Before the cardiologist goes nuclear w/ stress #AHA17

Measuring troponin in CAD patients before embarking on stress testing may provide Read more

Virus hunting season open

Previously unknown viruses, identified by Winship + UCSF scientists, come from a patient with a melanoma that had metastasized to the Read more

#AHA17 highlight: cardiac pacemaker cells

Highlighting new research on engineering induced pacemaker cells from Hee Cheol Cho's Read more

inflammation

Starvation signals control intestinal inflammation in mice

Intestinal inflammation in mice can be dampened by giving them a diet restricted in amino acids, the building blocks of proteins, researchers have found. The results were published online by Nature on Wednesday, March 16.

The findings highlight an ancient connection between nutrient availability and control of inflammation. They also suggest that a low protein diet — or drugs that mimic its effects on immune cells — could be tools for the treatment of inflammatory bowel diseases, such as Crohn’s disease or ulcerative colitis.

The research team, led by Emory Vaccine Center immunologist Bali Pulendran, discovered that mice lacking the amino acid sensor GCN2 are more sensitive to the chemical irritant DSS (dextran sodium sulfate), often used to model colitis in animals. This line of research grew out of the discovery by Pulendran and colleagues that GCN2 is pivotal for induction of immunity to the yellow fever vaccine.

“It is well known that the immune system can detect and respond to pathogens, but these results highlight its capacity to sense and adapt to environmental changes, such as nutritional starvation, which cause cellular stress,” he says.

Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Sidestepping the placebo effect when studying depression

Research on depression must deal with a major obstacle: the placebo effect. This is the observation that patients improve in response to the sugar pills given as controls in clinical studies.

Clinical trial designers can incorporate various clever strategies to minimize the placebo effect, which is actually comprised of several statistical and psychological factors. Investigators can try to enhance, dissect or even “harness” them. [A recent piece in the New York Times from Jo Marchant focuses on the placebo effect in studies of pain relief.]

Emory psychiatrist Andrew Miller and his team have been developing a different approach over the last few years: studying symptoms of depression in people who are being treated for something else. This allows them to sidestep, at least partially, the cultural construct of depression, from William Styron to Peter Kramer to direct-to-consumer television ads.

Interferon alpha, a treatment used against hepatitis C virus infection and some forms of cancer, is a protein produced by the immune system that spurs inflammation. It also can induce symptoms of depression, such as fatigue and malaise. There are some slight differences with psychiatric depression, which Miller’s team describes here (less guilt!), but they conclude that there is a “high degree of overlap.”

Miller and his colleagues, including Jennifer Felger and Ebrahim Haroon, have documented how interferon-alpha-induced inflammation affects the brains of hepatitis C and cancer patients in several papers. That research, in turn, informs their more recent fruitful investigations of inflammation in the context of major depression. More on that soon.

Posted on by Quinn Eastman in Immunology, Neuro Leave a comment

Inflammation linked to weakened reward circuits in depression

About one third of people with depression have high levels of inflammation markers in their blood. New research indicates that persistent inflammation affects the brain in ways that are connected with stubborn symptoms of depression, such as anhedonia, the inability to experience pleasure.

The results were published online on Nov. 10 in Molecular Psychiatry.

The findings bolster the case that the high-inflammation form of depression is distinct, and are guiding researchers’ plans to test treatments tailored for it.

Anhedonia is a core symptom of depression that is particularly difficult to treat, says lead author Jennifer Felger, PhD, assistant professor of psychiatry and behavioral sciences at Emory University School of Medicine and Winship Cancer Institute.

“Some patients taking antidepressants continue to suffer from anhedonia,” Felger says. “Our data suggest that by blocking inflammation or its effects on the brain, we may be able to reverse anhedonia and help depressed individuals who fail to respond to antidepressants.”

In a study of 48 patients with depression, high levels of the inflammatory marker CRP (C-reactive protein) were linked with a “failure to communicate”, seen through brain imaging, between regions of the brain important for motivation and reward.

Emory researchers have found that high inflammation in depression is linked to a "failure to communicate" between two parts of the brain: the ventral striatum (VS, vertical cross section) and the ventromedial prefrontal cortex (vmPFC, horizontal).

