Cardiologists are increasingly checking patients’ unique genetic profiles as a first step in caring for them. This may partly explain why the American Heart Association last year elected a UAB genetic epidemiologist as its president in Donna Arnett, Ph.D. As her term ends this week, we thought to talk to her about her year in office and what's next in the treatment of massive, global health problems like high blood pressure.
Within the UAB School of Public Health, Dr. Arnett is chair of the Department of Epidemiology, the science that examines patterns in populations, including who is at risk for major diseases and why. She leads several nationwide studies looking at whether genetic variations in each person make them more at risk for heart diseases – or less likely to respond to commonly used anti-cholesterol or anti-inflammatory drugs.
What came across is her passion for scientific inquiry and determination to find better treatments for the families at higher risk for heart disease thanks to their genes. At the same time, she is the first to recommend that Americans get some exercise and eat better, rather than depend on genetics to eventually yield cures.
Show notes for the podcast:
1:40 Dr. Arnett began her career as a clinical research nurse working in a veterans hospital, and proceeded to become a leading genetic epidemiologist in cardiology and AHA president. Much of her inspiration has come from her strong curiosity, a need to ask questions. Early in her career at the veterans hospital, she wanted to know, for instance, why African Americans with the same level of high blood pressure as whites often had more serious kidney damage. Why were African Americans also more likely to have left ventricular hypertrophy. It's a thickening of the muscle in the left ventricle, one of the heart's chambers, that comes with fibrosis (scarring) and increased risk for heart attack and stroke. Why did people have different responses to the same doses of the same drug?
2.04 Unanswered questions drove her forward into the field of genetic epidemiology just as it was being founded. She said it was just good luck that she got into a field just as it was taking off.
3:00 She worked as a research nurse in general cardiovascular studies, but her office at the time was down the hall from the hospital's dialysis center. She got to know some of the veterans, and was struck by how many of the dialysis patients with severe kidney damage were African Americans. The experience brought home the human cost of the genetic contribution to disease.
4:15 Dr. Arnett said cardiology as a field is behind neurology and oncology, not only in genetic epidemiology, but also in pharmacogenomics, the study of the effect of each person's genetic variations on their response to drug treatments.
5:25 In her speech last year as began her term as AHA president, Dr. Arnett spoke about on the theme of “transforming cardiovascular health through genes and environment.” As a genetic epidemiologist she has a passionate interest in searching for genetic clues that may influence each person's disease risk. Some families with no traditional risk factors (not overweight; don't smoke) have struggled with tremendous disease burden and premature deaths. So learning how genes contribute to that is a must. That said, the thing that could save most lives from heart disease in America today would be a focus on environmental factors like the obesity epidemic. Our lifestyle is dominated by processed foods and sedentary inactivity, so Dr. Arnett believes we need to be "battling at both ends."
6:50 A focus of Dr. Arnett's tenure as AHA president has been hypertension or high blood pressure. It affects more than a billion people in the world, and does tremendous damage. On the bright side, nations and international institutions are starting to pay attention. The United Nations has held summits in recent years on diseases like hypertension that are caused by diet and lifestyle, where past efforts focused on infectious diseases. The World Health Organization has launched a campaign meant to reduce non-communicable diseases by 25 percent by 2025, with hypertension as a major focus.
7:25 In the U.S., the American Heart Association this year has partnered with the Million Hearts Initiative led by the Department of Health and Human Services, in an effort to prevent one million heart attacks in the next four years. The partnership will seek to achieve this goal through a combination of awareness campaigns, better access to care, new monitoring programs and initiatives that help people to take their medicine. Dr. Arnett said only a multi-pronged approach that include individuals, physicians, pharmacists, employers, companies and government agencies, combined with culture change, has a chance of making a difference. New technologies may help the cause, including smart phone apps that monitor blood pressure and upload it directly to a patient's electronic medical record.
9:45 The field of genetics within cardiology continues its high-speed evolution, she said. It's moving toward analysis of each person's entire gene code, or genome, to look for small differences that contribute to that person's risk for heart disease. Past approaches that tried to find a few genetic differences that placed large numbers of people at risk across populations are giving way to the study of individuals. Technologies have evolved to the point that whole genome sequencing of individuals is becoming affordable. It is being used around the country, said Dr. Arnett, to help diagnose diseases that seemingly have no cause. She and her colleagues are also using it to search for rare genetic variations that cause higher risk for left ventricular hypertrophy in some families.
11:45 Dr. Arnett has focused on left ventricular hypertrophy in her work because it is one of the four basic causes of heart disease -- along with smoking, high blood pressure and high cholesterol -- first identified by the landmark Framingham Heart Study in 1967. It is also the only one of the four that still has no known treatment for it (apart from lowering blood pressure).
12:38 The modern day life of the human body has changed drastically from the one in which it evolved, said Dr. Arnett. We went from running constantly to hunt and eating mostly plants during the first 8,000 generations of human existence, to sitting on the couch eating a steady diet of fatty, heavily salted food for the last four generations. Looking back even further, Dr. Arnett said, we evolved from saltwater fish, and with fine-tuned bodily mechanisms for regulating salt. The refrigeration and processing of food came about after World War II, drastically changing the way we eat. Heavily salted foods have changed the fluid balance in our bodies, which is regulated by the kidneys, to result in pandemic high blood pressure. Our genes may be slowly evolving to better handle salt but it will take many generations. .
Thursday, June 27, 2013
Wednesday, June 26, 2013
Image post 6: spinal cord cell reaches for its neighbor
While many posts from The Mix feature a science story, we also share images coming out of UAB research. Below is a description of what we are looking at and related hints about how the brain forms in the womb.
Pictured here is one star-shaped astrocyte "reaching out" to another in a dish. The most abundant cell type in the brain and spinal cord, astrocytes are not nerve cells, but instead provide support, nutrients and protection to nerve cells. Recent work has shown that astrocytes help to shape the messages being passed from nerve cell to nerve cell, and that problems with astrocyte function may throw off nerve cell performance.
