep deprivation.”

As often discussed here, sleep disorders are linked with a wide range of diseases, from diabetes to depression to hypertension. Hayden added another sleep co-morbidity to the list: epilepsy. In epileptic mice, interfering with adenosine release also decreased the number of seizures and the damage caused by them, suggesting that astrocytes might be a good target for anti-epileptic drug design and other neuroprotective effects.

“The way we think of the brain is NASCAR racing,” Hayden said. “Though the car and driver are important - they’re the neurons - in the difference between a car winning and coming second, how well the pit crew is changing the engine can really make a difference. We feel the astrocyte is tuning the system and helping to optimize performance.”

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Many people who suffer from regular migraines experience a kind of prelude to their attack, known as a migraine aura. Less than an hour before the headache begins, the person experiences a sensory or motor disturbance, such as flickering shapes and a blind spot, or disturbances of a motor or language nature. In 1941, a psychologist named Karl Lashley took the very scientific step of measuring how fast his own migraine aura moved across his visual field, indirectly calculating the speed of the unknown brain process causing his symptoms. In an organ where normal communication is as fast as flicking on a light switch, the aura moved at a relative crawl - only 3 millimeters/minute.

Seventy years later, University of Chicago scientists have discovered a highly unusual consequence of that slow brain phenomenon. Brains are dynamic structures, with neurons constantly changing the strength of their connections and extending and retracting their branches. But cells in the brain don’t normally pick up and travel. So when Yelena Grinberg, a graduate student in the laboratory of neurologist Richard Kraig, simulated the electrical changes thought to underlie migraine aura in a slice of brain, the response of a type of cell called microglia was quite amazing.

“We have found cells doing something different than they’ve ever been known to do,” said Kraig, a professor of neurology and expert on migraines. “They’re moving the same way an organism would…that’s never been seen before in cells from a tissue.”

Microglia are the resident immune cells of the central nervous system, attacking infection and repairing damage in the brain. To get to the brain in the first place, microglia must travel from the bone marrow (where they are born as monocytes) across the blood-brain barrier into the brain, so their wanderlust is well known. But once they set up shop in a neighborhood of neurons, their subsequent movement was largely thought to be restricted to the motion of their branches.

In an article for the journal PLoS ONE, Grinberg roused microglia from their new homes by triggering an effect called “spreading depression” in her cultured rat brain slices. In the 1950’s, the slow speed of Lashley’s aura was matched to this electrical phenomenon, which travels at an equally methodical crawl through the brain tissue, inhibiting neurons as it passes. From its origin point, the spreading depression spirals out through susceptible gray matter areas of the brain, “like a ripple on a pond,” Grinberg said. When it crosses the cells of the occipital lobe responsible for visual perception, it corresponds to the flickering dots and blind spots of a migraine aura.

After triggering the synaptic depression, Grinberg tracked the movement of microglia for 6 hours, and observed another interesting pattern. To the naked eye, the microglia might look as though they are moving at random with no discernible purpose. But a mathematical analysis suggested by co-author John Milton revealed that the microglia wanderings actually conformed to a well-known natural pattern known as a Lévy flight. Described as an optimal search pattern, Lévy flights are marked by a flurry of small movements interrupted by large steps - behavior often observed in animals scavenging or hunting in the wild (or as Grinberg said, someone looking for their lost keys).

“Scientists have observed the same pattern in the swimming or flight of sharks and seagulls,” Grinberg said. “The idea is that within these stops along the journey they are searching the nearby environment, and once they do or don’t find something there they move to a different spot.”

[Video: Microglia move in response to a spreading depression. The video is sped up to show the distance traveled in the hours following the stimulus. From Grinberg et al., PLoS ONE, 2011]

Why would microglia take Lévy flight after a spreading depression?

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A Magic 8-Ball for Cardiac Arrest

Cardiac arrest is one of the most common ways that people die, and hospitals need to be constantly vigilant about the threat of heart stoppage in their patients. So physicians have long sought to develop a way of predicting who is most at risk for cardiac arrest when checked into the hospital, such that extra care and surveillance can be taken. At the 2011 international meeting of the American Thoracic Society, held this past week in Denver, two Medical Center fellows presented research refining these early warning systems to make them a more effective hospital tool.

In the first study, pulmonary and critical care fellow Gordon E. Carr connected cardiac arrest with another frequent sight on the hospital ward: pneumonia. Carr’s study found that patients admitted with pneumonia are at elevated risk of cardiac arrest over the next three days after admission, and that almost 40 percent of these cardiac arrests occurred while the patient was outside of the intensive care unit. “We found a compelling signal that some patients with pneumonia may develop cardiac arrest outside of the ICU, without apparent shock or respiratory failure,” Carr said in a press release. “If this is true, then we need to improve how we assess risk in pneumonia.”

