Editorial on bilateral vs single coronary bypass surgery

John Puskas, chief of cardiac surgery at Emory University Hospital Midtown, recently had an editorial in the journal Circulation on the topic of coronary bypass surgery.

John Puskas, MD

Specifically, he says that many cardiac surgeons are reluctant to employ bilateral internal thoracic artery grafts (as opposed to a single graft), even though there is a long-term benefit, because of perceived risk of infection and suboptimal financial incentives.

Puskas’ key message paragraph was so clear that it demands reposting here:

Why are American surgeons doing so few BITA [bilateral internal thoracic artery] grafts? Fundamentally, U.S. surgeons are responding to their practice environment, especially to a fear of deep sternal wound infection in an increasingly obese, diabetic population of patients. The surgeon pays a large and immediate political price for a deep sternal wound infection and receives relatively little credit for the extra years that BITA grafting adds to a patient’s life in the future. There is also a relative financial disincentive to perform BITA grafting: incremental payment for the second internal thoracic artery graft is small considering the extra time required in the operating room. Moreover, the Centers for Medicare and Medicaid Services no longer reimburse for extra care necessary for treatment of mediastinitis [internal chest inflammation/infection] after cardiac surgery, because this is now deemed a never event. Thus, surgeons, who are increasingly employed by hospitals and hospital systems, are under intense pressure to perform CABG surgery that is safe and cost-effective according to short-term metrics.

Puskas and his colleagues have published an analysis of bilateral vs single grafting at Emory, as well as a proposed metric for when single grafting should be used in the context of patients with diabetes:

Our present practice is generally to use BITA grafting in patients who are <75 years, have suitable coronary artery targets, are not morbidly obese, and whose glycosylated hemoglobin level is <7.0% to 7.5%.

Striking graph showing gene-stress interactions in PTSD

This graph, from a recent paper in Nature Neuroscience, describes how variations in the gene FKBP5 make individuals more susceptible to physical and sexual abuse, and thus more likely to develop PTSD (post-traumatic stress disorder).nn.3275-F1

The paper is the result of a collaboration between Elisabeth Binder and her colleagues at the Max Planck Institute of Psychiatry in Munich, and Emory psychiatrists Kerry Ressler and Bekh Bradley. The population under study is made up of inner-city Atlanta residents, part of the Grady Trauma Project overseen by Ressler and Bradley. This paper analyzes samples from a group of individuals that is more than twice as large as the original 2008 paper defining the effect of FKBP5, and adds mechanistic understanding: how regulation of the FKBP5 gene is perturbed.

Back to the graph — in addition to the effects of the different forms of the gene, it is striking how high the rate of PTSD is for both individuals with the protective and risk forms of FKBP5. Also, for individuals who did not experience abuse, the PTSD rate is actually higher for the “protective” form of the gene. On this point, the authors write:

It is, however, possible that the described polymorphisms define not only risk versus resilience, but possibly environmentally reactive versus less reactive individuals. This would imply that the so-called risk-allele carriers may also profit more from positive environmental change.

The FKBP5 gene encodes a protein that regulates responses to the stress hormone cortisol. Thus, it acts in blood and immune system cells, not only the brain, and is involved in terminating the stress response after the end of a threat. In the paper’s discussion, the authors propose that FKBP5 may have a role in sensitivity to other immune and metabolic diseases, in addition to PTSD and depression.

Max Planck press release on Binder paper

Recent post on Shannon Gourley’s related work (how stress hormone exposure leads to depression)

 

 

Seeing in triangles with grid cells

When processing what the eyes see, the brains of primates don’t use square grids, but instead use triangles, research from Yerkes neuroscientist Beth Buffalo’s lab suggests.

Elizabeth Buffalo, PhD

She and graduate student Nathan Killian recently published (in Nature) their description of grid cells, neurons in the entorhinal cortex that fire when the eyes focus on particular locations.

Their findings broaden our understanding of how visual information makes its way into memory. It also helps us grasp why deterioration of the entorhinal cortex, a region of the brain often affected early by Alzheimer’s disease, produces disorientation.