In her research, Michelle Olsen, Ph.D., assistant professor in the UAB Department of Cell, Developmental and Integrative Biology, seeks to determine how the overlap between nerve cells and astrocytes contributes to normal brain development, and to brain abnormalities when something goes wrong.
Dr. Olsen's experiments with isolated cells seek to model processes underway in the brain as it forms during development. Nerve cells are known to put out "roots" that reach out, find nearby cells and link up to form signaling networks. The above picture suggests that astrocytes do something similar.
Named for their star shape, astrocytes put out extensions that wrap around synapses, the gaps between nerve cells in signaling pathways. Each nerve cell in a pathway sends an electric pulse down itself until it reaches a synapse, a gap between itself and the next cell in line. When it reaches the cell's end, the pulse triggers the release of chemicals called neurotransmitters that float across the gap. Arriving at the other side, they cause the downstream nerve cell to “fire” and, depending on the synapse type, to either pass on or stop the message.
In this way, each synapse between nerve cells “decides” whether or not a message continues down that pathway. The balance of messages passed on (excitation) and messages halted (inhibition) is crucial to brain function. One theory has it that astrocytes influence that balance at synapses with their own set of extensions and transmitters.
Dr. Olson captured the image using an inverted Zeiss Observer microscope.
In her research, Michelle Olsen, Ph.D., assistant professor in the UAB Department of Cell, Developmental and Integrative Biology, seeks to determine how the overlap between nerve cells and astrocytes contributes to normal brain development, and to brain abnormalities when something goes wrong.
Dr. Olsen's experiments with isolated cells seek to model processes underway in the brain as it forms during development. Nerve cells are known to put out "roots" that reach out, find nearby cells and link up to form signaling networks. The above picture suggests that astrocytes do something similar.
Named for their star shape, astrocytes put out extensions that wrap around synapses, the gaps between nerve cells in signaling pathways. Each nerve cell in a pathway sends an electric pulse down itself until it reaches a synapse, a gap between itself and the next cell in line. When it reaches the cell's end, the pulse triggers the release of chemicals called neurotransmitters that float across the gap. Arriving at the other side, they cause the downstream nerve cell to “fire” and, depending on the synapse type, to either pass on or stop the message.
In this way, each synapse between nerve cells “decides” whether or not a message continues down that pathway. The balance of messages passed on (excitation) and messages halted (inhibition) is crucial to brain function. One theory has it that astrocytes influence that balance at synapses with their own set of extensions and transmitters.
Dr. Olson captured the image using an inverted Zeiss Observer microscope.
Monday, June 24, 2013
Human body as skin-growing factory?
It happens quickly, say surgeons. You step off a curb or light a backyard grill, and your life is changed forever by profound injury. Patients arrive at major trauma centers every day with burns covering most of their bodies, or with a combination of skin, bone and muscle lost to terrible circumstance. Trauma surgeons do what they can to put things back together but are limited by today's tools.
In recent decades, surgeons have partnered with bioengineers to try to create better technologies for the replacement of lost tissue. They still have a ways to go, but surgeons may one day take a product "out of a box" and use it to patch large gaps of missing tissue.
Along these lines, research efforts captured in a recent Wired Article seek to create truly artificial replacement skin out of self-healing polymers and flexible electronics. Another near-future approach will be to use a patient's own body as a high-speed skin-producing factory with the help of appliances, engineered proteins and biochemicals.
We asked Steven Thomas, M.D., a UAB specialist in reconstructive surgery for patients with complex wounds and severe burns, for his take on both approaches. As an assistant professor in the Department of Surgery within the UAB School of Medicine and a former army surgeon, Dr. Thomas has spent much of his career looking for a better way to repair damaged tissue, layer by layer.
Show notes for the podcast:
00:56 UAB has the biggest burn and trauma centers in Alabama and Mississippi, and Dr. Thomas' team deals regularly with patients that have lost large amounts of skin, muscle and bone.
2:21 Burns pose a particular challenge when it comes to repairing skin, especially when all layers of skin (dermis, epidermis, etc.) have been destroyed. This requires surgeons to borrow skin from the non-burned areas. They can then use bioengineering techniques to regrow skin, but currently technologies do so slowly. When burns cover the majority of the patient's body, it is a challenge to regrow enough skin fast enough to avoid scarring.
3:22 According to Dr. Thomas, there is no current treatment option that efficiently and quickly makes available large amounts of replacement skin. Those that are available cost hundreds of thousands of dollars, require multiple procedures and don't work for all patients.
3:45 One product on the market now called the cultured epidermal autograph is grown from a patient's own skin cells by the biotech company Genzyme. From 2 postage stamp-sized biopsies, the company says it can grow enough skin to cover a patient’s entire body, but it may cost $600,000, said Dr. Thomas. What the field needs is inexpensive replacement skin that you could take off a shelf and apply.
5:10 Many current research efforts seek to create good artificial skin, but no one product has gelled yet. Today's attempts are not durable enough, he said, and need to be replaced by something that can be shipped and stored without losing its useful properties.
6:48 Some of the frontiers in artificial skin research include polymers that can knit themselves the way real skin does, but nothing to date does the job as well as the body itself The problem is large gaps in skin, which scar instead of knit.
7:58 Dr. Thomas is convinced that the future of the field will be in using the patient's own body as a high-speed bioreactor to make replacement skin, but it needs help. A current UAB research project led by graduate student Paul Bonvallet in the lab of Susan Bellis, Ph.D. seeks to provide that help using the protein collagen taken from cows. Collagen is the ingredient that gives shape, strength and structure to the body's connective tissues like bone and tendon, as well as to skin.
8:15 The UAB project is having some success in laying a mat of collagen across large areas where a patient has lost all layers of skin. The mat serves as a framework or scaffold that enables the skin to re-knit in an orderly way over of the dermis. The experimental product contains no cells, but the body populates it as needed.