Adding extra caution about cardiac arrest to the care of patients with pneumonia is a specific way to improve surveillance. But to apply to more patients, a broader scale is needed, one that can be easily assembled from the vital signs that are already routinely measured in the wards. One such scale, called the Modified Early Warning Score or MEWS was tested by pulmonary and critical care fellow Matthew Churpek as a predictor of cardiac arrest, who found it to be better at predicting a cardiac arrest in the next 48 hours than any individual vital sign. But MEWS was designed for general risk of death, not specifically for cardiac arrest, and Churpek suggested a more specialized risk score could be calculated for use by hospitals. The benefits of such a measure, he said in a press release, would be immense.

“Rapid response teams are a complex and resource-intensive intervention, so providing evidence-based criteria for their activation is crucial,” Churpek said. “Our patients will do better if we can detect who is at high risk early enough to intervene and prevent a cardiac arrest.”

Doctors Against Ronald McDonald

Childhood obesity is a growing problem in the United States, and doctors point the finger of blame directly at increased consumption of junk food and fast food. Chains such as McDonalds have made noise about making their food healthier, especially for children, by posting calorie counts on menus and offering snacks such as apples and carrots instead of fries. But according to an open letter signed by over 500 health care professionals and placed in newspapers around the country this week, they have not done enough.

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An enzyme from three different species is compared, with structural "flaws" shown in green. (From Fernández & Lynch, Nature, 2011)

One common misconception about evolution is that it produces “better” organisms with time - a seductive opinion to humans who would like to think of themselves as the pinnacle of natural selection. In a way, it’s an easy error to make, for who would look at a single-celled bacterium next to a human and think that the four billion years of evolution between the two species hadn’t produced some improvements? But when Ariel Fernández and Michael Lynch compared the proteins that bacteria and humans share, they found that the unicellular organisms held a surprising advantage. Though the overall shape of the proteins were the same, the human proteins were leakier, more vulnerable to the destabilizing effects of water than those of the bacteria.

But according to the paper published yesterday by Fernández and Lynch in Nature, those protein flaws may have been the key spark that led to the evolution of complex organisms.

“We hate to hear that our structures are actually lousier,” said Fernández, a visiting scholar at the University of Chicago and senior researcher at the Mathematics Institute of Argentina (IAM) in Buenos Aires . “But that has a good side to it. Because they are lousier, they are more likely to participate in complexes, and we have a much better chance of achieving more sophisticated function through teamwork. Instead of being a loner, the protein is a team player.”

The engineering advantage of bacteria over humans boils down to one simple fact: they will always far outnumber us. Billions of bacterial organisms can fit into a single Petri dish, and in a single human body there are over 100 times more bacterial cells than there are humans on Earth . When a genetic mutation with a negative effect pops into existence in these huge populations, natural selection quickly disposes of it, preserving the integrity of the protein that gene encodes. But when a mildly negative mutation appears in a relatively small population, such as that of humans or elephants or pine trees, selection is less efficient and the mutation may spread - a phenomenon called genetic drift.

The direct effect of these mild mutations would be to introduce minor flaws into the structure of proteins. If the change in protein function was too severe, it would cease to function and likely kill the organism. But if the change was just a small nick in the armor of the protein, making it chemically more vulnerable to water, the mutation might stick around long enough to be passed on to offspring. That theory informed Fernández and Lynch’s hypothesis: proteins from species with small population sizes would contain more of these flaws than those from species with large populations.

Their idea was proven true: compare the same protein between, say, humans, flatworms, and bacteria, and you’ll find a descending frequency of protein flaws. Even within a single species, the difference can be measured. Some bacteria have both endosymbiotic populations that live inside other organisms and larger, free-living populations, and the proteins from the endosymbiotes were found to contain more structural errors than their free-living peers.

But the exciting part is what happens after those errors accumulate. read more

By John Easton

Even by academic standards, the language was restrained. “It is likely,” the authors note, near the end of the discussion section, “that more patients with this tumor will appear as girls who were exposed in utero come to maturity.”

That quaint, passive construction, in the April 22, 1971, issue of the New England Journal of Medicine, triggered an active response. The three-page paper, “Adenocarinoma of the Vagina,” focused on eight young women, ages 15 to 22, with an extraordinarily rare tumor.

