Quinn Eastman

How much does idiopathic hypersomnia overlap with ME/CFS?

In everyday linguistic usage among non-specialists, sleepiness can blend together with tiredness and fatigue. Someone might feel “tired” after climbing a mountain or chopping down a tree, while “sleepiness” is different. Emory sleep scientists explore the pathological distinctions in a paper published in Journal of Sleep Research.

A team led by neurologists Lynn Marie Trotti and David Rye has been studying idiopathic hypersomnia (IH) for several years: people who experience excessive daytime sleepiness and “sleep drunkenness,” not explained by other medical conditions.

IH’s symptoms don’t usually include persistent muscle pain or a severe response to exertion. This separates the disorder from myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS). But there is some overlap, which is what neurology resident Caroline Maness, Trotti and colleagues report in the new paper. The authors use the official term SEID (systemic exertion intolerance disease), which was recommended by an Institute of Medicine panel in 2015, but hasn’t really stuck among those in the ME/CFS field.

Some people with IH have disclosed that they were previously diagnosed with ME/CFS. Outside of the sleepy vs tired issue, some people with IH report symptoms shared with ME/CFS, such as impaired circulation in their extremities in response to cold, or dizziness upon standing. Speculatively, this may point to a possible problem with the autonomic nervous system. Trotti and a collaborator at Stanford, Mitchell Miglis, are now examining this issue further.

ME/CFS has had a history of controversy. Despite its devastating impacts, some have viewed it as psychological or somehow unreal, and sufferers have felt neglected or maligned by mainstream medicine. The National Institutes of Health has made efforts to turn that situation around by investing in ME/CFS research, and there has been a surge of attention recently covering ME/CFS (Amy Maxmen items in Nature, Stanford magazine feature, Unrest documentary).

Trotti, Maness and colleagues didn’t set out to dive into ME/CFS – they explicitly label this paper a pilot study, and the results say more about the “hypersomnolent” group of patients they have been seeing for the last several years, rather than the broader ME/CFS population. Read more

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Duel of the inflammatory master regulators: insights for drug discovery

Anti-inflammatory drugs such as dexamethasone can have harmful side effects on the skin, bones and metabolism. Structural biology research from Emory University School of Medicine has implications for the long-standing quest to separate these drugs’ benefits from their side effects.

The findings were recently published in Nature Communications (open access).

Dexamethasone is a synthetic glucocorticoid hormone, used to treat conditions such as allergies, asthma, autoimmune diseases and cancer. It mimics the action of the natural hormone cortisol. Both cortisol and synthetic hormones act by binding the glucocorticoid receptor (GR) protein.

The market for synthetic glucocorticoid hormones, oral and topical, is estimated at $10 billion. Examples include dexamethasone, prednisone, and hydrocortisone. Yet these drugs might not be approved today, given the array of known side effects.

GR can bind DNA in two modes. At some sites, it pairs up or “dimerizes” – turning genes on. At others, it binds one at a time, turning genes off. For GR-targeting drugs, the side effects are thought to come from turning on genes involved in processes such as metabolism and bone growth, while the desired anti-inflammatory effects result mainly from turning inflammatory and immune system genes off.

In their new paper, Eric Ortlund, PhD, and colleagues report that GR’s ability to directly bind DNA extends more broadly than previously appreciated. The first author is Will Hudson, PhD, previously a graduate student with Ortlund and now a postdoctoral fellow in Rafi Ahmed’s lab at Emory Vaccine Center.

GR was known to interfere with another important family of DNA-binding proteins, master regulators of inflammation, which are together called NFkB. Ortlund’s team found that GR can directly bind one at a time to many of the same stretches of DNA that NFkB interacts with.

“This type of interaction, where GR is acting one at a time – we think it’s druggable,” says Ortlund, who is associate professor of biochemistry at Emory University School of Medicine. Read more

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What are rods and rings?

This image of mouse embryonic fibroblasts comes from Cara Schiavon, a graduate student in Rick Kahn’s lab in the Department of Biochemistry. It was impressive enough to capture interest from Emory Medicine‘s graphics designer Peta Westmaas. The light green shapes are “Rods and Rings,” structures that were identified just a few years ago by scientists studying how cells respond to antiviral drugs, such as those used against hepatitis C.