8:42 UAB is among the first in the country to combine dermis scaffold and skin grafts to get patients re-covered with skin after major injuries. Dr. Thomas mentioned one accident victim that was hit and dragged underneath a garbage truck, loosing much of his skin, along with some bone and muscle, from the waist down. Through a combination of therapies, the surgeons were able to re-grow the lost skin, and the man is up and walking today. Dr. Thomas believes that in most places that man would have lost his legs.
9:21 Underway already at UAB are efforts to combine scaffolds with different mixes of stem cells and enzymes that encourage growth. The combination of framework and tailored cells is getting closer and closer to mimicking native tissue, itself a mix of cells and scaffolds.
10:09 Depending on the type of collagen used, it can act as the highway with guide rails that shows skin cells the pattern they need to grow in to cover over a wound or burn. Some types of collagen are better at doing this without leaving a scar. Dr. Thomas' team has been able to get good-sized wounds to heal in a few weeks using collagen biotechnology that used to take months.
11:57 Returning to the effort to generate truly artificial skin mentioned in the Wired article, Dr, Thomas said that the military has invested in such technologies in hopes of better regenerating skin for wounded soldiers. Institutions like DARPA, the Defense Advanced Research Projects Agency, and AFIRM, the Armed Forces Institute of Regenerative Medicine, fund related research projects.
12:15 Dr. Thomas thinks that, while the body may be best at creating skin for burns and wounds, artificial skin made from polymers has the potential to dramatically improve the nature of artificial limbs. During his years at the Brooke Army Medical Center burn unit, Dr. Thomas saw lots of amputees come in, and worked with many soldiers trying to get used to prosthetic limbs. He said today's prosthetic arms have no proprioception, the sense of where the limb is in space and with respect to the rest of the body. They also have no sense of touch. Creating limbs with these capabilities would represent a huge leap for people with prosthetics, he said.
14:00 Dr. Thomas has worked with the Bellis lab experimenting with electrospinning, a process that uses electrical charge to draw a nano-scale thread of material from a liquid. It is particularly suited for the production of fibers out of large and complex molecules like collagen. Electrospun collage can be woven into mats that promote cell growth and the penetration of cells into the engineered scaffold. The other great thing about electrospun materials is that they are inexpensive.
15:59 To fill in a complex wound, Dr. Thomas would like to have a treatment that could regrow skin, muscle and bone in layers. Stem cells engineered in concert and in layers to achieve such complex healing is a future possibility, he said. It may be too much to ask one product to achieve all that, and may require a combination of stem cell-driven products used together with precise timing.
Along these lines, research efforts captured in a recent Wired Article seek to create truly artificial replacement skin out of self-healing polymers and flexible electronics. Another near-future approach will be to use a patient's own body as a high-speed skin-producing factory with the help of appliances, engineered proteins and biochemicals.
We asked Steven Thomas, M.D., a UAB specialist in reconstructive surgery for patients with complex wounds and severe burns, for his take on both approaches. As an assistant professor in the Department of Surgery within the UAB School of Medicine and a former army surgeon, Dr. Thomas has spent much of his career looking for a better way to repair damaged tissue, layer by layer.
Show notes for the podcast:
00:56 UAB has the biggest burn and trauma centers in Alabama and Mississippi, and Dr. Thomas' team deals regularly with patients that have lost large amounts of skin, muscle and bone.
2:21 Burns pose a particular challenge when it comes to repairing skin, especially when all layers of skin (dermis, epidermis, etc.) have been destroyed. This requires surgeons to borrow skin from the non-burned areas. They can then use bioengineering techniques to regrow skin, but currently technologies do so slowly. When burns cover the majority of the patient's body, it is a challenge to regrow enough skin fast enough to avoid scarring.
3:22 According to Dr. Thomas, there is no current treatment option that efficiently and quickly makes available large amounts of replacement skin. Those that are available cost hundreds of thousands of dollars, require multiple procedures and don't work for all patients.
3:45 One product on the market now called the cultured epidermal autograph is grown from a patient's own skin cells by the biotech company Genzyme. From 2 postage stamp-sized biopsies, the company says it can grow enough skin to cover a patient’s entire body, but it may cost $600,000, said Dr. Thomas. What the field needs is inexpensive replacement skin that you could take off a shelf and apply.
5:10 Many current research efforts seek to create good artificial skin, but no one product has gelled yet. Today's attempts are not durable enough, he said, and need to be replaced by something that can be shipped and stored without losing its useful properties.
6:48 Some of the frontiers in artificial skin research include polymers that can knit themselves the way real skin does, but nothing to date does the job as well as the body itself The problem is large gaps in skin, which scar instead of knit.
7:58 Dr. Thomas is convinced that the future of the field will be in using the patient's own body as a high-speed bioreactor to make replacement skin, but it needs help. A current UAB research project led by graduate student Paul Bonvallet in the lab of Susan Bellis, Ph.D. seeks to provide that help using the protein collagen taken from cows. Collagen is the ingredient that gives shape, strength and structure to the body's connective tissues like bone and tendon, as well as to skin.
8:15 The UAB project is having some success in laying a mat of collagen across large areas where a patient has lost all layers of skin. The mat serves as a framework or scaffold that enables the skin to re-knit in an orderly way over of the dermis. The experimental product contains no cells, but the body populates it as needed.
8:42 UAB is among the first in the country to combine dermis scaffold and skin grafts to get patients re-covered with skin after major injuries. Dr. Thomas mentioned one accident victim that was hit and dragged underneath a garbage truck, loosing much of his skin, along with some bone and muscle, from the waist down. Through a combination of therapies, the surgeons were able to re-grow the lost skin, and the man is up and walking today. Dr. Thomas believes that in most places that man would have lost his legs.
9:21 Underway already at UAB are efforts to combine scaffolds with different mixes of stem cells and enzymes that encourage growth. The combination of framework and tailored cells is getting closer and closer to mimicking native tissue, itself a mix of cells and scaffolds.