“While the disease had been described in older women, none of us had heard of it in young people,” recalled study author Arthur Herbst, MD, the Joseph Bolivar DeLee distinguished service professor emeritus and former chairman of obstetrics and gynecology at the University of Chicago.

Thanks to luck, diligence and some clever detective work, Herbst and colleagues figured out why. Early in their pregnancies, the mothers of seven of the eight women had taken a drug - a synthetic hormone called diethylstilbestrol, DES for short - to prevent miscarriage. The problem was that in the previous 25 years, an estimated 4.8 million women in the United States - and as many as 10 million worldwide - had taken DES during pregnancy. These eight cases were the first warning of a rare, delayed, but devastating side effect.

“While the medical community was being cautious,” recalled Susan Helmrich, a DES daughter who is now 55, “mothers who took DES were hysterical. They were basket cases. The daughters,” she added, “also went a little crazy.”

DES, created in 1938, was the first synthetic estrogen. It was a cheap, potent, unpatented pill - for humans or livestock. The FDA approved it in 1941 for a wide range of “estrogen-deficient states.” In 1947 they added miscarriage prevention. One advertisement claimed that DES could prevent abortion, miscarriage and premature labor and was “recommended for routine prophylaxis in ALL pregnancies.” In 1953, William Dieckmann, MD, chairman of obstetrics at the University of Chicago at the time, showed that DES had “no beneficial effect whatsoever on the prevention of miscarriage.” Nevertheless, the drug remained in use for that purpose. But then, beginning in 1966, the first few odd cases began turning up - young women with an old-lady tumor.

“Dr. Robert Scully, gynecologic pathologist at the Mass General and I got together seven cases of clear-cell adenocarcinoma and described their clinical and pathological characteristics,” said Herbst. They began interviewing the mothers. One mentioned that she took a drug during pregnancy, something called DES, and wondered if that had anything to do with it.”

“I was also following a mother whose daughter unfortunately died of this disease because it had never been diagnosed properly,” Herbst said, “and she mentioned the same thing.”

So he, his section chief Howard Ulfelder, MD, and epidemiologist David Poskanzer, MD, decided to design a study. By that time they had an eighth case; they then selected 32 controls: four for each case, daughters born at about the same time to women at the same hospitals. They found that seven of the eight mothers of daughters with cancer took DES during the first trimester for either bleeding or prior miscarriage, and only one of the 32 controls did. The odds of that happening by chance were less than one in 100,000.

As soon as the paper was published “it was all over the news,” Herbst said. read more

In Akira Kurosawa’s 1950 film Rashomon, the story of a crime is told three times from the perspective of three different witnesses/participants. Due to the biases of each storyteller, the details of the three accounts fail to align, ultimately leaving the film’s narrator - and the viewer - unsure about what truly happened in the central incident. Historians have their own version of the Rashomon effect, filtering past events and organizing historical narratives according to their own beliefs, whether the influence is subtle or overt.

In an attempt to offset any such potential bias in his Regis J. Fallon Lecture at the University of Chicago, health law expert Timothy Jost of Washington and Lee University School of Law chose to present three parallel narratives in his discussion of the history and future of American health insurance. Despite a relatively brief run as a major player in our country’s health care system (”there are many people alive today in Chicago who were born before modern health insurance arrived,” Jost said), health insurance has quickly risen to a place of great importance, as demonstrated by the industry’s role in last year’s passing of the Affordable Care Act. The goal of that legislation to make sure that all American citizens have health coverage will likely be a key turning point in the story of American health insurance. But to understand which direction health insurance will travel after the ACA is fully implemented, you need to understand how it got there in the first place, for which Jost offered three tales.

1. A Failure of Socialized Medicine

In this tale, the public’s push for universal government health care was repeatedly rebuffed by special interests and conservative politicians throughout the 20th century. Though incremental victories were achieved, from the push by labor unions for employer-provided health benefits to the passage of Medicare and Medicaid during the Johnson Administration, the century ended with a whimper for socialized medicine advocates thanks to the doomed health care reform of the Clintons. Opposition from organized medicine, small-government Republicans, and an increasingly powerful private insurance industry thwarted the push to join other developed countries who had switched over to government-run health care after World War II - “for two decades, we saw no progress,” Jost said.

2. A Failure of Market-Driven Medicine

But according to the second narrative, this lack of progress was good news. From this perspective, Americans are “overinsured…because of misguided government policies that have encouraged private insurance for routine as well as catastrophic medical costs,” Jost said. By placing the cost burden on employers and government programs, the American health insurance system has severed consumers from the true price of their own health care - the main culprit, many economists believe, for the exponential rise in medical spending over the last century. Under this narrative, the steering wheel of health care should be handed back to the market with a strategy of tax credits, vouchers, and the roll-back of Medicare - key components of the current Republican budget plan.

