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

Before the cardiologist goes nuclear w/ stress #AHA17

Exercise stress testing to diagnose heart disease has a long history. This year, cardiologists can celebrate the 50-year anniversary of a study connecting abnormal stress test results and obstructive coronary artery disease (CAD).

The basic stress test procedure can involve walking on a tilting treadmill as the heart is monitored via electrocardiogram. A variant called the nuclear stress test involves introducing a radioactive tracer into the body to visualize alterations in blood flow within the heart.

Some stress tests are considered inappropriate, leading to additional medical costs. Arshed Quyyumi and colleagues from Emory Clinical Cardiovascular Research Institute presented research on Sunday at the American Heart Association Scientific Sessions meeting on the use of a blood test along with an exercise stress test. First author Bryan Kindya is a 2017-18 internal medicine resident.

The blood test detects troponin, a sign of recent damage to the cardiac muscle. Very high levels indicate that someone is having a heart attack. As testing for troponin has become more sensitive in recent years, the implications of lower but still detectable troponin levels need to be backed up by follow-up outcomes. That’s what the Emory data can provide.

Quyyumi’s team found that more than 25 percent of CAD patients will have troponin levels below a certain cut-off (2.45 picograms per milliliter), predicting that they have a low risk of having heart problems during a stress test or adverse events (hospitalization/heart attack/death) over the next three years.

The researchers conclude that measuring troponin in CAD patients before embarking on stress testing “may provide major cost-savings.” Disclosure: the research was done in cooperation with Abbott Labs, the maker of the high-sensitivity troponin test.

Posted on by Quinn Eastman in Heart Leave a comment

Virus hunting season open

New viruses have been popping up in industrial water-cooling towers, in Antarctica and salty deserts. Erwin van Meir, from Winship Cancer Institute of Emory University, and his collaborators managed to find two inside someone’s metastatic tumor.

Working with Terry Fei Fan Ng and Eric Delwart from UCSF, Van Meir identified two new species of anellovirus, a family of viruses first discovered in the 1990s. The new viruses come from a patient with a melanoma that had metastasized to the brain and was operated on at Emory University Hospital.

The results were recently published in Oncotarget.

“We have no evidence that these two viruses were involved in the tumor’s formation, but the data are proof of principle that the metagenomics method used can discover more unknown viruses in human brain tumors,” Van Meir says.

Erwin Van Meir, PhD

Metagenomics is the study of genetic material obtained directly from the environment. The approach is often used to study bacteria, but it is equally valid for viruses. In this paper, investigators used enzymes to chew up human and bacterial DNA, enriching for viral DNA protected by the viral capsid.

Estimates from the USAID’s PREDICT program point to thousands or even millions of viruses, present in mammals and birds, which remain unknown to humans. According to Annual Review of Virology from this summer, Viruses with Circular Single-Stranded DNA Genomes are Everywhere! – and that includes Anelloviridae, for which there is “still no convincing direct causal relation to any specific disease.”

Anelloviruses are relatively primitive in that they do not encode a viral polymerase (the enzyme that copies DNA) and thus need to rely upon the host cell and replicate inside the nucleus. The new ones were named Torque teno mini virus Emory1 (TTMV Emory1) and Torque teno mini virus Emory2 (TTMV Emory2). The research team gave a nod to Emory by using its colors in the virus genome cartoons accompanying the publication. Read more

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#AHA17 highlight: cardiac pacemaker cells

At the American Heart Association Scientific Sessions meeting this week, Hee Cheol Cho’s lab is presenting three abstracts on pacemaker cells. These cells make up the sinoatrial node, which generates electrical impulses driving our heart beats. Knowing how to engineer them could enhance cardiologists’ ability to treat arrhythmias, especially in pediatric patients, but that goal is still some distance away.

Just a glimpse of the challenge comes from graduate student Sandra Grijalva’s late breaking oral abstract describing “Induced Pacemaker Spheroids as a Model to Reverse-Engineer the Native Sinoatrial Node”, which was presented yesterday.

Cho has previously published how induced pacemaker cells can be created by introducing the TBX18 gene into rat cardiac muscle cells. In the new research, when a spheroid of induced pacemaker cells was surrounded by a layer of cardiac muscle cells, the IPM cells were able to drive the previously quiescent nearby cells at around 145 beats per minute. [For reference, rats’ hearts beat in living animals at around 300 beats per minute.] Read more

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Long-lasting blood vessel repair in animals via stem cells

Stem cell researchers at Emory University School of Medicine have made an advance toward having a long-lasting “repair caulk” for blood vessels. The research could form the basis of a treatment for peripheral artery disease, derived from a patient’s own cells. Their results were recently published in the journal Circulation.