The Web site RedOrbit has an extended interview with Buffalo. An excerpt:

The amazing thing about grid cells is that the multiple place fields are in precise geometric relation to each other and form a tessellated array of equilateral triangles, a ‘grid’ that tiles the entire environment. A spatial autocorrelation of the grid field map produces a hexagonal structure, with 60º rotational symmetry. In 2008, grid cells were identified in mice, in bats in 2011, and now our work has shown that grid cells are also present in the primate brain.

Please read the whole thing!

Grid cells fire at different rates depending on where the eyes are focused. Mapping that activity across the visual field produces triangular patterns.

Tangled up with tau

Pathologist Keqiang Ye and his colleagues have identified a new potential drug target in Alzheimer’s disease. It’s called SRPK2 (serine-arginine protein kinase 2).

Keqiang Ye, PhD

Depleting this enzyme from the brain using genetic engineering tools alleviates cognitive impairment in an animal model of Alzheimer’s. The result suggests that drugs that target this enzyme could be valuable in the treatment of Alzheimer’s, although additional studies on human brain samples are necessary to fully confirm the findings, Ye says.

The results were published Tuesday in Journal of Neuroscience. The first author is postdoctoral fellow Yi Hong.

Hong and colleagues found that SRPK2 has elevated activity in a mouse model of Alzheimer’s. It acts on tau, one of the two major toxic clumpy proteins in Alzheimer’s. (beta-amyloid is outside the cell and forms plaques, tau is inside and forms tangles). Previous research on SRPK2 indicated that it had something to do with RNA splicing, so its “entanglement” with tau is a surprise.

Dissecting how chronic stress leads to depression

How can we study depression and antidepressants in animals? They can’t talk and tell us how they’re feeling. Previously, researchers have used the model of “behavioral despair,” with examples of the forced swimming test or the tail suspension test.

Shannon Gourley, PhD

Several psychiatrists have been arguing that a new framework is needed, which better simulates aspects of depression in humans, such as the variety of behavioral changes and the several week time period needed for antidepressants to function. This new framework could help illuminate how depression develops, and lead to new antidepressants that are effective for more people.

Shannon Gourley, who recently joined the Emory-Children’s Pediatric Research Center has been taking the approach of examining the lack of motivation and self-defeating behavior that are integral parts of depression.

The Pediatric Research Center is an effort led by Emory University and Children’s Healthcare of Atlanta, including partnerships with the Georgia Institute of Technology and Morehouse School of Medicine.

Note: Gretchen Neigh in psychiatry/physiology has been doing work with a similar theme, looking at the effects of adolescent social stress in animal models.

Gourley, neuroscience graduate student Andrew Swanson and their colleagues at Yale, where Gourley was a postdoc with Jane Taylor and Tony Koleske, have a new paper in PNAS on this topic. In particular, they dissect how chronic stress – or exposure to the stress hormone corticosterone – can produce loss of motivation and impaired decision making.

First, the researchers found that exposing rodents to corticosterone shut off a growth factor called BDNF (brain-derived neurotrophic factor) in the frontal cortex, a region of the brain important for planning and goal-directed behavior. BDNF nourishes neurons and helps keep them alive.

To confirm that BDNF was important in this region of the brain, researchers selectively silenced the gene for BDNF only in the frontal cortex. Both mice exposed to stress hormones and the BDNF-altered mice showed reduced motivation to earn food rewards. Mice would ordinarily press a lever dozens of times to get a food pellet, but the BDNF-altered animals would stop trying earlier – the “break point” is 2/3 as high.

“Depression is a leading cause of unemployment because people are unable to break out of self-defeating behavioral patterns and to muster the motivation to engage with the world. If we can better understand how to treat these symptoms, we can effect better outcomes for individuals suffering from depression,” Gourley says. “The BDNF deficiency alone could account for the loss of motivation that individuals with depression suffer.”