3. A Messy Compromise That Kind of Works

Mixing the two narratives together creates a third storyline, one that Jost seemed to prefer despite describing it as “muddling through to moderate success.” In this history of health insurance, the industry grew haphazardly over the 20th century, incorporating elements of both government- and market-driven approaches according to the fickle political winds of different eras. From the birth of modern health insurance as “health services plans” (guaranteeing coverage of hospital costs) in Dallas in 1929, through the expansion of coverage to all types of care including routine visits, pharmaceuticals, and even dental, the unlikely bedfellows of consumer demand and labor union pressure combined to nurture the explosive growth of the industry. And for a while, this worked, Jost said - 82.4 percent of the population held private heath insurance in 1980, the peak of such coverage.

“The United States seemed to have solved, through private initiative supplemented by public programs…the problem of health security that other nations had addressed through social insurance or public provision,” Jost said.

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Kristen Knutson, PhD, recently added to the growing body of research from the University of Chicago on the long-term consequences of skimping on sleep. She found that diabetics who sleep poorly have a harder time controlling their insulin and glucose levels than diabetics who sleep well. The research was published in the journal Diabetes Care. We conducted an extended interview with Kristen Knutson about her research, and below are some of the highlights.

Q: Why study diabetes and chronic sleep problems?

A: Many of our laboratory studies, led by Dr. Eve Van Cauter, have shown that restriction of sleep is associated with alterations in glucose metabolism. Usually, these lab studies are a week. But we wonder about the long-term effects of being a chronic short sleeper.

We think that chronic poor sleep could put people at risk of many health problems, including diabetes.

Q: How did you design your study?

A: We used data from an epidemiologic study called CARDIA (coronary artery risk development in young adults). It started in 1985, and has been going on for more than 20 years.

We gave the participants wrist activity monitors—it’s like a wristwatch that measures the subject’s sleep duration. The participants wore the activity monitors for three nights in a row. A year later, they wore the monitors three more nights. So we had a total of six days of data.

We also asked them about their sleep. Did they wake up frequently during the night, three or more times per week? Did they have trouble falling asleep?

To get the measurements of their fasting blood glucose and fasting blood insulin, we used the data from the CARDIA study, in which the participants gave fasting blood samples. Their fasting blood glucose and insulin give us an estimate of insulin resistance.

Q: Explain your most striking findings, especially with the diabetics who slept poorly.

A: We saw more significant associations between measures of sleep and glucose metabolism markers in the patients with diabetes. In particular, we saw that poor sleep quality was associated with higher fasting glucose and greater estimated insulin resistance. So poor sleep quality meant worse control of their blood glucose levels.

Also, we separated people with and without insomnia. Among the people with type 2 diabetes, those who also had insomnia had worse glucose levels and greater estimated insulin resistance. That suggests that it’s not just sleep duration that’s important, which laboratory studies have shown. But sleep quality is important as well.

The data show that people with diabetes who are poor sleepers will have a more difficult time controlling their glucose levels.

Q: Does this mean that sleeping poorly makes diabetes worse?

A: It could go the other way. It could be that people who are having trouble controlling their glucose will have more complications, more pain, more need to get up in the middle of the night to urinate, and therefore they’re not sleeping as well. What we need to do now is find people with diabetes who aren’t sleeping well, and see if improving their sleep also improves their glucose metabolism.

This study is observational, but suggests that there is a relationship between poor sleep and controlling glucose. We don’t know which factor leads to which outcome. read more

Reducing health disparities in the United States has been a top priority for our health care system in these early years of the 21st century. But efforts to narrow the health gap between black and white patients go much farther back, to the start of the previous century when the first African-Americans were graduating from medical schools and Ph.D. programs around the United States. Those early black professionals looked at the state of African-American health at the turn of the 20th century and were appalled, said Vanessa Northington Gamble, professor of medical humanities and history at George Washington University, at her MacLean Center for Clinical Medical Ethics seminar in late April. No less a figure than Booker T. Washington spoke out about the direct link between African-American health and civil rights in the early 1900’s, saying:

“Without health … it will be impossible for us to have permanent success in business, in property getting, [and] in acquiring education …. Without health and long life all else fails.”