A team led by Young-sup Yoon, MD, PhD developed a new method for generating endothelial cells, which make up the lining of blood vessels, from human induced pluripotent stem cells.. When endothelial cells are surrounded by a supportive gel and implanted into mice with damaged blood vessels, they become part of the animals’ blood vessels, surviving for more than 10 months.

“We tried several different gels before finding the best one,” Yoon says. “This is the part that is my dream come true: the endothelial cells are really contributing to endogenous vessels. When I’ve shown these results to people in the field, they say ‘Wow.'”

Previous attempts to achieve the same effect elsewhere had implanted cells lasting only a few days to weeks, although those studies mostly used adult stem cells, such as mesenchymal stem cells or endothelial progenitor cells, he says.

“When cells are implanted on their own, many of them die quickly, and the main therapeutic benefits are from growth factors they secrete,” he adds. “When these endothelial cells are delivered in a gel, they are protected. It takes several weeks for most of them to migrate to vessels and incorporate into them.” Read more

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Skin disease studies go deep: depression/inflammation insight

The placebo effect plays a big role in clinical trials for mood disorders such as depression. Emory psychiatrist Andy Miller hit upon something several years ago that could clear a path around the placebo effect.

Miller and his colleagues have been looking at the connection between inflammation and depression, whose evolutionary dimensions we have previously explored. They’ve examined the ability of inflammation-inducing treatments for hepatitis C and cancer to trigger symptoms of depression, and have shown that the anti-inflammatory drug infliximab (mainly used for rheumatoid arthritis) can resolve some cases of treatment-resistant depression. [Lots of praise for Miller in this September 2017 Nature Medicine feature.]

A recent paper in Psychotherapy and Psychosomatics from Miller and psychiatry chair Mark Rapaport looks at clinical trials testing an anti-inflammatory drug against psoriasis, to see whether participants’ depressive symptoms improved. This sidesteps a situation where doctors’ main targets are the patients’ moods.

When it comes to approving new antidepressants, the FDA is still probably going to want a frontal assault on depression, despite provisions in the 21st Century Cures Act to broaden the types of admissible evidence.

“These studies emphasize how difficult it is to interpret findings when these drugs are treating more than one problem,” Miller says. “Better to have a simpler study with just depression.”

Still, this line of research could clarify who could benefit from anti-inflammatory treatments and illuminate viable biomarkers and pathways. Two studies now underway at Emory specifically recruit patients with high levels of the inflammatory marker CRP, which Miller’s previous study showed was helpful in predicting response to infliximab.

The new paper results from a collaboration with Eli Lilly. Lilly’s ixekizumab (commercial name: Taltz) is an antibody against the cytokine IL-17A, used to treat moderate to severe psoriasis. Taltz was approved by the FDA in 2016, after clinical trials published in the New England Journal of Medicine. Read more

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

New insight into how brain cells die in Alzheimer’s and FTD

Removal of a regulatory gene called LSD1 in adult mice induces changes in gene activity that look unexpectedly like Alzheimer’s disease, scientists have discovered.

Researchers also discovered that LSD1 protein is perturbed in brain samples from humans with Alzheimer’s disease and frontotemporal dementia (FTD). Based on their findings in human patients and mice, the research team is proposing LSD1 as a central player in these neurodegenerative diseases and a drug target.

David Katz, PhD

The results were published Oct. 9 in Nature Communications.

In the brain, LSD1 (lysine specific histone demethylase 1) maintains silence among genes that are supposed to be turned off. When the researchers engineered mice that have the LSD1 gene snipped out in adulthood, the mice became cognitively impaired and paralyzed. Plenty of neurons were dying in the brains of LSD1-deleted mice, although other organs seemed fine. However, they lacked aggregated proteins in their brains, like those thought to drive Alzheimer’s disease and FTD.

“In these mice, we are skipping the aggregated proteins, which are usually thought of as the triggers of dementia, and going straight to the downstream effects,” says David Katz, PhD, assistant professor of cell biology at Emory University School of Medicine. Read more

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2B4: potential immune target for sepsis survival

Emory immunologists have identified a potential target for treatments aimed at reducing mortality in sepsis, an often deadly reaction to infection.

2B4 is an inhibitory molecule found on immune cells. You may have heard of PD1, which cancer immunotherapy drugs block in order to re-energize the immune system. 2B4 appears to be similar; it appears on exhausted T cells after chronic viral infection, and its absence can contribute to autoimmunity.