10:09 Depending on the type of collagen used, it can act as the highway with guide rails that shows skin cells the pattern they need to grow in to cover over a wound or burn. Some types of collagen are better at doing this without leaving a scar. Dr. Thomas' team has been able to get good-sized wounds to heal in a few weeks using collagen biotechnology that used to take months.
11:57 Returning to the effort to generate truly artificial skin mentioned in the Wired article, Dr, Thomas said that the military has invested in such technologies in hopes of better regenerating skin for wounded soldiers. Institutions like DARPA, the Defense Advanced Research Projects Agency, and AFIRM, the Armed Forces Institute of Regenerative Medicine, fund related research projects.
12:15 Dr. Thomas thinks that, while the body may be best at creating skin for burns and wounds, artificial skin made from polymers has the potential to dramatically improve the nature of artificial limbs. During his years at the Brooke Army Medical Center burn unit, Dr. Thomas saw lots of amputees come in, and worked with many soldiers trying to get used to prosthetic limbs. He said today's prosthetic arms have no proprioception, the sense of where the limb is in space and with respect to the rest of the body. They also have no sense of touch. Creating limbs with these capabilities would represent a huge leap for people with prosthetics, he said.
14:00 Dr. Thomas has worked with the Bellis lab experimenting with electrospinning, a process that uses electrical charge to draw a nano-scale thread of material from a liquid. It is particularly suited for the production of fibers out of large and complex molecules like collagen. Electrospun collage can be woven into mats that promote cell growth and the penetration of cells into the engineered scaffold. The other great thing about electrospun materials is that they are inexpensive.
15:59 To fill in a complex wound, Dr. Thomas would like to have a treatment that could regrow skin, muscle and bone in layers. Stem cells engineered in concert and in layers to achieve such complex healing is a future possibility, he said. It may be too much to ask one product to achieve all that, and may require a combination of stem cell-driven products used together with precise timing.
Wednesday, June 12, 2013
Keep using magnesium to stop moms' seizures
I remember when my wife, in labor with our firstborn, had to take magnesium sulfate to prevent preecamplesia-related seizures. She had the baby, and mother and baby were fine, if sluggish for a day or two.
So I paid attention to recent headlines that said the FDA had curtailed the use of magnesium because it may weaken a developing baby's bones. Had my wife and newborn been given a dangerous drug? When I read the article carefully, I learned that it wasn't so.
The real concern is that people might, after a cursory read of the headlines, be less willing to get a short-term prescription for magnesium, a vital tool in managing pregnancies, said Joseph Biggio Jr., M.D., director of Division of Maternal and Fetal Medicine within the UAB Department of Obstetrics & Gynecology.
In most cases, he said, magnesium is used for just a few hours or days in women who develop preeclampsia, a form of pregnancy-related high blood pressure that can lead to seizures. Magnesium is much more effective than any other anti-seizure medications for this use, said Dr. Biggio.
Last week’s FDA advisory concerned instead a second, less common use of magnesium, where things are not so clear cut. In some cases, physicians have administered the drug continiously for a few months in hopes of delaying otherwise premature births (before 32 weeks gestation).
Recent data suggests that magnesium might protect the brains of potentially premature babies from cerebral palsy. That finding, and the lack of good drugs for the delay of preterm labor, may have encouraged more doctors to use magnesium sulfate for longer periods, said Dr. Biggio. The new FDA advisory is meant to curb attempts to stretch the boundaries of the drug’s traditional, short-term use.
The theory on how magnesium might delay labor proceeds from its similarity to calcium, which muscle cells rely on to contract. If magnesium has slipped into muscle cells in place of calcium, they can’t contract to deliver the baby. Magnesium taken by mothers also gets into their babies, which are often born listless, with low muscle tone for a couple of days after birth.
If around long enough, magnesium can compete with calcium in a second, essential role: forming bones. Bones formed in the presence of magnesium over several months may be weaker and prone to fracture.
Specifically, the FDA advised clinicians not to give pregnant women magnesium sulfate to prevent preterm labor for more than five to seven days because it may harm weaken fetal bones. It also reiterated that magnesium is approved for short-term prevention of seizures in preeclampsia, but not for longer off-label administration of magnesium to delay labor.
“No infant treated with magnesium for just the standard one or two days had any bone problems,” said Dr. Biggio, whose continued support of short-term magnesium use was echoed by the Society for Maternal-Fetal Medicine.
So I paid attention to recent headlines that said the FDA had curtailed the use of magnesium because it may weaken a developing baby's bones. Had my wife and newborn been given a dangerous drug? When I read the article carefully, I learned that it wasn't so.
The real concern is that people might, after a cursory read of the headlines, be less willing to get a short-term prescription for magnesium, a vital tool in managing pregnancies, said Joseph Biggio Jr., M.D., director of Division of Maternal and Fetal Medicine within the UAB Department of Obstetrics & Gynecology.
In most cases, he said, magnesium is used for just a few hours or days in women who develop preeclampsia, a form of pregnancy-related high blood pressure that can lead to seizures. Magnesium is much more effective than any other anti-seizure medications for this use, said Dr. Biggio.
Last week’s FDA advisory concerned instead a second, less common use of magnesium, where things are not so clear cut. In some cases, physicians have administered the drug continiously for a few months in hopes of delaying otherwise premature births (before 32 weeks gestation).
Recent data suggests that magnesium might protect the brains of potentially premature babies from cerebral palsy. That finding, and the lack of good drugs for the delay of preterm labor, may have encouraged more doctors to use magnesium sulfate for longer periods, said Dr. Biggio. The new FDA advisory is meant to curb attempts to stretch the boundaries of the drug’s traditional, short-term use.
The theory on how magnesium might delay labor proceeds from its similarity to calcium, which muscle cells rely on to contract. If magnesium has slipped into muscle cells in place of calcium, they can’t contract to deliver the baby. Magnesium taken by mothers also gets into their babies, which are often born listless, with low muscle tone for a couple of days after birth.