The rod and ring structures appear to contain enzymes that cells use for synthesizing DNA building blocks. Patients treated with some antiviral drugs develop antibodies against these enzymes.

The turquoise color represents microtubules, components of cells’ internal skeletons. The orange color shows DNA within nuclei. The spots in the nuclei are areas where DNA is more compact. The overall image is a “z-stack projection” acquired using the Olympus FV1000 confocal microscope in Emory’s Integrated Cellular Imaging Core.

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An exceptional electrical thrill ride #CNS2018

A recent paper in Neuropsychologia got a lot of attention on Twitter and at the Cognitive Neuroscience Society meeting in Boston over the weekend. It discusses what can happen when the amygdala, a region of the brain known for regulating emotional responses, receives direct electrical stimulation. A thrill ride – but for only one study participant. Two of nine people noticed the electrical stimulation. One individual reported (a video is included in the paper):

“It was, um, it was terrifying, it was just…it was like I was about to get attacked by a dog. Like the moment, like someone unleashes a dog on you, and it’s just like it’s so close…

He also spontaneously reported “this is fun.” He further explained that he could distinguish feelings in his body that would normally be associated with fear recognized and the absence of an actual threat, making the experience “fun”.

But wait, why were Emory neuroscientists Cory Inman, Jon Willie and Stephan Hamann and colleagues doing this? Read more

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For nanomedicine, cell sex matters

The biological differences between male and female cells may influence their uptake of nanoparticles, which have been much discussed as specific delivery vehicles for medicines.

Biomedical engineer Vahid Serpooshan, PhD

New Emory/Georgia Tech BME faculty member Vahid Serpooshan has a recent paper published in ACS Nano making this point. He and his colleagues from Brigham and Women’s Hospital and Stanford/McGill/UC Berkeley tested amniotic stem cells, derived from placental tissue. They found that female amniotic cells had significantly higher uptake of nanoparticles (quantum dots) than male cells. The effect of cell sex on nanoparticle uptake was reversed in fibroblasts. The researchers also found out that female versus male amniotic stem cells exhibited different responses to reprogramming into induced pluripotent stem cells (iPSCs).

Female human amniotic stem cells with nanoparticles .Green: quantum dots/ nanoparticles; red: cell staining; blue: nuclei.

“We believe this is a substantial discovery and a game changer in the field of nanomedicine, in taking safer and more effective and accurate steps towards successful clinical applications,” says Serpooshan, who is part of the Department of Pediatrics and the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.

Serpooshan’s interests lie in the realm of pediatric cardiology. His K99 grant indicates that he is planning to develop techniques for recruiting and activating cardiomyoblasts, via “a bioengineered cardiac patch delivery of small molecules.” Here at Emory, he joins labs with overlapping interests such as those of Mike Davis, Hee Cheol Cho and Nawazish Naqvi. Welcome!

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Toe in the water for Emory cryo-EM structures

Congratulations to Christine Dunham and colleagues in the Department of Biochemistry for their first cryo-electron microscopy paper, recently published in the journal Structure.

The paper solves the structure of a bacterial ribosome bound to a messenger RNA containing a loop that regulates translation. This process is important for the study of several neurological diseases such as fragile X syndrome, for example.

Christine Dunham, PhD

Dunham writes: “We are focusing on establishing this in bacteria to understand frameshifting and protein folding as a consequence of codon preference. We will then build up our knowledge to potentially study eukaryotic translational control.”

The paper neatly links up with two Nobel Prizes: the 2017 Chemistry prize for cryo-electron microscopy and the 2009 Chemistry prize for ribosome structure, awarded in part to Dunham’s mentor Venki Ramakrishnan. Also, see this 2015 feature from Nature’s Ewen Callaway outlining how cryo-EM is a must have for structural biologists wanting to probe large molecules that are difficult to crystallize.

