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

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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Late last year, we relayed the announcement of an exciting new academic program here at the University of Chicago, the Institute of Molecular Engineering. At the time, the IME had a future home (sharing the new William Eckhardt Research Center with the Physical Sciences Division) and a vision, but did not yet have a leader. Yesterday, that crucial headpiece was officially put in place, as biomolecular engineering and nanotechnology expert Matthew Tirrell was named the first Pritzker Director of the IME.

Tirrell will come to UChicago from California, where he has spent time at the University of California campuses in Berkeley and Santa Barbara over the last 12 years. His research specialty is the surface properties of polymers, chains of molecules that can be manipulated for building better materials used for everything from energy to technology to medicine. Those versatile aspirations make Tirrell the perfect leader for the IME, where the mission is to bridge disciplines at UChicago and Argonne National Laboratory and bring the tools of biology, chemistry, engineering, and physics to bear on finding solutions to some of science’s most important challenges.

“This isn’t going to be directed narrowly toward one scientific discipline, but at creating an institute that attacks societal problems from a technological viewpoint,” he said in the official announcement. “Many important societal problems in energy or health care or the environment can be addressed by new molecular-level science. When you are trying to solve problems, you need people from different kinds of disciplines. That’s something the Institute for Molecular Engineering can create right from the beginning.”

In his nearly 300 scientific publications, Tirrell has often studied and discussed how the surface properties of polymers are important for the success of biomaterials. Materials “communicate” with their surroundings through their surfaces, and designing new synthetic devices for technological uses requires a firm grasp on this process. As a result, bioengineers have taken inspiration from how natural materials such as mollusk shells and animal tissue solve surface compatibility problems to understand these interactions on a molecular level.

One application of that accumulated knowledge about biomaterials is novel solutions to clinical problems. In a phone interview Monday with ScienceLife about the biomedical goals of the IME, Tirrell talked about how these new technologies will not be merely passive construction materials, but active biological compounds.

“There are going to be ways of using biology not only to make things but also to do things,” Tirrell said. “Therapeutic organisms can be engineered with the tools of modern biology: living devices, if you will, as well as man-made devices.”

One example from Tirrell’s own research career expands upon designing living machines as a sort of multi-functional Swiss Army knife for diagnosing and treating diseases such as cancer and cardiovascular disease. A 2009 paper, published in Proceedings of the National Academy of Sciences, used a self-assembling lipid sphere called a micelle (pictured at right) to target the fatty plaques that form in blood vessels during atherosclerosis. When those plaques rupture, dangerous clots can form and  block blood vessels. To treat those clots, physicians currently prescribe blood thinning drugs that can produce unwelcome side effects, because the drug is not specifically targeted to the clot and acts throughout the body.

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photo by Cheryl Reed

A quick round-up of science around the web to end a busy, snowy week:

The “facepalm” has become a popular piece of the internet lexicon, alongside peers such as “epic fail” and “OMG.” But, as Ed Yong writes at Not Exactly Rocket Science, humans aren’t the only ones who make the universal expression of disgust and embarrassment. A group of Mandrill monkeys in an English zoo have started to make the expression. However, he writes, they may be signaling something different than facepalming humans: “Why are they doing it? It’s unlikely that they’ve found something stupid on the Internet.”

Jerry Coyne posts another example of purportedly human behavior observed in animals with the green heron - a bird that not only has a crazy expandable neck, but also has been filmed “fishing” by using a piece of bread as bait (yes, there is video). A webpage he links to at Tufts University contains a few other examples of bird tool use.

Earlier this week, in discussing his study on sleep and child obesity, David Gozal theorized that the modern family structure of two working parents has disturbed sleep routines for adults and children alike. Another study, released this week, appears to support that hypothesis, as a team including Ariel Kalil of the Harris School for Public Policy found an association between working mothers and their children’s body-mass index. Lead author Taryn Morrissey of American University stressed to Time magazine that the study is not meant to bash working moms, but rather to remind busy families about the importance of maintaining sleep schedules.”If all moms were to leave the workforce tomorrow, it wouldn’t solve childhood obesity,” she says.

With the Super Bowl coming up this weekend, allow us to point you back to a post written last year at the start of the World Cup about heart attacks in sports fans while watching important games. Some new research has come out in time for this year’s Big Game, including a study of LA fans during the 1980 and 1984 Super Bowls profiled by Ferris Jabr at New Scientist.