However, she reports her team was surprised that the loss of BDNF could not account for another aspect of depression: cyclical self-defeating behavior. They modeled this by asking whether mice continue to press a lever for a food reward even when the reward is no longer available.

“When we made the discovery that reduced BDNF could not account for all of the depression symptoms that we study, we took a step back and looked at the stress response system,” Gourley says.

Stress hormone exposure impairs the ability of mice to switch away from fruitless behaviors, but loss of BDNF in the frontal cortex does not. Here, the stress response system itself was the culprit. When her team temporarily blocked the ability of mice to shut off their stress response systems using the drug mifepristone, mice had impaired decision-making. However, their motivation to obtain rewards was not altered. When the drug wore off, they returned to normal.

Gourley says the implication is that effective antidepressants need to be able to attack not one, but two physiological systems: they need to increase levels of BDNF, and they need to help the stress system recover so that it can shut itself off better. A classic trycyclic antidepressant, amitriptyline, can do both and was effective in treating both the motivation and decision making parts of depression in animal models.

The use of tricyclic antidepressants is limited because of side effects and overdose potential. In addition, another challenge in treating depression is that current antidepressants only begin to work after several weeks or months of treatment. This is thought to be because it takes several weeks for these drugs—which act only indirectly on BDNF—to restore BDNF levels back to normal.

New compounds that act directly on BDNF’s receptor TrkB, such as those identified and tested by Emory researcher Keqiang Ye, could be promising in the development of new approaches to depression, Gourley says.

She and her team also showed that a drug called riluzole, which acts indirectly but rapidly on BDNF systems, has antidepressant effects in the animal models. Riluzole is currently in use to treat ALS, and reportedly has antidepressant effects in humans. Clinical trials with riluzole in the context of depression are underway.

Antiviral sugars in human milk

Biochemists Rick Cummings and David Smith have a paper in Journal of Biological Chemistry describing antiviral sugar molecules present in human milk. The first author is postdoctoral fellow Ying Yu.

Cummings and Smith are pioneers in the field of glycomics, studying the sugar molecules that decorate our proteins and coat our cells. They have found that human milk contains specialized glycans (carbohydrate linked to other molecules such as protein or lipid) that bind to influenza virus. This is separate from, and a supplement to, the adaptive immunity of antibodies and vaccines.

“The anti-flu glycans are not induced to our knowledge, but are part of a naturally occurring ‘liquid innate immune system’ in human milk,” Cummings says. “We’re very excited about this, and the availability of the human milk glycome in printed microarray formats will now allow screening for glycan binding to a wide variety of infant pathogens. This came from a single donor, so as to not complicate the matter yet, but work in progress shows that glycans from other donors have many related but also different glycans.”

He adds that his lab is finding that the glycans in human milk are different overall in complexity and makeup from those in other mammals.

Smith hypothesizes that the glycans may be functioning as “decoy receptors,” interfering with the molecules on the surfaces of human cells that viruses use to gain access.

AHA meeting highlights — an Emory-centric view

Poring over the abundance of information presented at major scientific meetings is like trying to drink from a firehose.  Imposing an Emory-centric filter on this year’s American Heart Association Scientific Sessions meeting in Los Angeles, here are three highlights, with a shoutout to the AHA journal Circulation, which provides a database of meeting abstracts.

Alginate encapsulation, a therapeutic delivery tactic to get stem cells to stay in the heart

Presenter Rebecca Levit, MD, a postdoc in cardiology division chair W. Robert Taylor’s laboratory, was a finalist for an Early Career Investigator Award.

 Stem cell therapies for myocardial repair have shown promise in preclinical trials, but lower than expected retention and viability of transplanted cells. In an effort to improve this, we employed an alginate encapsulation strategy for human mesenchymal stem cells (hMSCs) and attached them to the heart with a biocompatible PEG hydrogel patch in a rat MI model. Encapsulation allows for diffusion of pro-angiogenic cytokines and growth factors made by the hMSCs while maintaining them at the site of implantation…Alginate encapsulated hMSCs attached to the heart with a hydrogel patch resulted in a highly significant improvement in left ventricular function after acute myocardial infarction. The mechanism for this markedly enhanced effect appears to be increased cell survival and retention.