If around long enough, magnesium can compete with calcium in a second, essential role: forming bones. Bones formed in the presence of magnesium over several months may be weaker and prone to fracture.
Specifically, the FDA advised clinicians not to give pregnant women magnesium sulfate to prevent preterm labor for more than five to seven days because it may harm weaken fetal bones. It also reiterated that magnesium is approved for short-term prevention of seizures in preeclampsia, but not for longer off-label administration of magnesium to delay labor.
“No infant treated with magnesium for just the standard one or two days had any bone problems,” said Dr. Biggio, whose continued support of short-term magnesium use was echoed by the Society for Maternal-Fetal Medicine.
Wednesday, June 5, 2013
The illusion of a single perfect dose
Imagine if the recommended dose of a medication, the dose printed on its package, was correct for only about half of the people taking it. Then picture some people needing 30 times as much of the drug as others. What if either too high or too low a dose could have life-threatening consequences?
This worrisome scenario is the reality for patients taking warfarin, the 59-year-old blood thinner meant to help people avoid blood clots.
It serves as an example of the fact that, for many drugs, the idea of one correct dose for everyone is an illusion. In this light, I find it strange to think that the doses of medications I took growing up were best guesses, based on things like body weight, age, sex and race.
A wave of studies in recent years revealed that each person's genetic quirks greatly influence how well his or her body uses a drug, and on top of the classic factors mentioned above. How each person processes a drug determines not only whether or not that drug will work for them at all, but also how much of it is needed. Human genetic material is always changing, and many small variations at key spots in genes across a population create a range of responses to the same drug. Complicating matters, some of the variations with an impact on drug response are different for people with different ancestries.
That brings us to a study published this week and co-led by a UAB researcher. It found that a new genetic marker can better predict the right starting dose of warfarin dose in African-Americans. If confirmed in further studies, the finding may help avert more of the bleeds and blood clots that come when a patient’s dose misses the drug’s narrow safety window.
Clots form to patch holes in blood vessels. Unfortunately, clotting can also be triggered by atrial fibrillation, cancer, surgery, aging and inactivity. Once formed, clots can float through the circulatory system to clog blood vessels elsewhere, causing heart attacks and strokes.
For these reasons, 33 million Americans got a prescription for warfarin in 2012, most of whom started on an average starting dose of 5 mg. The drug is very effective at preventing clots, but if the dose is too-high for any individual, that patient is at risk for internal bleeding. If the dose is too small, they may not be protected against clots. Doctors monitor patients' clotting speed closely in the first few weeks of treatment, trying to get each person's dose right before serious side effects occur. Such efforts fail often enough that warfarin made a recent top-ten list of drugs causing side-effect related hospitalizations in the United States, mostly because of bleeds.
Most of why dose varies so greatly across the population remained unexplained. A study just published in The Lancet and co-led by UAB's Nita Limdi, Pharm.D., associate professor in the Department of Neurology within the UAB School of Medicine, chipped away at this mystery.
The new study was a genome-wide association (GWA) study, a kind of analysis that looks at differences in genetic code to see if one or more variations are found more often across a population with a given trait. Traits can be high risk for a disease, needed drug dose or how tall you are. Even the smallest genetic variations, called single nucleotide polymorphisms (SNPS), can have a major impact on a trait by swapping just one of 3.2 billion “letters” making up the human DNA code.
The current GWA study found a statistically significant association between a SNP called rs12777823 and reduced warfarin dose requirements in African-Americans. Patients with this SNP needed 20 percent less warfarin, an effect not seen in patients of European or Asian ancestry. When incorporated into dosing algorithms, the new variant enabled the prediction of best dose with 21 percent greater accuracy than the standard formula. Past GWA studies had sought to identify genetic factors that could improve warfarin dose prediction, but none of them included patients of African ancestry.
For more information, see our press release on the study.
This worrisome scenario is the reality for patients taking warfarin, the 59-year-old blood thinner meant to help people avoid blood clots.
It serves as an example of the fact that, for many drugs, the idea of one correct dose for everyone is an illusion. In this light, I find it strange to think that the doses of medications I took growing up were best guesses, based on things like body weight, age, sex and race.A wave of studies in recent years revealed that each person's genetic quirks greatly influence how well his or her body uses a drug, and on top of the classic factors mentioned above. How each person processes a drug determines not only whether or not that drug will work for them at all, but also how much of it is needed. Human genetic material is always changing, and many small variations at key spots in genes across a population create a range of responses to the same drug. Complicating matters, some of the variations with an impact on drug response are different for people with different ancestries.
That brings us to a study published this week and co-led by a UAB researcher. It found that a new genetic marker can better predict the right starting dose of warfarin dose in African-Americans. If confirmed in further studies, the finding may help avert more of the bleeds and blood clots that come when a patient’s dose misses the drug’s narrow safety window.
Clots form to patch holes in blood vessels. Unfortunately, clotting can also be triggered by atrial fibrillation, cancer, surgery, aging and inactivity. Once formed, clots can float through the circulatory system to clog blood vessels elsewhere, causing heart attacks and strokes.
For these reasons, 33 million Americans got a prescription for warfarin in 2012, most of whom started on an average starting dose of 5 mg. The drug is very effective at preventing clots, but if the dose is too-high for any individual, that patient is at risk for internal bleeding. If the dose is too small, they may not be protected against clots. Doctors monitor patients' clotting speed closely in the first few weeks of treatment, trying to get each person's dose right before serious side effects occur. Such efforts fail often enough that warfarin made a recent top-ten list of drugs causing side-effect related hospitalizations in the United States, mostly because of bleeds.
Most of why dose varies so greatly across the population remained unexplained. A study just published in The Lancet and co-led by UAB's Nita Limdi, Pharm.D., associate professor in the Department of Neurology within the UAB School of Medicine, chipped away at this mystery.