When you’re a hospital, you can’t call a snow day. If you’re curious as to how the Medical Center handled this week’s third-snowiest Chicago blizzard ever, here’s your answer: a lot of cots, and free lunch.

University of Chicago chemistry post-doc Niels Holton-Andersen views evolution as a “beautiful, amazingly huge experiment” that has produced elegant solutions to biological problems. His latest discovery is a self-healing, powerful adhesive produced by mussels, published last week in the Proceedings of the National Academy of Sciences. Mussels secrete the substance to stick to rocks in rivers and lakes, and researchers found that tweaking the pH of the adhesive can turn it into a self-healing gel, “kind of like Silly Putty,” Holton-Anderson said. The potential of the discovery was covered by “Green movement” blog Tainted Green.

A sickle cell (left) and a normal red blood cell (right). From carnegiescience.edu.

In 2006, Rice University football player Dale Lloyd II collapsed during a practice and later died. The cause of death was acute exertional rhabdomyolysis, a sudden breakdown of muscle tissue into the blood brought on by strenuous exercise. But the trigger for Lloyd’s death may have been sickle cell trait, the name for when a person carries one of the two genes required for full-blown sickle cell disease.

People with sickle cell disease form abnormal red blood cells that can lead to chronic pain, hypertension, stroke, and death, while people with sickle cell trait (approximately 2 million in the U.S.) are generally thought to be symptom-free. But Lloyd’s death drew attention to potentially fatal consequences for athletes with sickle cell trait, and a lawsuit filed by the player’s family led to the NCAA mandating testing for all Division I athletes in 2010.

But is screening for sickle cell trait the best preventive measure for college athletes? That was the topic on the table at the first Department of Pediatrics Grand Rounds of 2011 last week, where both the medical and ethical implications of the NCAA’s new policy were considered. Though mandatory sickle cell trait screening has previously been adopted by the military and the National Football League, the NCAA stance could cause a “trickle-down” effect to high schools and youth sports, leading to millions of tests that might cause more harm and expense than good.

At least fifteen NCAA athletes have died from sickle cell trait-related causes in the last 30 years. But given that there have been approximately 2 million total athletes over that time span, that’s only 1 death for every 400,000 people, said Holly Benjamin, associate professor of pediatrics and surgery. Compared to more common, harmful occurrences such as concussions and spinal cord injuries, that’s an exceedingly rare event.

Which is not to say that it shouldn’t be closely monitored. Sickling, the name for a sickle-cell-related attack, can develop after as little as 2 or 3 minutes of strenuous exercise, and can be exacerbated by heat, altitude, and dehydration, Benjamin said. Parents, coaches, and trainers should be vigilant about athletes who suddenly collapse, giving them fluids and oxygen and transporting them to the nearest emergency department.

But while screening athletes for sickle cell trait might improve the response to an athlete’s collapse, preventing that collapse in the first place would be even more beneficial. As a demonstration, Lainie Ross, professor of pediatrics, surgery, and medicine, used the history of sickle cell trait testing in the American military, which has faced similar tragedies and pressure to screen.

After 4 sickle cell trait-related deaths in 1970, a study found that African-American recruits with the gene were 30 times more likely to die during basic training. In response, the Armed Forces considered screening for carriers of the gene and restricting service in those with positive tests. Meanwhile, another study was started to test whether the danger could be reduced by using the wet-bulb globe temperature (WBGT) index, a measure incorporating temperature, humidity and other factors to determine how dangerous conditions are for physical activity. An intervention based around reducing exertion and increasing rest for basic training recruits on days with a high WGBT index was successful not only in completely eliminating deaths related to sickle cell trait, but reduced deaths in non-carriers as well.

“What this shows is that effective intervention does not require the identification of sickle cell trait,” Ross said.

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ScienceLife ran 219 posts in 2010, and choosing the best of them is as hard as picking a favorite gene.  So here’s a month-by-month scan of a busy year at the University of Chicago Medical Center, full of exciting discoveries in the laboratory and the clinic. The impact of some of this research is already being felt by patients receiving improved, evidence-based medical care. For other studies, the clinical benefit may be years in the future, and may take unpredictable forms. As a closing message for 2010, we’ll re-quote the recently departed Eugene Goldwasser, whose laboratory research isolating and purifying the hormone erythropoietin has helped millions of people worldwide.