Emory researchers have found that high inflammation in depression is linked to a “failure to communicate” between two parts of the brain: the ventral striatum (VS, vertical cross section) and the ventromedial prefrontal cortex (vmPFC, horizontal). Images from Felger et al, Molecular Psychiatry (2015).

Neuroscientists can infer that two regions of the brain talk to each other by watching whether they light up in magnetic resonance imaging at the same times or in the same patterns, even when someone is not doing anything in particular. They describe this as “functional connectivity.”

More here.

Posted on by Quinn Eastman in Neuro Leave a comment

Immune studies suggest remedies for parathyroid hormone-driven bone loss

A common cause of bone loss is an overactive parathyroid gland, which doctors usually treat with surgery. New research on how excess parathyroid hormone affects immune cells suggests that doctors could repurpose existing drugs to treat hyperparathyroidism without surgery.

The results were published October 8 in Cell Metabolism. [My apologies for not posting this in October.]

“Surgery is sometimes not an appropriate remedy for hyperparathyroidism because of the condition of the patient, and it is also expensive,” says lead author Roberto Pacifici, MD. “Also, the one pharmacological treatment that is available, cinacalcet, is not always the ideal solution. This work could potentially lead to alternatives.”

Roberto Pacifici, MD

Researchers at Emory University School of Medicine led by Pacifici teamed up with doctors from the University of Turin in Italy, combining observations of human patients with an overactive parathyroid with experiments on mice.

The drugs identified as potential treatments are: calcium channel blockers, now used to treat high blood pressure, and antibodies that block the inflammatory molecule IL-17A, under development for the skin disease psoriasis. Clinical trials would be necessary to show that these drugs are effective against parathyroid hormone-induced bone loss in humans. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Everything in moderation, especially TH17 cells

I was struck by one part of Mirko Paiardini’s paper that was published this week in Journal of Clinical Investigation. It describes a treatment aimed at repairing immune function in SIV-infected monkeys, with an eye toward helping people with HIV one day. One of the goals of their IL-21 treatment is to restore intestinal Th17 cells, which are depleted by viral infection. In this context, IL-21’s effect is anti-inflammatory.

However, Th17 cells are also involved in autoimmune disease. A recent Cell Metabolism paper from endocrinologist Roberto Pacifici and colleagues examines Th17 cells, with the goal of treating bone loss coming from an overactive parathyroid. In that situation, too many Th17 cells are bad and they need to be beaten back. Fortunately, both an inexpensive blood pressure medication and a drug under development for psoriasis seem to do just that.

Note for microbiome fans: connections between Th17 cells and intestinal microbes (segmented filamentous bacteria) are strengthening. It gets complicated because gut microbiota, together with Th17 cells, may influence metabolic disease and Th17-like cells are also in the skin — location matters.

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Strategy to defend vs double hit at beginning of life

Chorioamnionitis is a complication of pregnancy: inflammation of the membranes surrounding the fetus, caused by a bacterial infection. It has the potential to inflict damage to the brain of the fetus, especially when combined with fetal hypoxia, and is a known risk factor for developing cerebral palsy.

Chia-Yi (Alex) Kuan and his team, who study fetal brain injury in the Department of Pediatrics, have a new paper in Journal of Neuroscience on a strategy for inhibiting fetal brain inflammation. Postdoctoral fellows Dianer Yang, Yu-Yo Sun and Siddhartha Kumar Bhaumik are co-first authors.

The researchers show that a type of immune cells called Th17 cells seems to be driving inflammation because the rest of the fetal immune system is still immature. A marker of Th17 cells is elevated in blood samples from human infants with chorioamnionitis, the researchers found. Th17 cells are thought to be important for both autoimmunity and anti-microbial responses.

A drug called fingolimod, which stops immune cells from circulating out of the lymph nodes, was effective in reducing inflammation-induced fetal brain injury in animal models. Fingolimod has been approved by the FDA for use with multiple sclerosis and has been studied in clinical trials of kidney transplantation. The authors write that it may be a potential add-on to hypothermia as a treatment for infants in danger of hypoxia + infection-induced brain damage.