The new study was a genome-wide association (GWA) study, a kind of analysis that looks at differences in genetic code to see if one or more variations are found more often across a population with a given trait. Traits can be high risk for a disease, needed drug dose or how tall you are. Even the smallest genetic variations, called single nucleotide polymorphisms (SNPS), can have a major impact on a trait by swapping just one of 3.2 billion “letters” making up the human DNA code.
The current GWA study found a statistically significant association between a SNP called rs12777823 and reduced warfarin dose requirements in African-Americans. Patients with this SNP needed 20 percent less warfarin, an effect not seen in patients of European or Asian ancestry. When incorporated into dosing algorithms, the new variant enabled the prediction of best dose with 21 percent greater accuracy than the standard formula. Past GWA studies had sought to identify genetic factors that could improve warfarin dose prediction, but none of them included patients of African ancestry.
For more information, see our press release on the study.
Thursday, May 30, 2013
Image post 5: eye nerves shed light on memory disorders
While most posts from The Mix feature a science story, we have also begun sharing images coming out of UAB research. Below is a brief description of what we are looking at and how related work may contribute to a better understanding of Alzheimer's disease.
Pictured here is a retinal ganglion (center), a kind of nerve cell near the eye’s retina that helps to process light into the images we perceive. It had been injected with a fluorescent dye, which made it glow green along with the cells connected to it electrically. In each of our eyes, 125 million photoreceptors capture light. They then trigger nerve messages in 1.5 million retinal ganglion cells, long extensions of which bundle together to form the optic nerve.
Captured by Christianne Strang, Ph.D., research instructor in the Department of Vision Sciences within the UAB School of Optometry, this image represents signaling mechanisms between the retina and surrounding nerve cells. Strang's lab seeks to understand how photoreceptors connect to surrounding nerve pathways, as well as the degree to which they signal using the neurotransmitter acetylcholine.
Within nerve pathways, each nerve cell sends an electric pulse down an extension of itself called an axon until it reaches a synapse, a gap between itself and the next cell in line. When it reaches an axon’s end, the pulse triggers the release of chemicals called neurotransmitters that float across the gap. Upon reaching the other side, they either cause the downstream nerve cell to “fire” and pass on the message, or stop the message. Certain neurological diseases, including Alzheimer’s, have been linked to a decrease in acetylcholine signals in nerve pathways related to vision and memory.
As for rest of the color scheme, the pictured eye tissue has also been treated with dyes that interact with choline acetyltransferase (blue), which helps to produce acetylcholine, and synaptophysin (red), which reveals the location of synapses. The work was done in the lab of Kent Keyser, Ph.D., professor in the School of Optometry.
Thursday, May 16, 2013
The hard work of making cities smart and green
By 2050, 90 percent of Americans will live in cities that consume most of the nation's energy and generate most of its greenhouse gases. Whether sprawling cities devolve into ecological disasters or slowly transform into smart, sustainable economic growth engines will depend partly on the next generation of engineers and the technologies they invent.
To face the challenges posed by megalopolises, experts say Americans need to do more than just upgrade the current, rusting infrastructure. In a perfect world, future cities would boast advanced public transportation systems, renewable energy resources,"complete streets" and green roofs. Birmingham aspires to become such a place, with a new kind of UAB campus at its heart. Solar-powered electric vehicles would traverse its avenues passing facilities cooled in part by the breeze instead of fossil-fuel-burning air conditioning.
As a step toward this futuristic vision, Fouad H. Fouad, chair of the UAB Department of Civil, Construction and Environmental Engineering – and director of the UAB Sustainable Smart Cites Research Center – recently convened the second annual Sustainable Smart Cities Symposium. We thought the meeting made for a good occasion to ask him about related research frontiers. It's an exciting time, but there is still a long way to go, with progress slowed by economic hard times and the slow pace of technological development. When will U.S.-made solar panels, for instance, be cheap enough to compete with fossil-fuel-generated electricity?
For any city re-imagining itself as sustainable, the effort must start with investment in smart, green infrastructure – power, transportation and buildings, according to Dr. Fouad.
Power
On the frontiers of alternative power generation, Alabama Power is currently testing solar panels at 50 locations across the state. Unfortunately, Alabama is not windy enough for massive wind power projects using current technologies, but engineers continue to experiment with the viability of rooftop units.
Research is underway in UAB Mechanical Engineering on the next generation of solar cells, some of the work done in combination with Alabama Power, said Dr. Fouad. UAB Energy Management’s dream is to carpet the roofs of UAB’s buildings with solar panels but presently, projects would take 30 years to generate enough savings to pay for themselves – in part due to the relatively low utility rates in Alabama.
Transportation
Smart, green transportation systems are a major ingredient in future-looking cities, with related efforts seeking to create new street plans that favor non-motorized traffic, take advantage of biofuels and launch electric vehicle fleets.
In terms of city planning research, Fouad said his team is doing many studies on congestion management. Dynamic signaling systems may make it possible to better route traffic to lessen traffic jams. Thanks to a grant from the U.S. Department of Transportation, UAB recently joined the National Center for Transportation Performance and Management to conduct multi-disciplinary research on sustainable transportation infrastructure, economic competitiveness and safety.
Other concepts under investigation by UAB civil engineers include the "complete street," where city streets are designed to accommodate foot and bike traffic as much as motorized traffic. A UAB demonstration project is planned for 10th Avenue in combination with The Regional Planning Commission of Greater Birmingham, said Dr. Fouad.
Under the heading of green fuels and vehicle fleets, the planning commission's partnering initiatives include Alabama Partners for Clean Air and the Alabama Clean Fuels Coalition. Recent related news includes the announcement by the City of Trussville that it's expanding its fleet of compressed natural gas vehicles and opening a CNG fueling station. Compressed natural gas is a fossil fuel substitute for gasoline that is more environmentally sound. CNG may also be mixed with biogas, produced from landfills or waste water, which doesn't increase the concentration of carbon in the atmosphere.