“It is a particularly impressive example of how basic research can pay a dividend that could not be anticipated at the start,” Goldwasser wrote about his life’s work, “and it is a pity that the lesson still has not been learned by those who control public funding of science.”

January: Tong Chuan-He looked at how cancer may result from cells who don’t want to grow up. Scientists studied how sleep affects the language learning skills of starlings (with painstakingly acquired video of the experiment!). Richard Jones combined two laboratory staples - Western blots and DNA micro-arrays - to develop a new method for studying protein networks. While physicians such as Tammy Utset treat patients with lupus, UChicago scientists are looking for the genetic origins of the autoimmune disorder.

February: Many Medical Center employees returned from volunteering with relief efforts in Haiti, and we filmed video interviews with Rex Haydon, Tiffany Cupp, Richard Cook, and Dima Awad on their experiences. Most of the human genome is “junk” between protein-encoding regions, but Marcelo Nobrega developed a way to find important regulatory elements in that genetic sea. Like birds, human learning can be affected by sleep, and Leila Kheirandish-Gozal reported on the impact of obstructive sleep apnea upon learning in children. Can a single protein in the brain create behaviors associated with drug addiction in rats?

March: Everyone knows air travel is stressful, but did you know that eastbound flights cause stronger cortisol changes than westbound trips? The laboratory of Milan Mrksich found a way to direct stem cells to form fat or bone by shaping them into stars or flowers, a brilliant example of bioengineering. Computational neuroscientists discovered how touch is like vision in the brain, knowledge that could be used to someday re-engineer Luke Skywalker’s robot hand. Dartmouth president and Partners in Health co-founder Jim Yong Kim visited to talk about a new, needed area of research: health care delivery.

April: Researchers at the Field Museum and the University of Chicago teamed up for the Emerging Pathogens Project, an effort to find new viruses in animals before they jump to humans. Cardiologist Martin Burke tested out a new type of internal defibrillator device that can go under the skin, instead of into the heart (the clinical trial, reported in May, was a success). In a lecture to the MacLean Center of Clinical Medical Ethics, transplant surgeon J. Michael Millis described his efforts to bring American organ transplant practices to China.

May: A trial testing the erectile dysfunction drug Viagra for a rare, untreatable lung disease failed, but pulmonologist Imre Noth found a silver lining. Lauren Sallan and Michael Coates uncovered evidence of a previously unappreciated mass extinction event 360 million years ago that changed the path of life on Earth. Researchers from the University of Chicago and around the world presented science at the frontier of biotechnology at the annual BIO conference.

June: In a study that is literally the size of an entire country, epidemiologist Habibul Ahsan measured the toll of a tragic, accidental exposure of millions to arsenic in Bangladesh. Putting a gene from fireflies into the pancreas of mice isn’t mad science, it’s an imaging tool that will help study cures for diabetes. Epigenetics, the modifications that turn genes on and off, took off in 2010, and cardiologists Stephen Archer and Jalees Rehman linked one epigenetic factor to pulmonary artery hypertension.

July: Scientists don’t often get to see the fruits of their research in the flesh, but the Celebrating the Miracles gathering of diabetic children weaned off injected insulin thanks to genetic research was a moving exception (video of the event can also be viewed). Another hot topic in science and medicine this year was the use of computational analysis to sift through rapidly accumulating data, topics explored by Gary An and Andrey Rzhetsky. Or you can build a computer model of a brain network to study the dynamics of epilepsy, like neurologist Wim van Drongelen.

August: Air pollution is a problem indoors as well as outdoors in developing countries where dung and firewood are used to cook food - a problem being tackled in a project led by Sola Olopade. A study of the hormonal changes induced by a stressful test revealed a surprising protective effect of marriage and long relationships. Microbiologist Olaf Schneewind’s laboratory developed two new strategies against MRSA, the most-wanted cause of hospital-acquired infections.

September: To study multiple sclerosis, neurologist Brian Popko’ s laboratory developed a new mouse model that can replicate the disease, then spontaneously recover. Meanwhile, a new drug to treat MS, originally isolated from fungus found in wasps, was approved by the FDA and is being studied for broader uses at the Medical Center. The micro-organisms that live in humans were analyzed as part of a “microbiome” study looking at the protective effects of breast-feeding against a intestinal disease.