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Cell death drug discovery: come at the king, you best not miss

It may seem like a stretch to compare an enzyme to a notorious criminal, especially one as distinctive as Omar Little, a character from the HBO drama The Wire played by Michael Kenneth Williams.

But stick with me, I’ll explain.

TheWire-OmarLittle2-Portable

Omar is a stick-up man who robs street-level drug dealers. When drug dealer henchmen Stinkum and Weebay ambush him, they are unsuccessful and Stinkum is killed. Omar tells Weebay, who is hiding behind a car: “Come at the king, you best not miss.”

At Emory, Ed Mocarski, Bill Kaiser and colleagues at GlaxoSmithKline have been studying an enzyme called RIP3. RIP3 is the king of a form of programmed cell death called necroptosis. RIP3 is involved in killing cells as a result of several inflammation-, infection- or injury-related triggers, so inhibitors of RIP3 could be useful in modulating inflammation in many diseases.

In a new Molecular Cell paper, Mocarski, Kaiser and their co-authors lay out what happened when they examined the effects of several compounds that inhibit RIP3 in cell culture. These compounds stopped necroptosis, but unexpectedly, they unleashed apoptosis, another form of programmed cell death.  Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Anti-inflammatory drug prevents neuron loss in Parkinson’s model

A lot of evidence has piled up suggesting that inflammation plays a big role in the progression of Parkinson’s.

Immune system genes are linked to disease risk. People who regularly take NSAIDs such as ibuprofen have lower risk. Microglia, the immune system’s ambassadors to the brain, have been observed in PD patients.

Malu Tansey and her postdoc CJ Barnum make a convincing case for an anti-inflammatory — specifically, anti-TNF– therapy to Parkinson’s. They’ve been working with the Michael J. Fox Foundation for Parkinson’s Research to push this promising approach forward. Please check it out.

Posted on by Quinn Eastman in Immunology, Neuro Leave a comment

Targeting naked DNA in the heart

Hoechst-Structure-300px

The first thing that comes up in a Google search for “Hoechst” is the family of fluorescent dyes used to stain DNA in cells before microscopy. The Hoechst dyes derive their names from their manufacturer: a company, now part of Sanofi, named after the town where it was founded, which is now part of Frankfurt, Germany. The word itself means “highest [spot].”

Although DNA runs the show in every cell, it’s usually well-hidden inside the nucleus or the mitochondria. Extracellular DNA’s presence is a signal that injury is happening and cells are dying.

Biomedical engineer Mike Davis and collaborator Niren Murthy have been exploiting the properties of a DNA-binding dye called Hoechst 33342, often used to stain DNA in cells before microscopy. The dye can only bind DNA if it can get to the DNA – that is, if membranes are broken. This property makes the dye a good way to target injured tissue, either as an imaging agent or for therapy.

At the recent Pediatric Healthcare Innovation retreat, Davis discussed the potential use of such Hoechst derivatives to diagnose myocarditis (inflammation of the heart muscle) in children.

In addition, in a recent paper published in Scientific Reports, Davis and his colleagues attach the Hoechst dye to the cardioprotective growth factor IGF-1, creating a version of IGF-1 that is targeted to injured heart muscle. The first author of the paper is cardiology fellow Raffay Khan, MD. Screen Shot 2014-04-24 at 1.18.35 PM

IGF-1 has shown a lot of potential for treating heart disease, but it’s not the most cooperative as a drug, because it doesn’t last long in the body and doesn’t stick around in the heart. Linked up to the dye, IGF-1 behaves better. When used to treat mouse hearts after a heart attack, the Hoechst-IGF-1 treated-hearts have better function and less scar tissue (seen here as red).

The authors conclude:

With the broad chemistry surrounding functionalized PEG used to create Hoechst derivatives, it may be possible to target other therapies such as cells, small molecules, and even nanoparticles. We believe that the use of DNA binding agents such as Hoechst can be used to target exposed DNA in other diseases where necrotic cell death plays a critical role and could be used as a platform therapy.

 

 

Posted on by Quinn Eastman in Heart Leave a comment

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.

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