 Note: alginate already has a wide variety of uses, for example in culinary arts and to make dental impressions.

suPAR, a biomarker connected with depression, inflammation and cardiovascular outcomes. Step back, C-reactive protein

Depression, inflammation (Manocha, Vaccarino)

Cardiovascular outcomes (Eapen, Quyyumi)

Coronary microvascular dysfunction (Corban, Samady)

Predicting mental-stress myocardial ischemia via a public speaking test

A study probing myocardial ischemia (a lack of blood flow to the heart) induced by psychological stress, described in this Emory Public Health article. The presentation by Ronnie Ramadan examines physiological responses to a public speaking test as a way of predicting more severe problems.

Cilia = not silly

Please check out the news story on “Cilia guide neuronal migration in  developing brain,” illustrating the dynamic role played by cilia. Cilia are tiny hair-like structures on the surfaces of cells, but in the brain they are acting more like radio antennae.

In developing mouse embryos, Emory and UNC researchers were able to see cilia extending and retracting as neurons migrate. The cilia appear to be receiving signals needed for neurons to find their places.

The Developmental Cell paper is here. As a bonus, we have a video featuring two of the paper’s authors, geneticist Tamara Caspary and “Neurotypical?” blogger Laura Mariani, a graduate student in Caspary’s lab.

On the FastTrac to entrepreneurship

A recent feature in Nature Jobs highlights the growing trend of entrepreneurship training for scientists. Emory’s Office of Technology Transfer, together with their counterparts at UGA and Georgia Tech, organized a six week FastTrac entrepreneurship course which just wrapped up last week.

An article in Emory Medicine describes this course, which was also offered in the spring.

Flexibility and forgiveness during embryonic development

Geneticist Tamara Caspary’s laboratory has a recent paper in the journal Development showing how a developing mammalian embryo can correct a mispatterned neural tube over time. Former Genetics + Molecular Biology graduate student Chen-Ying Su, now a postdoctoral fellow at the Fred Hutchinson Cancer Research Center in Seattle, is the first author of the paper.

A molecule called “Sonic Hedgehog” is needed for proper patterning of the brain, spinal cord and eyes – it provides signals to the cells in the embryo, telling them what to become. Mutations that enhance Sonic Hedgehog signaling can lead to neural tube defects, some of the most common birth defects in humans, while those that diminish it can lead to holoprosencephaly, malformations of the brain and face. However, the majority of neural tube defects such as spina bifida do not come solely as a result of genetics – doctors think that getting enough (and possibly, not too much) of the B vitamin folic acid can prevent most of them.

Red = motor neuron precursor, green = later motor neuron marker
Mutation of Arl13b causes expansion of motor neurons (B and J)
Later deletion causes temporary expansion (C), corrected two days later (K)

Su and her colleagues examined mouse development in a situation where patterning of the neural tube is disrupted for a short time, because of a deletion in a gene (Arl13b), which helps to carry out Sonic Hedgehog’s instructions.

If Arl13b is not working starting from the beginning of development, embryos have an expansion of motor neurons, at the expense of other types of cells. The mutation leads to an open neural tube as well as abnormal eye, heart and limb development. However, if the deletion of Arl13b occurs on the ninth day, the embryo can recover proper patterning over the next few days. Mouse pregnancies last roughly three weeks.

Caspary says that while the relationship between Hedgehog signaling and neural tube defects is complicated, her lab’s recent work “does help define the time window during which we could non-surgically correct neural tube defects in utero.”

“In addition, it points to the importance of what we call “plasticity”- that cells can make incorrect decisions and correct them if still in a competency window, much like we think of adolescence,” she says. “It hints at the promise of stem cell research, that cells might be coaxed into other fates even though they start expressing tissue-specific markers. And it shows that the embryo is still much better at it than we are in a tissue culture dish.”