October: Common wisdom on quitting smoking says to stay away from cigarette-associated cues, but research from psychiatrist Harriet de Wit’s laboratory revealed that abstinence could make craving even worse. A study of how getting a good night’s rest affects dieting results suggested that “sleeping off the pounds” isn’t merely a fantasy. Graduate student Daniel Matute solved a 100-year-old riddle about how quickly new species become reproductively incompatible with each other.

November: In perhaps our favorite study of the year, geneticist George Perry found a way to acquire the genomic information of endangered species from…poop. The evolutionary biologist Leigh Van Valen passed away, but his Lewis Caroll-inspired Red Queen Hypothesis lives on. Sometimes statistics don’t tell the whole truth, as in the curious case of the aspirin paradox - why the cardio-protective drug may actually predict worse outcomes after heart attack.

December: Evolution textbooks may need a rewrite after geneticist Manyuan Long’s laboratory discovered that new genes can be just as essential as old genes. A study by neurobiologist Nicholas Hatsopoulos proved that the only thing better than a thought-controlled device is a thought-controlled device equipped with a robot arm. Ripped from the headlines: microbiologist Jack Miller weighed in on the hype over arsenic-based bacteria, and ethicist/physician/friar Daniel Sulmasy discussed the Presidential Bioethics Commission’s report on synthetic biology.

All told, it was a great year of science and medicine. Let’s do it again in 2011! Regular posting will resume Jan. 3rd. Happy Holidays.

When Eugene Goldwasser launched the project that would become his life’s work, he thought it would only take a matter of months. Since the early 20th century, biologists had predicted that a hormone they named erythropoietin must exist to promote the production of red blood cells when the body was running low. But in 1955, nobody had found it. Working at the University of Chicago after World War II, Goldwasser was challenged by his mentor, Leon Jacobson, to find erythropoietin, or Epo as it would come to be known.

“Very few biochemists were foolhardy enough to commit themselves to working on this seemingly intractable protein,” wrote Goldwasser, who passed away last week at the age of 88. “My thought was that any reasonably good biochemist ought to be able, in a relatively short time, to purify a hormone with a measurable biological effect.”

It took 22 years. But the purification of Epo, and the hormone’s eventual commercialization as the drug Epogen, ended up being one of the most significant discoveries of its time. A godsend for people struggling with anemia, either directly or as a consequence of kidney failure, cancer, or AIDS, Epo has helped millions of patients avoid blood transfusions that were once a regular part of their disease. A less savory use of Epo, as a performance-boosting drug, led to widespread controversy in the Tour de France in the late 1990’s. The billions of dollars made off of Epogen, and the legal and political battles over that windfall, also made it an important landmark (for better and worse) in the early days of the biotechnology industry.

Goldwasser himself was the recipient of almost none of that fortune, having failed to pursue a patent on the hormone when his purification experiments finally reached fruition in 1977. For him, the pursuit of Epo was pure basic science, and the potential for clinical application, never mind the money to be made off that translation, was a low priority. In a 1996 essay for the journal Perspectives in Biology and Medicine (not online, sadly), Goldwasser wrote about how he was so unconcerned with patenting his discovery, he forgot that he had even tried until discovering an unanswered disclosure form in his files decades later.

“After submitting the form I promptly forgot about it, since nothing was ever done about filing for a patent,” Goldwasser wrote. When the hormones was eventually patented and sold by the company Amgen, Epo brought them well over a billion dollars a year in revenue.

Even in the midst of this boom, Goldwasser was more interested in the scientific history of Epo than its profitability and legal wrangling. The 1996 essay is a gripping narrative of a scientific hunt, riddled with pitfalls and obstacles that Goldwasser and his collaborators were forced to navigate in order to grab hold of the elusive Epo. The biggest obstacle was the hormone itself, which is so effective in promoting red blood cell production that it is only secreted for brief periods and in very small amounts to produce millions of cells. As Merrill Goozner, author of “The $800 Million Pill,” wrote: “the amount of Epo needed to produce that lifetime supply could be dried and formed into a tablet no larger than an aspirin.” Finding such an ephemeral factor and then gathering a quantity large enough to study and replicate it was a gargantuan task, despite Goldwasser’s early confidence.

When Goldwasser began his search, scientists weren’t even sure which organ secreted Epo. So they started with a crude experiment: removing different organs from rats and injecting them with a salt known to induce red blood cell production. When the kidneys were removed, the salt had no effect, leading the researchers to believe they had found their organ (another clue was the anemia often seen in people with chronic kidney disease).