The solutions those black intellectuals chose to improve the health of their race, in a time of national segregation, were very different from the options under consideration today. But Gamble said that discussion of those efforts is missing from the conversation about health disparities interventions in today’s society.

“We don’t talk about the history of these disparities - what are some of the programs that came in the past to address these disparities,” Gamble said. “I do think that many people think it’s only been in the past 20 to 25 years… but I want to talk about what the black community did to take care of itself.”

At the time, black patients faced segregated hospitals and racist theories, such as those put forth by statistician Frederick L. Hoffman in his book, “Race Traits and Tendencies of the American Negro.” Hoffman, an actuary for Prudential insurance, argued that the company should not cover African-Americans because they were destined to die out due to unchangeable biological factors of their race. To refute those claims, W.E.B. Du Bois published his 1906 study, “The Health and Physique of the Negro American,” which pinpointed socioeconomic factors, rather than biology, as the cause of poor health in the black community.

“Du Bois agreed that the health status of African-Americans was worse than that of white Americans,” Gamble said. “Where there was disagreement was on what were the causes of what we would now call health disparities or inequities…for example, he said the high infant mortality rate in Philadelphia was not a ‘Negro affair,’ but an index of social conditions.”

In the wake of that research, black professionals united to try to beat back higher rates of infant mortality, pneumonia, and tuberculosis - the latter of which Du Bois called “the greatest enemy of black people.” One of the best strategies, in the face of segregated hospitals and discrimination from white physicians, was to establish black hospitals to improve access to health care. One example on the South Side of Chicago was Provident Hospital, founded in 1891 by Emma Reynolds and Daniel Hale Williams, who would go on to perform the first successful open-heart surgery there. Similarly, black doctors formed the National Medical Association in 1895, because of their difficulties in joining the American Medical Association. Playing along with segregation wasn’t unanimously popular in the black population of the time; in fact, Gamble said one minister prayed Provident would burn to the ground because it catered to racism.

“You have to look at [black hospitals] in the context of segregation,” Gamble said. “Many black physicians said we wish we didn’t have to start black hospitals, but if we wait for integration, the health of the race would suffer.”

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Today, nearly everyone is aware of the dangerous health effects of smoking cigarettes. Even fewer people would deny the harmful effects of drinking water contaminated with arsenic. But when these two toxic influences are mixed together, is the sum of their damage more than the individual effect of each? To put it another way: for a person in an area with low, “safe” amounts of arsenic in the groundwater smokes, is their risk of disease increased as though they were drinking unsafely contaminated water?

To study this question, University of Chicago epidemiologist Habibul Ahsan returned to his project studying the consequences of accidental arsenic exposure in the people of Bangladesh. Ahsan’s Health Effects of Arsenic Longitudinal Study (HEALS) has tracked thousands of Bangladeshi citizens who unknowingly consumed well water with high levels of arsenic after health organizations installed wells to reduce water-borne infectious disease. That study, which has expanded to 20,000 subjects, discovered a 70 percent higher risk of death from chronic disease in those drinking water with the highest levels of arsenic. Even people exposed to moderate levels of arsenic, amounts that can be found naturally in some regions of the United States, were at a 20 to 30 percent higher risk of dying from chronic disease.

Ahsan and his team from UChicago, Columbia University, New York University, and Bangladesh, looked at whether the combination of arsenic exposure and smoking made the odds even scarier on one particular mortality endpoint: cardiovascular disease. While arsenic is traditionally thought of as causing different types of cancer and skin lesions, chronic exposure can also produce various heart and circulatory problems such as hypertension and atherosclerosis. Previous studies of these cardiovascular effects have been small, retrospective, and focused on extremely high exposures in Taiwan and Chile. With the Bangladesh study, Ahsan and colleagues could look at a broader spectrum of exposure, and follow subjects carefully over time to isolate the effect of arsenic from other factors.

For the study, published last week in the British Medical Journal, the researchers tracked nearly 12,000 Bangladeshis, taking urine samples to measure arsenic exposure and registering the cause of death in those who died over the time they were tracked (an average of 6.6 years). Overall, 460 subjects died, with nearly half of those (198 people) dying from some form of cardiovascular disease. Associating those deaths with arsenic exposure confirmed the Taiwan and Chile studies on people exposed to high concentrations (as high as 80 times the safe limit of 10 parts per million) of the toxin. But a worrisome trend also emerged for more moderate exposures, with a 50 percent increase in cardiovascular mortality risk observed at levels as low as 2.5 times the safe limit.

“We were able to show that, even at lower doses than previously reported, there seems to be a deleterious effect of arsenic regarding cardiovascular disease mortality, particularly from ischemic and other heart diseases,” Ahsan said.