In their new paper in Journal of Immunology, Mandy Ford, Craig Coopersmith and colleagues show that 2B4 levels are increased on certain types of T cells (CD4+ memory cells) in human sepsis patients and in a mouse model of sepsis called CLP (cecal ligation + puncture). Genetically knocking out 2B4 or blocking it with an antibody both reduce mortality in the CLP model. The effect of the knockout is striking: 82 percent survival vs 13 percent for controls.

How does it work? When fighting sepsis, 2B4 knockout animals don’t have reduced bacterial levels, but they do seem to have CD4+ T cels that survive better. CD4+ T cells, especially memory cells, get killed in large numbers during sepsis, and this is thought to contribute to mortality. Read more

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EHR data superior for studying sepsis

Are there more cases of a given disease because something is causing more, or because doctors have become more aware of that disease? A recent paper in JAMA tackles this question for sepsis, the often deadly response to infection that is the most expensive condition treated in US hospitals.

Researchers from several academic medical centers, including Emory, teamed up to analyze sepsis cases using two methods. The first is based on the ICD (International Classification of Diseases) codes recorded for the patient’s stay in the hospital, which the authors refer to as “claims-based.” The second mines electronic medical record (EHR) data, monitoring the procedures and tests physicians used when treating a patient. The first approach is easier, but might be affected by changing diagnosis and coding practices, while the second is not possible at every hospital.

“This project was undertaken by several large, high quality institutions that have the ability to well characterize their sepsis patients and connect their EHR data,” says Greg Martin, MD, who is a co-author of the JAMA paper along with David Murphy, MD, PhD. The lead author, Chanu Rhee, MD, MPH, is from Brigham and Women’s Hospital, and the entire project was part of a Prevention Epicenter program sponsored by the Centers for Disease Control and Prevention.  Read more

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New pediatric digestive/liver disease gene identified by international team

In a study published this month in Hepatology, a multinational team of researchers describes a newly identified cause of congenital diarrhea and liver disease in children.

The rare disorder is characterized by significant diarrhea beginning soon after birth, low serum levels of fat-soluble vitamins and evidence of liver disease. Despite continued symptoms, with medical support, the children grow and develop normally, at least to the age of 12.

From left to right: Mutaz Sultan, Orly Elpeleg and Paul Dawson, representing three collaborating institutions.

Researchers from Emory University School of Medicine and Children’s Healthcare of Atlanta, working with colleagues from Makassed Hospital, Al-Quds University and Hadassah Medical Center, Hebrew University of Jerusalem studied a family with two children from the Palestinian territories who suffer from the disorder.

The team found that both children had inherited a mutation in a gene responsible for the transport of bile acids, which facilitate the digestion and absorption of dietary fats and fat-soluble vitamins. Although mutations had been identified in other genes important for the recycling of bile acids, this is the first report in humans of disease-associated defects in this gene, called Organic Solute Transporter-beta (SLC51B).

Almost 20 years ago, pediatric GI & hepatology researcher Paul Dawson, PhD, and colleagues identified mutations in another bile acid transporter gene (ASBT; SLC10A2) that caused congenital bile acid diarrhea.

“Even at that time, we knew that there were patients with similar symptoms that did not carry mutations in ASBT. But the genetic cause remained a mystery.” Dawson says. “What’s distinctive about this report is that these patients also have features of liver disease, which was not observed in previously described congenital bile acid diarrhea patients.” Read more

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Tug of war between Parkinson’s protein and growth factors

Alpha-synuclein, a sticky and sometimes toxic protein involved in Parkinson’s disease (PD), blocks signals from an important brain growth factor, researchers have discovered.

The results were published this week in PNAS.

The finding adds to evidence that alpha-synuclein is a pivot for damage to brain cells in PD, and helps to explain why brain cells that produce the neurotransmitter dopamine are more vulnerable to degeneration.

Alpha-synuclein is a major component of Lewy bodies, the protein clumps that are a pathological sign of PD. Also, duplications of or mutations in the gene encoding alpha-synuclein drive some rare familial cases.

In the current paper, researchers led by Keqiang Ye, PhD demonstrated that alpha-synuclein binds and interferes with TrkB, the receptor for BDNF (brain derived neurotrophic factor). BDNF promotes brain cells’ survival and was known to be deficient in Parkinson’s patients. When applied to neurons, BDNF in turn sends alpha-synuclein away from TrkB.  [Ye’s team has extensively studied the pharmacology of 7,8-dihydroxyflavone, a TrkB agonist.]

A “tug of war” situation thus exists between alpha-synuclein and BDNF, struggling for dominance over TrkB. In cultured neurons and in mice, alpha-synuclein inhibits BDNF’s ability to protect brain cells from neurotoxins that mimic PD-related damage, Ye’s team found. Read more

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