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Ultrasound imaging is best known for pictures of developing fetuses; 3D is typically associated with monster movies. But when you put the two together and aim the technology at the heart, they create a valuable tool that is changing the way heart disease is treated. Three-dimensional echocardiography is a cutting edge imaging technique used to obtain a detailed look at a patient’s heart in motion, figure out what may be wrong, and determine the best way to fix it.

The high-definition images collected by “3D Echo” can detect holes in the heart, problems with the valves that let blood pass between chambers, and irregularities in muscle contraction and blood flow. Information gathered during an echocardiogram can help surgeons create detailed plans for procedures to correct heart problems and can give them immediate feedback in the operating room after the surgery to make sure it was successful. For the increasing number of procedures that can be performed with cardiac catheterization instead of open heart surgery, a 3D echocardiogram provides live information to help guide cardiologists in their repairs.

“This is progressing very quickly and in many diseases, it really, really changes the way that people think about cardiology,” said Roberto Lang, professor of medicine and the director of the Noninvasive Cardiac Imaging Lab at the University of Chicago Medical Center. “We can look at the heart and tell the surgeon what he or she is going to encounter at the time of surgery.”

At this month’s American Heart Association meeting in Chicago, Lang presented research and participated in panels on the latest uses of 3D echocardiography. Since its submarine-sonar-inspired origin in 1953, the sonogram has been applied to cardiac function in many ways, through 2D images (similar to today’s fetal ultrasounds), through 3D reconstructions built from 2D data, to today’s instantaneous 3D view. Though real-time 3D imaging was only made possible 8 years ago, it is rapidly sweeping into the hospitals around the world, and new uses are still being discovered as the technology improves further.

During the AHA meeting, Lang presented what he calls “fusion imaging,” a combination of 3D Echo and computed tomography (CT) scanning to help determine the best place to implant a pacemaker for restoring normal heart contraction. Another presentation focuses on how 3D Echo can collect information about problems with the mitral valve - the portal between the left atrium and left ventricle of the heart. The precise location of leaks and other abnormalities can be mapped from the same angle the surgeon will see during surgery, Lang said, minimizing surprises on the operating table.

The best way to grasp the value of 3D echocardiograms is to see one, and last year, a production company came to the Medical Center and filmed Lang at work and talking about his field. Watch the results below.

“When we do these studies, we use all the different modalities and integrate them into a simple study,” Lang says in the video. “You want to be a detective and find out exactly what is happening to the patient, so you use all the technologies available and integrate them in order to come up with a good question or a good answer.”

[Thanks to Philips and Tomorrow Media for the video footage.]

Originally developed in 1897 as a painkiller, aspirin has become a valuable cardiology tool in the 21st century for preventing and treating cardiovascular disease. Because of the drug’s ability to reduce blood clotting, doctors commonly recommend a daily aspirin to patients at high risk or with a history of heart attacks, strokes, and other cardiovascular ailments. Extensive research has largely supported the drug as a cheap and effective way to prevent these life-threatening events and to help nullify what remains the leading cause of death in the United States.

But in 2000, a group of Boston cardiologists trying to identify risk factors that might predict poor outcomes after a heart attack made a strange discovery. Most of the predictive risk factors they discovered and ultimately incorporated into their well-known 7-point “TIMI risk score” made perfect sense. For example, if you came to the emergency room with chest pain and had an abnormal electrocardiogram or elevated levels in the blood signaling heart damage, you were more likely to be at risk for future adverse events. But the team also discovered one risk factor for predicting worse outcomes that was far from expected: the prior use of aspirin. According to their analysis, patients who were taking aspirin to prevent cardiovascular disease actually did worse after suffering a heart attack.

“It seemed to make little sense, because aspirin had clearly proven itself in other settings to be protective against heart attacks,” said Jonathan Rich, an instructor of medicine in the section of cardiology at the University of Chicago Medical Center. “If you suffered a heart attack, to prevent you from having another, your doctor invariably puts you on aspirin. So this unexpected discovery caught everyone’s attention. Did this mean that aspirin use could actually be hurting people?”

Dubbed the “aspirin paradox,” this observation did not deter doctors from continuing to prescribe aspirin for the prevention of cardiovascular disease. But the mystery caused some to wonder whether there was a biological reason for aspirin’s unexpected role as a risk factor, such as “aspirin resistance” in some patients, or if there was instead an epidemiological or statistical explanation. While working in Boston with the TIMI study group, Rich took charge of an effort to comb through the data for a way to explain the paradox.