For those subjects who were smokers - even those who had quit - a deadly synergy emerged. For a current smoker exposed to the high levels of arsenic, the increased risk of dying from cardiovascular disease jumped from 50 percent to 328 percent. Former smokers saw a lower bump in risk, but if exposed to moderate levels of arsenic, they shared the same risk as those exposed to high levels that had never smoked. Ahsan said that the result emphasized the importance of targeting multiple risk factors in improving public health around the world.

“This tells us that there are some individuals who are dying from cardiovascular disease solely because of the presence of both factors, not because of the presence of one or the other,” Ahsan said. “It’s one more reason to pay attention to arsenic exposure, but yet another reason that will underscore the importance of smoking cessation.”

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In the Norman Rockwell past, patients had one doctor who followed them from home to clinic to hospital, managing their health care over a significant portion of their lives. That sort of doctor-patient relationship in today’s medical world seems about as outdated as a family gathered around the fireplace listening to the radio. Now, patients are growing used to unfamiliar people in white coats, seeing multiple doctors at their clinic and a parade of physicians from their hospital bed.

Part of this shift has been the move toward medical specialization, with more medical students choosing careers in surgery, cardiology, neurology or other specialties. The coincident decrease in primary care or family medicine doctors has reduced the ability of those who remain to visit their patients when they are hospitalized and monitor their care. Into this void has rushed the hospitalist, a physician who spends more than a quarter of their time on inpatient service.

Since the mid-90s, hospitals have increasingly relied on this new class of doctor to handle the work of the wards, and David Meltzer, associate professor of medicine, economics, and public policy, has studied the impact of this cultural change. In his talk for the MacLean Center for Clinical Medical Ethics seminar series, Meltzer detailed the impact of an increased role for hospitalists, for both patient health and the hospital’s bottom line. But with the Affordable Care Act rewriting the rules about how Americans receive and pay for their health care, a new kind of hands-on hospitalist may be a key player in the medical landscape of the future.

Meltzer started his research by looking in his own backyard: at the Medical Center’s hospitalist program that he himself directs. From 1997 to 1999, one of the four general medicine services at the Medical Center was run by two hospitalists rather than the rotating house staff and general internists who normally take in new patients. Time revealed the benefits of the more consistent care provided by the hospitalists - by the second year, patient stays were a half-day shorter in the hospitalist service, survival 30 and 60 days after discharge was higher, and costs per patient were nearly $800 lower.

Why would hospitalists show such a profound advantage? The answer may come down to repetition and experience with commonly encountered conditions, Meltzer said. He compared the improvements on the hospitalist service to the growing efficiency of shipbuilders during World War II as they built more ships.

“The total effect was explained by disease-specific experience,” Meltzer said. “Hospitalists seemed to have shorter length of stay and lower costs not because they spend so much time in the hospital, per se, or have so much more experience overall, but because they actually saw these diseases again and again.”

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Every new experience leaves a mark on our brain, from a fleeting burst of electricity and neurotransmitters to a longer-lasting architectural shift. When we meet a new person, learn a new fact, or visit a new place, connections in our brains strengthen and weaken accordingly to store a memory for minutes, days, months, or years. But there are other ways to produce long-term changes in brain structures, forming “memories” that may drive behavior in subconscious ways. A recent strain of research has discovered that the drugs humans use - from alcohol to cocaine to heroin - all produce long-lasting changes in the brain, hijacking the mechanisms of memory with sometimes dangerous results.

The laboratory of Daniel McGehee, a neuroscientist and associate professor in the Department of Anesthesia & Critical Care, studies how one of the world’s most popular drugs, nicotine, can dramatically alter regions of the brain involved in reward. Normally, these brain areas (which include the ventral tegmental area and nucleus accumbens) help motivate animals to pursue natural rewards such as food and sex that are necessary for life and reproduction. But for centuries, humans have been drawn to substances that produce those same rewarding sensations despite being inessential for life - cigarettes, alcoholic drinks, or harder stuff. When these rewarding drugs are used often enough, people can become dependent or addictive upon their effects, suggesting that their brain reward system has been somehow re-tuned to pursue the drug despite significant personal cost.