Construction now underway in the Biochemistry Connector will allow installation of microscopes (worth $6 million) necessary for Dunham and others to do cryo-EM here at Emory, although she advises that it will be several months until they are photo-op ready. For the Structure paper, Dunham collaborated with George Skiniotis at University of Michigan; he recently moved to Stanford. Read more

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Biomedical career fair April 13

We learned about this from Tami Hutto at BEST (Broadening Experiences in Scientific Training) and Maria Thacker Goethe at Georgia Bio . We will provide more information when it is available. Friday, April 13. Emory Conference Center + Hotel, 1615 Clifton.

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Elevated (but still low) troponin as a long term cardio biomarker

This weekend (March 10) at the American College of Cardiology meeting, data will emerge on whether expensive and much-discussed PCSK9 inhibitors can lower the risk of heart disease as much as they reduce LDL cholesterol.

To help doctors decide who should take cholesterol-lowering drugs that cost thousands of dollars a year, the focus of discussion could fall on risk models, such as the Framingham score and its successors, or other biomarkers besides various forms of cholesterol. What a coincidence! We have experts on those topics at Emory Clinical Cardiovascular Research Institute: ECCRI co-director Arshed Quyyumi, MD and Laurence Sperling, MD, Director of Preventive Cardiology at the Emory Clinic.

Cardiologists led by Quyyumi have a recent paper in Journal of the American Heart Association looking at troponin as a long-term cardiovascular disease biomarker. Troponin is familiar to cardiologists because it is a sign of acute damage to the heart muscle. If someone with chest pain goes to the emergency department of a hospital, a test for troponin in the blood can say whether a heart attack occurred.

However, as clinical tests for troponin have become more sensitive in the last decade, interpretation has moved past just a “yes/no” question. The levels of troponin now detectable are much smaller than those used to confirm a heart attack. Elevated troponin can be detected in all sorts of situations where the heart is under stress, including after strenuous exercise in healthy individuals. The “optimal cutoff” the Emory authors use in some of their statistical analyses is 5.2 picograms per milliliter. This graph, derived from a 2011 Circulation paper, illustrates just how low that is. Read more

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When circulating ambulances disappear

Someone driving around a city on a regular basis will see ambulances. At times they’re going somewhere fast; sometimes they’re just driving. What if, on a given day, fewer ambulances are visible?

One possible conclusion might be: the ambulances are away responding to a group of people who need help. This effect resembles what Arshed Quyyumi and colleagues from Emory Clinical Cardiovascular Research Institute observed in a recent paper, published in the Journal of the American Heart Association.

Arshed Quyyumi, MD

Quyyumi’s team looked at progenitor cells, which circulate in the blood and are attracted to sites of injury.  In a group of 356 patients with stable coronary artery disease, the researchers saw that some (31 percent) had “ExMI” – exercise-mediated myocardial ischemia. That means impairments in blood flow were visible via cardiac imaging under the stress of exercise. This is a relatively mild impairment; participants did not report chest pain. This paper emerges from the MIPS (Mental Stress Ischemia Prognosis) study, 2011-2014.

The ambulance-progenitor cell analogy isn’t perfect; exercise, generally a good thing, increases progenitor cell levels in the blood, says co-first author and cardiology fellow Muhammad Hammadah. The study supports the idea that patients with coronary artery disease may benefit from cardiac rehab programs, which drive the progenitor cells into the ischemic tissue, so they can contribute into vascular repair and regeneration. Read more

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FMT microbial transplant for C diff gaining acceptance

In February, the Infectious Diseases Society of America issued new guidelines for fighting Clostridium difficile, the hardy bacterium that can cause life-threatening diarrhea and whose dominance is sometimes a consequence of antibiotic treatment. The guidelines recommend for the first time that FMT (fecal microbiota transplant) be considered for individuals who have repeatedly failed standard antibiotics.

In a nice coincidence, Emory FMT specialists Colleen Kraft and Tanvi Dhere recently published a look at their clinical outcomes with C diff going back to 2012, in Clinical Infectious Diseases. They report 95 percent of patients (122/128) indicated they would undergo FMT again and 70 percent of the 122 said they would prefer FMT to antibiotics as initial treatment if they were to have a recurrence. Read more

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