The research ultimately led to a study, published last month in the Journal of the American College of Cardiology, which seems to take aspirin off the hook. When researchers controlled for a long list of potential confounding variables such as age, sex, smoking, and previous history of cardiovascular events, the association of prior aspirin use with a higher chance of post-event mortality entirely disappeared. Aspirin, they concluded, was not directly causing worse outcomes after a heart attack. Instead, it was simply a common drug that people with previous cardiovascular disease - by definition, a population at high risk for poorer outcomes, were frequently taking.

“Aspirin is probably an innocent bystander,” Rich said. “The reason people who take aspirin do worse than those not taking aspirin is because those taking aspirin have already suffered a heart attack, a stroke, or have heart failure for which they were prescribed the drug. In actuality, when we looked closer at the heart attacks that people suffered, those who were taking aspirin actually had less severe heart attacks than those not taking aspirin, suggesting that perhaps aspirin was indeed beneficial, but simply insufficient to prevent the heart attack entirely.”

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It’s well established that environment can influence a person’s weight as much as their genes or their behavior. For people growing up in inner city environments where fast food restaurants and liquor stores far outnumber grocery stores with fresh food options, it’s a struggle to piece together healthy meals on a consistent basis. But beyond “food deserts,” can a person’s neighborhood also influence their weight and their health in more subtle ways? Could less tangible factors such as crime rates and community networks contribute to the health disparities of race and socioeconomic status?

University of Chicago researcher Kathleen Cagney and Christopher Browning of Ohio State University set out to answer those intriguing questions by merging enormous data sets of health information and crime rates. The results of that study, presented by Cagney on October 6 at the MacLean Center Seminar Series, suggested that a person’s social surroundings - and the local police blotter - can exert a great influence on their health and fitness.

Cagney and Browning started with the Dallas Heart Study, a survey of thousands of residents of the Texas city on parameters relevant to cardiovascular heath. Focusing on one measure - body mass index, or BMI - the researchers then plotted the data against changes in local crime rate from police data for each patient, focusing in particular on short-term “crime spikes.” The hypothesis was that an increase in crime nearby the person’s home could produce stress and discourage outdoor activity, leading to less exercise, increased consumption of unhealthy “comfort food,” and activation of the hormonal “fight-or-flight” response.

“If something changes dramatically in your environment or in your community, you can imagine that your life behaviors and patterns would change in concert with that,” Cagney said.

After controlling for several other factors (a necessity for so broad a research question), Cagney said a significant effect of crime spikes on BMI was found for one group: women. Females from neighborhoods that had experienced the largest increase in crime over the past six months experienced a rise in BMI, equivalent to roughly a 2.7-pound weight gain for a typical 130-pound person. The weight of men in the study was found to be slightly sensitive to the overall crime rate in their neighborhood, but not the short-term dynamics of crime spikes, Cagney said.

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When the FDA adds a “Boxed Warning” to a drug - known casually and more dramatically as a “black box” - it can have dramatic consequences. The information is intended to warn physicians of potential adverse effects associated with the drug, issues that are not deemed serious enough to pull the drug from the market but which should prompt extra attention and care. Antidepressants, the diabetes drug Avandia, and Depo-Provera birth control have all received black boxes in recent years, prompting widespread media coverage and medical comment.

Earlier this year, the anticoagulant medication clopidogrel (marketed as Plavix) became the latest drug to be black-boxed by the FDA. The warning fit the purported age of genetic medicine, as it was meant to draw attention to certain patients for whom the anti-clotting drug is less effective due to the presence of a gene variant for an important enzyme. These “poor metabolizers” exhibited reduced ability to convert the drug into its active components, and the black box warned that physicians should run genetic tests and consider alternative treatments in patients with the polymorphism.

But clopidogrel has become an important medical tool, used in millions of patients at high risk for heart attack, stroke, and other cardiovascular events. The drug has increasingly been incorporated into the long-term care of patients with drug-eluting stents - devices implanted to keep arteries open that secrete medication to prevent the vessels from re-narrowing. In patients where genetics renders clopidogrel less effective, the lost protection can lead to a stent thrombosis (where a clot forms on the device and blocks the artery) or other grave problems. Those concerns, and the expense of conducting genetic tests in every patient, have sent ripples through the field of interventional cardiology, said Sandeep Nathan, assistant professor of medicine at the University of Chicago Medical Center.