UAB Civil Engineering has a project underway in conjunction with the Jefferson County Transit Authority and the U.S. Federal Transit Administration to design and construct a prototype for a hydrogen fuel cell powered bus, which they hope could be the workhorse of new green public transportation fleets in Birmingham. The first vehicles should on the road later this summer, said Fouad. Such vehicles make electricity to power the car using hydrogen, and they give off nothing more than water vapor from the tailpipe. On the consumer front, Honda and Toyota are getting closer to producing hydrogen-powered cars that could be sold to consumers, but they will be costly to start.
Alabama Power is also experimenting with fleets powered by alternative energy sources, and to date has more than 100 electric vehicles and 50 charging installations. The UAB Department of Energy Management has purchased two electric cars that are charged entirely by solar panels, which offer them the chance to evaluate a grid-free transportation technology with no carbon footprint.
Buildings and bridges
The UAB Department of Materials Science & Engineering has great research strength in the design of green composite materials for building, Dr. Fouad said. Often such materials are made from recycled materials and are lightweight, stronger and less expensive to use. His smart cities center will be participating in the Alabama Composites Conference starting on June 18 in Birmingham.
UAB civil engineers are also looking at what's next for materials used to make bridges. Along with bridge materials research, projects underway are studying "bridge way in motion" sensors that send messages continually about the structural health of bridges to ensure timely maintenance, not to mention alerting authorities when trucks breaking weight limit laws cross bridges.
Also maturing are research efforts to develop green roof technology, where plants grown in soil beds on roofs conserve energy and improve air quality as plants turn carbon dioxide generated by cars into oxygen. Green roof test beds are currently in place atop the Hulsey Center, the Business and Engineering Complex, Campbell Hall and Hill University Center at UAB. They limit water runoff into the storm water drains, pumping it back through the irrigation system, which keeps polluted water from running into area creeks and the Black Warrior River. The presence of plants and surrounding soil controls water evaporation in a way that creates a cooling effect. Combined with the moist soil, this helps drop temperatures and has resulted in a 20 to 25 percent savings in power bills.
Both the vegetative and white reflective roofs are perhaps 80 degrees cooler in the mid-day summertime than standard black roofs, which can literally be used to fry eggs. The Alabama Department of Environmental Management is interested in promoting the adoption of vegetative roofs across the state.
Impact on health
One of the most exciting projects underway is a partnership between Civil Engineering and the UAB School of Medicine's Division of Preventive Medicine. Called the "Go-ing Forward Project," it seeks to determine how the condition of the "built environment" in a city - the streets, lighting, housing, sidewalks, etc., - impacts the health of city dwellers. UAB researchers are going door to door surveying residents to determine how various aspects of the built environment are impacting their lives. The project's emphasis is looking at how transportation options, urban design, infrastructure decay, safety and security, and housing conditions affect obesity. More than one third of the American population is obese.
From the layout of streets to the options available for exercise, to the quality of air and water and to the condition and upkeep of residences, the built environment exerts silent but significant influence on the likelihood that people will be obese. Of all the engineering factors correlated with negative health outcomes, housing conditions are the most closely tied to health impacts. The presence of mold and its impact on asthma, poor indoor air quality in private homes and certain pollutants (e.g. estrogen-related compounds) in drinking water are all hypothesized to contribute to obesity risk.
Looking for partners
It was no accident that Richard Michos - global vice president, Smarter Cities, from IBM, was invited to speak at Fouad's recent UAB Smart Sustainable Cities symposium. UAB and the City of Birmingham hope to partner with IBM, perhaps through its Smarter Cities Challenge. This competitive IBM grant program is in the process of awarding $50 million worth of technology to 100 cities around the globe. These grants are designed to address the wide range of financial and infrastructure challenges facing cities today. Fouad met with Michos and Mayor Bell while Michos was in Birmingham, with their discussion covering the potential for IBM doing an assessment of the city's greatest sustainability needs, which is expected to yield a report and contribute to an action plan.
Speaking of partnerships, the City of Birmingham and UAB took a step toward smarter, healthier and more sustainable development with the Feb. 27, 2013, signing of a memorandum of understanding to partner on projects such as energy efficiency and city planning that accounts for a more “livable” city. Pilot projects expected out of the partnership include research into new recycling systems and lighting systems downtown that use less energy, perhaps in partnership with IBM.
UAB is also discussing the idea of creating a master's program in Sustainable Smart Cities, which would move forward with contribution from the deans and leadership of several schools across UAB.
For those interested in more information, other good sources include the UAB sustainabiltiy page and My Green Birmingham.
To face the challenges posed by megalopolises, experts say Americans need to do more than just upgrade the current, rusting infrastructure. In a perfect world, future cities would boast advanced public transportation systems, renewable energy resources,"complete streets" and green roofs. Birmingham aspires to become such a place, with a new kind of UAB campus at its heart. Solar-powered electric vehicles would traverse its avenues passing facilities cooled in part by the breeze instead of fossil-fuel-burning air conditioning.As a step toward this futuristic vision, Fouad H. Fouad, chair of the UAB Department of Civil, Construction and Environmental Engineering – and director of the UAB Sustainable Smart Cites Research Center – recently convened the second annual Sustainable Smart Cities Symposium. We thought the meeting made for a good occasion to ask him about related research frontiers. It's an exciting time, but there is still a long way to go, with progress slowed by economic hard times and the slow pace of technological development. When will U.S.-made solar panels, for instance, be cheap enough to compete with fossil-fuel-generated electricity?
For any city re-imagining itself as sustainable, the effort must start with investment in smart, green infrastructure – power, transportation and buildings, according to Dr. Fouad.
Power
On the frontiers of alternative power generation, Alabama Power is currently testing solar panels at 50 locations across the state. Unfortunately, Alabama is not windy enough for massive wind power projects using current technologies, but engineers continue to experiment with the viability of rooftop units.