In 2000 and 2002, McGehee and former post-doc Huibert Mansvelder published two papers that characterized how nicotine can produce memory-like long-term changes in the ventral tegmental area (VTA). The excitability of neurons that release the neurotransmitter dopamine is known to be related to reward - loosely put, when the neurons are more active and release more dopamine in the nucleus accumbens, the feeling of reward is stronger. McGehee and Mansvelder took slices of rat brain that can be kept “alive” in solution for a few hours after dissection, and measured the activity of dopamine neurons before and after exposing the slices to nicotine. The effects mirrored a well-studied process of memory formation called long-term potentiation (LTP) - the excitatory drive to dopamine neurons increased, while the inhibitory drive decreased, producing a lasting increase, a sort of nicotine-induced “memory” in the reward system.

“When we’re learning things consciously, we repeat things, and that apparently reinforces the memories,” McGehee said. “We believe that cells are working in a similar way: the stronger the activation, the more repetition of excitation of that synapse, the stronger it becomes. That is a sort of memory, as it lasts for extended periods of time.”

In a new paper, published last week in The Journal of Neuroscience, McGehee and post-doc Danyan Mao looked at the longer-term effects of nicotine in VTA. In the Mansvelder experiments, changes in dopamine neuron excitability was observed in the minutes following nicotine exposure. In Mao’s experiments, she exposed the slices to the amount of nicotine the brain encounters after a single cigarette, then waited as much as 5 hours after drug to measure the electrical activity of the neurons. Once again, VTA dopamine neurons were more excitable, even long after the nicotine was removed. But the way those long-term changes are formed were found to be subtly different in Mao’s study, bringing the effects of nicotine in line with another commonly-abused drug.

“We found that nicotine and cocaine employ similar mechanisms to induce synaptic plasticity in dopamine neurons in VTA,” Mao said.

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More Honors for Shubin

In 1863, in the midst of the Civil War, Abraham Lincoln signed an order creating the National Academy of Sciences, an organization bringing together the country’s most esteemed scientists to “investigate, examine, experiment, and report upon any subject of science or art.” From the original 50 members, the group has blossomed to 2,100 today, with roughly 200 of those Nobel Laureates. Any club with a 10 percent Nobel ratio is pretty exclusive, so being elected to the Academy’s lifetime membership is a thrilling honor for a scientist.

This week, evolutionary biologist Neil Shubin was the latest UChicago scientist given the honor of NAS membership, part of this year’s class of 72 new members and 18 “foreign associates.” Shubin becomes the 40th current member of the NAS located at the University of Chicago, and joins Medical Center faculty such as Janet Rowley, Martin Weigert, Donald Steiner, Bernard Roizman, Robert Haselkorn, and David Jablonski, who was elected last year (Fermilab director and professor of physics Pier Oddone was also elected in this year’s class). Election is no simple matter - each new member must pass a 10-step process [pdf] and be voted in to the academy by their potential peers.

Shubin is most famous for the discovery of the pivotal fossil named Tiktaalik roseae, a transitional species between ancient fish and the first limbed creatures to walk the land. But Shubin’s research is more than just fossil-hunting, as he studies the genetic programs that control development of limbs in the embryos of species such as sharks and salamanders. On the blog, we recently featured a paper by Shubin and former graduate student Andrew Gillis, where the embryos of strange creatures called holocephalons revealed some of the earliest steps in limb evolution.

In all likelihood, Shubin’s election was helped by his scientific communication skills as well. From his book about the discovery of Tiktaalik and the story of human evolution, Your Inner Fish: A Journey Through the 3.5-Billion-Year History of the Human Body, to his appearances as a correspondent on WTTW, to his anatomy teaching duties at Pritzker Medical School, Shubin has proven himself eager to educate the public at large about science. Appropriately enough, a second honor announced for Shubin this week was the Distinguished Service Award for Enhancing Education through Biological Research from the National Association of Biology Teachers. Once again, he finds himself in good company, as previous recipients include James Watson, Stephen Jay Gould, and Richard Dawkins.

“I am deeply honored to receive the NABT Distinguished Service Award. In an age where the ideas and tools of biology are increasingly playing a role in our lives, it is a deep honor to be recognized by those who are at the front lines of educating the next generation,” Shubin said.

The Science of Killing Bin Laden

A news story as big as the killing of Osama Bin Laden spares no beats, and there were plenty of science stories written this week in the aftermath of Sunday night’s surprise news. The most direct scientific angle was in the identification of the terrorist leader’s body, a step U.S. officials wanted to prove beyond a doubt before going public with the news. Like many of the events surrounding the raid, many of the details remain classified. But that hasn’t stopped science writers from writing explainers on how biometrics and DNA matching likely would have been used to make sure the Navy SEALS really had killed Bin Laden. President Obama himself confirmed that DNA testing was used to confirm they had the right body, but one fascinating mystery is where the DNA used to make the comparison was gathered. Nature blog The Great Beyond describes the candidates - from Bin Laden’s half-brothers and half-sister to one of his purported 26 children - and talks a bit about the recent history of using DNA identification techniques in criminal matters, including one crook busted by DNA he left on a slice of pizza.