“There’s a growing recognition that this sort of formulaic approach to anti-platelet therapy is probably not a good idea,” Nathan said. “What has been brewing as a suspicion for well over a decade has come to an explosive head in the past one or two years.”

In response, Nathan has launched a two-pronged research and clinical effort to rethink current use of clopidogrel while seeking the best possible way to address risk in the future. Instead of waiting for a post-stent adverse event to tragically prove a patient’s insensitivity to clopidogrel, Nathan’s group has become one of the first to offer anti-platelet testing before the stent is implanted in patients at high-risk for the drug being ineffective.

“I view this as testing a parachute. You better be sure that the pack you just strapped on before you jumped out of a plane actually contains a parachute and not camping gear,” Nathan said. “If somebody implanted a drug-eluting stent in me, you better believe that I’m going to want to know if the drug that is my sole protection against a catastrophic, potentially life-ending event, is working.”

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Last month, we discussed the garage doors of the body’s ion channels, the millions of microscopic machines that control the heart’s beat and the nervous system’s communication. Benoît Roux and his colleagues employed 25 million computational hours to model the potassium channel voltage sensor, a kind of garage door control box that determines when the channel opens its gate. But the metaphor breaks down a bit when the channel is open, as the potassium channel does more than just wait to close again. Instead, there’s an in-between phase that keeps excessive potassium from stampeding through the open gate while the door prepares to close, a state called inactivation.

Determining the mechanism for inactivation has befuddled scientists for the same reason as the voltage sensor: how do you reverse-engineer a biological machine that works at the  nanoscale level, moving less than one-billionth of a meter at a time? One solution is to take pictures of the channel in motion, but doing so in the channel’s native habitat of the cell is beyond current technical means. Scientists have therefore resorted to a method called X-ray crystallography, a trick of chemistry and physics where the atomic structure of a protein can be determined.

X-ray crystallography has been used on potassium channels before - one such experiment even won the Nobel Prize for Chemistry in 2003. But each crystallographic portrait only catches the channel frozen at one particular moment of time, leaving scientists to make (educated) guesses about the movements that take place between each laboriously-obtained picture. The more pictures available, the less guesswork required.

More pictures and better theory are the result of two papers appearing in Nature today from the laboratory of Eduardo Perozo, professor of biochemistry and molecular biology at the University of Chicago Medical Center. Perozo’s group added to the potassium channel crystallography gallery by using a slightly mutated channel to keep the gate locked open and expose the elusive inactivation state to portraiture. From experiments conducted at Argonne National Laboratory, they hoped to get a new snapshot portraying a form of inactivation known as the C-type. But to their surprise and delight, they got 15 slightly different structures for the channel, which were determined to represent sequential stages between the open and inactivated state.

“By sheer luck, we happened to trap the channel in the process of opening, just like a movie,” Perozo said.

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In the first part of his “The Genome at 10″ series on Sunday, Nicholas Wade of the New York Times wrote about frustration in the wake of the Human Genome Project. Despite optimistic promises at its unveiling in 2000, scientists haven’t found as many of the answers to disease in DNA as was initially hoped. Instead, our knowledge of the genome has created even more questions and complexity in the search for the genetic sources of disease.

As a result, more and more attention has been paid in recent years to epigenetics, the non-genetic control of gene expression. Through processes such as DNA methylation and histone acetylation, biology has developed ways of controlling the volume of protein production - silencing or activating a particular gene when its protein is needed.

“Picture the reading of DNA (gene transcription) as the opening of a zipper,” described Stephen Archer, chair of cardiology at the University of Chicago Medical Center. “Transcription factors must run along this DNA zipper to allow the DNA to open so the gene can be read. Methylation blocks this reading, much like having a thread stuck in the zipper prevents its opening. This way, methylation silences a perfectly normal gene.”

For a disease such as pulmonary arterial hypertension (PAH), which Archer studies, the search for a straight genetic cause has been unsatisfactory. PAH is marked by blockage of blood vessels to the lungs, and is known to run in families. 10 years ago, when a PAH-linked genetic mutation was found in a gene called BMPR2, researchers hoped that aberrant genetics were to blame for the disease. But at most, only a quarter of people with that mutation developed PAH, and not all people with PAH carried that mutation, Archer said. That led PAH researchers  to look elsewhere for answers, including at a mitochondrial protein called superoxide dismutase 2 (SOD2), which is known to be lower in PAH patients.