Research is underway in UAB Mechanical Engineering on the next generation of solar cells, some of the work done in combination with Alabama Power, said Dr. Fouad. UAB Energy Management’s dream is to carpet the roofs of UAB’s buildings with solar panels but presently, projects would take 30 years to generate enough savings to pay for themselves – in part due to the relatively low utility rates in Alabama.
Transportation
In terms of city planning research, Fouad said his team is doing many studies on congestion management. Dynamic signaling systems may make it possible to better route traffic to lessen traffic jams. Thanks to a grant from the U.S. Department of Transportation, UAB recently joined the National Center for Transportation Performance and Management to conduct multi-disciplinary research on sustainable transportation infrastructure, economic competitiveness and safety.
Other concepts under investigation by UAB civil engineers include the "complete street," where city streets are designed to accommodate foot and bike traffic as much as motorized traffic. A UAB demonstration project is planned for 10th Avenue in combination with The Regional Planning Commission of Greater Birmingham, said Dr. Fouad.
Under the heading of green fuels and vehicle fleets, the planning commission's partnering initiatives include Alabama Partners for Clean Air and the Alabama Clean Fuels Coalition. Recent related news includes the announcement by the City of Trussville that it's expanding its fleet of compressed natural gas vehicles and opening a CNG fueling station. Compressed natural gas is a fossil fuel substitute for gasoline that is more environmentally sound. CNG may also be mixed with biogas, produced from landfills or waste water, which doesn't increase the concentration of carbon in the atmosphere.
UAB Civil Engineering has a project underway in conjunction with the Jefferson County Transit Authority and the U.S. Federal Transit Administration to design and construct a prototype for a hydrogen fuel cell powered bus, which they hope could be the workhorse of new green public transportation fleets in Birmingham. The first vehicles should on the road later this summer, said Fouad. Such vehicles make electricity to power the car using hydrogen, and they give off nothing more than water vapor from the tailpipe. On the consumer front, Honda and Toyota are getting closer to producing hydrogen-powered cars that could be sold to consumers, but they will be costly to start.
Alabama Power is also experimenting with fleets powered by alternative energy sources, and to date has more than 100 electric vehicles and 50 charging installations. The UAB Department of Energy Management has purchased two electric cars that are charged entirely by solar panels, which offer them the chance to evaluate a grid-free transportation technology with no carbon footprint.
Buildings and bridges
The UAB Department of Materials Science & Engineering has great research strength in the design of green composite materials for building, Dr. Fouad said. Often such materials are made from recycled materials and are lightweight, stronger and less expensive to use. His smart cities center will be participating in the Alabama Composites Conference starting on June 18 in Birmingham.
UAB civil engineers are also looking at what's next for materials used to make bridges. Along with bridge materials research, projects underway are studying "bridge way in motion" sensors that send messages continually about the structural health of bridges to ensure timely maintenance, not to mention alerting authorities when trucks breaking weight limit laws cross bridges.
Also maturing are research efforts to develop green roof technology, where plants grown in soil beds on roofs conserve energy and improve air quality as plants turn carbon dioxide generated by cars into oxygen. Green roof test beds are currently in place atop the Hulsey Center, the Business and Engineering Complex, Campbell Hall and Hill University Center at UAB. They limit water runoff into the storm water drains, pumping it back through the irrigation system, which keeps polluted water from running into area creeks and the Black Warrior River. The presence of plants and surrounding soil controls water evaporation in a way that creates a cooling effect. Combined with the moist soil, this helps drop temperatures and has resulted in a 20 to 25 percent savings in power bills.
Both the vegetative and white reflective roofs are perhaps 80 degrees cooler in the mid-day summertime than standard black roofs, which can literally be used to fry eggs. The Alabama Department of Environmental Management is interested in promoting the adoption of vegetative roofs across the state.
Impact on health
One of the most exciting projects underway is a partnership between Civil Engineering and the UAB School of Medicine's Division of Preventive Medicine. Called the "Go-ing Forward Project," it seeks to determine how the condition of the "built environment" in a city - the streets, lighting, housing, sidewalks, etc., - impacts the health of city dwellers. UAB researchers are going door to door surveying residents to determine how various aspects of the built environment are impacting their lives. The project's emphasis is looking at how transportation options, urban design, infrastructure decay, safety and security, and housing conditions affect obesity. More than one third of the American population is obese.
From the layout of streets to the options available for exercise, to the quality of air and water and to the condition and upkeep of residences, the built environment exerts silent but significant influence on the likelihood that people will be obese. Of all the engineering factors correlated with negative health outcomes, housing conditions are the most closely tied to health impacts. The presence of mold and its impact on asthma, poor indoor air quality in private homes and certain pollutants (e.g. estrogen-related compounds) in drinking water are all hypothesized to contribute to obesity risk.
Looking for partners
It was no accident that Richard Michos - global vice president, Smarter Cities, from IBM, was invited to speak at Fouad's recent UAB Smart Sustainable Cities symposium. UAB and the City of Birmingham hope to partner with IBM, perhaps through its Smarter Cities Challenge. This competitive IBM grant program is in the process of awarding $50 million worth of technology to 100 cities around the globe. These grants are designed to address the wide range of financial and infrastructure challenges facing cities today. Fouad met with Michos and Mayor Bell while Michos was in Birmingham, with their discussion covering the potential for IBM doing an assessment of the city's greatest sustainability needs, which is expected to yield a report and contribute to an action plan.
Speaking of partnerships, the City of Birmingham and UAB took a step toward smarter, healthier and more sustainable development with the Feb. 27, 2013, signing of a memorandum of understanding to partner on projects such as energy efficiency and city planning that accounts for a more “livable” city. Pilot projects expected out of the partnership include research into new recycling systems and lighting systems downtown that use less energy, perhaps in partnership with IBM.
UAB is also discussing the idea of creating a master's program in Sustainable Smart Cities, which would move forward with contribution from the deans and leadership of several schools across UAB.
For those interested in more information, other good sources include the UAB sustainabiltiy page and My Green Birmingham.
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