Elsewhere…

The creation of new drugs, and the death of old drugs - Medical Center researchers commented on both sides of the pharmaceutical life cycle in newspaper stories this week. In the New York Times blog Fixes, reporter David Bornstein looks at the “valley of death” in developing new drugs for less-than-common diseases, and focused on the Myelin Repair Foundation and researchers such as Brian Popko (who we have featured twice). Then yesterday, the Chicago Tribune’s Bruce Japsen wrote about the upcoming patent expirations on the popular drugs Plavix, Lipitor, and Actos, and talks to our Caleb Alexander about the implications for health care.

How do you make a new species in the lab? It’s easier if you find a lizard species that is entirely female and can reproduce by cloning. Ed Yong at Not Exactly Rocket Science describes genome mash-ups, asexual reproduction, and the trickiness of species-naming in this great post.

A retired nurse and research coordinator at the Medical Center talks with Dawn Turner Trice about her experiences working with a small rural clinic in Ghana.

by Meghan Sullivan

It would be easy to mistake the images in Harry Noller’s presentation last Thursday for shards of gemstones or modern art. “This part of the talk was influenced by our visit to the Art Institute,” he quipped, advancing through a gallery of slides that showed off a variety of crystals, ranging in color and shape. This was not, however, a geology talk. Noller, professor of molecular cell & developmental biology at the University of California, Santa Cruz, was this year’s invited speaker for the 6th annual Haselkorn Lecture, a seminar series named for UChicago molecular biologist Robert Haselkorn that invites leading researchers to the University for several days to interact with young scientists. His visit drew to a close with a lecture on the molecule he’s spent most of his life studying, the ribosome.

Every living thing possesses ribosomes. It makes sense, then, that ribosomes are fundamentally necessary for life, and may predate proteins and even DNA in the history of life on Earth. Since the identification of DNA, an overarching rule of life has emerged called the Central Dogma, which states that an organism’s DNA is transcribed into RNA, which is then translated into proteins. It’s as if you’re copying instructions from a cookbook. The cookbook - in this case, DNA - holds all the recipes, and you can copy out only the individual recipe you need - the RNA. The copied recipe can then be used as a reference to make the final product, proteins. But as with cooking, you can’t simply turn words on a page into chocolate chip cookies. Like a baker might hold a recipe with one hand and mix the ingredients together with the other, the ribosome is the stepping stone between RNA and proteins.

“Going from DNA to RNA is something like going from Spanish to Portuguese - they’re similar types of molecules,” Noller pointed out, “But going from RNA to protein is like going from Portuguese to Chinese - they’re two totally unrelated languages. In this case, the ribosome is the Rosetta stone.”

The ribosome, which can be found in the fossil record going back 3.5 billion years, is a molecular machine that reads RNA and assembles the protein it encodes. Unlike many of our enzymes, it is composed mostly of RNA, not proteins. Its unusual composition and the fact that it lies at the heart of a process fundamental to life has made it a frequent subject of research.

Noller’s laboratory focuses on the structure and function of the ribosome. This is where the gallery of crystals comes in. Ribosomes, while relatively large cellular structures, are small enough that microscopy can’t provide the kind of detail necessary to understand the nuances of their structure. To get around this, scientists use a method called X-ray crystallography. In essence, Noller’s lab tries a variety of conditions to coax ribosomes into forming microscopic crystals, made up of repeating units, which forces the ribosomes to form symmetrical, 3D structures. At low power on the microscope, researchers can see angular crystals. However, when placed in the path of a X-ray, the crystal breaks up the X-ray beam into a complex scatter, which is caught and recorded. Using a mathematical operation called a Fourier transformation, the scatter of dots, each of which represents a single atom in the molecule, is resolved into a 3D model.

The problem with crystallography is that it only gives us a snapshot of its target. By forcing the ribosomes into crystals, they lose all ability to move. It’s well established that ribosomes, which must deal with growing proteins and move along the RNA, are dynamic molecules, moving and changing conformation as they work. Thus, still images don’t tell the whole story, a limitation Noller described with the parable of the cavemen and the Ferrari.

“The caveman and his cave-buddies are having beers and telling stories and they come out of the cave and see this.” Noller showed an image of a vintage Ferrari.

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