But when researchers looked at the SOD2 gene in people with PAH, they found no mutation. That suggested epigenetics may be to blame, Archer said.

“The question was why is SOD2 downregulated?,” Archer said. “So we began looking at the possibility it might be present but functionally inhibited.”

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For the next month, the world’s attention (and mine) will be focused on South Africa for the 2010 World Cup. Though it’s just starting to break through the public consciousness in the States, the World Cup is such a massive cultural force in the rest of the world that its tremors are felt even in scientific circles. A recent psychology study on how to take the best penalty kick got a lot of media play this week, and at least two different economists developed models to predict the winner via a country’s GDP and other factors (both picked Brazil).

I jumped into PubMed to see what other World Cup-related research could be found, and it turned out the water there was very deep. Since the last World Cup in 1996, dozens of scientific and medical articles have been published, ranging from editorials advising fans about potential diseases they need to be immunized against in South Africa to surveys of injuries suffered by referees during the tournament. But one topic appeared to drive much of the World Cup-related scientific debate, and it explains just how seriously the competition is taken around the world: does watching important World Cup games cause heart attacks?

The controversy started with a 2008 New England Journal of Medicine article called “Cardiovascular Events During World Cup Soccer.” A team of German researchers looked at emergency medicine records from June 9 to July 9, 2006, when the last World Cup was taking place in Germany, and compared the period to two control months free from international tournaments. According to the authors, “six of the seven games in which the German team participated were associated with an increase in the number of cardiac emergencies,” averaging out to a 2.5-fold increase in heart attacks. People with a history of coronary artery disease had an even higher health risk of watching their countrymen on the pitch: a four times increase in events. Blog founding father Jeremy Manier wrote about the study for the Chicago Tribune, and related it to local stress about the Cubs and Bears.

But wait - a counter-attack was sprung this year by an Italian team of researchers, who focused upon their own population during not only the 2006 World Cup, but the 2002 event as well as the 2004 European Championships. Studying more than 25,000 hospital admissions, the authors failed to find any uptick in heart-related events, even when Italy’s national team defeated France in a tense penalty shootout to win the ‘06 Cup (there was, however, at least one Italian with a chest injury that day). The Italian authors claim that their negative results are more in line with previous literature, including an English study that found only a small (but significant) increase in heart attacks and strokes during club soccer matches.

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Last October, a group of Illinois legislators visited the University of Chicago Medical Center for two days of education and discussion about cardiovascular medicine and health care reform, part of a nationwide “Legislator in the Lab” program. In addition to laboratory tours and panel discussions, the legislators and their staffs heard a series of brief, informative lectures on different cardiology topics, from prevention of sudden cardiac death to the use of stem cells for heart tissue regeneration. Many of these lectures were videotaped and posted to the Medical Center’s YouTube channel, and I thought I’d share a couple of them here today.

Dr. Matthew Sorrentino on Risk Factors for  Cardiovascular Disease

Everyone knows a little bit about risk factors for heart disease, such as obesity, age, family history, and tobacco use. But it’s important to remember that these factors don’t exist in isolation - instead, they interact in a way that can dramatically increase a person’s risk for heart attack or stroke. As such, cardiologists keep a scoresheet on their patients, adding up risk factors to determine a patient’s risk for heart attack. Matthew Sorrentino, professor of medicine in the section of cardiology, breaks down how doctors use these risk assessments, and how they can guide interventions that offer fast, powerful risk reduction.

Dr. Rupa Mehta on Heart Disease in Women

The undisputed leaders in the arena of women’s health awareness are breast cancer organizations, which routinely organize charity walks and fundraisers that draw thousands of participants and light city buildings pink. But as Rupa Mehta, assistant professor of medicine in the section of cardiology, reminded the audience in her talk, breast cancer and other diseases trail far behind cardiovascular disease as a killer of women. 460,000 women in the United States die from heart disease each year, which breaks down to about one death a minute. Mehta talks about the challenges that face physicians and patients in recognizing and treating heart disease in women, including watching out for the different set of symptoms - including fatigue, sleep disturbances, and shortness of breath - that signal an oncoming heart attack in females.