Posts tagged with "Making of Medicine"

Dentistry illustration by Kaelen Felix for 360 Magazine

Cold Sore Flareup Triggers

Virus Highjacks Important Immune Response, UVA Discovery Reveals

Researchers at the University of Virginia School of Medicine have shed light on what causes herpes simplex virus to flare up, explaining how stress, illness and even sunburn can trigger unwanted outbreaks.

The discovery could lead to new ways to prevent cold sores and recurrent herpes-related eye disease from reoccurring, the researchers report.

“Herpes simplex recurrence has long been associated with stress, fever and sunburn,” said researcher Anna R. Cliffe, PhD, of UVA’s Department of Microbiology, Immunology and Cancer Biology. “This study sheds light on how all these triggers can lead to herpes simplex-associated disease.”

About Herpes Simplex Recurrence

Once you’re infected with herpes simplex virus (HSV) – and more half of Americans are – the virus never really goes away. Instead, it lurks inside neurons, waiting for the right moment to strike again, a process known as reactivation.

Cold sores, also known as fever blisters, are one of the most common symptoms of HSV reactivation. Recurrent reactivation in the eye leads to herpes keratitis, which, if left untreated, can result in blindness. HSV infection has also been linked to the progression of Alzheimer’s disease.

Recurrences of HSV are typically associated with stress, illness or sunburn, but doctors have been uncertain exactly what causes the virus to reactivate. Cliffe and her collaborators found that when neurons harboring the virus were exposed to stimuli that induce “neuronal hyperexcitation,” the virus senses this particular change and seizes its opportunity to reactivate.

Working in a model developed by the Cliffe lab using mouse neurons infected with HSV, the researchers determined that the virus highjacks an important immune response within the body. In response to prolonged periods of inflammation or stress, the immune system releases a particular cytokine, Interleukin 1 beta. This cytokine is also present in epithelial cells in the skin and eye and is released when these cells are damaged by ultraviolet light.

Interleukin 1 beta then increases the excitability in the affected neurons, setting the stage for HSV to flare up, the UVA researchers discovered.

“It is really remarkable that the virus has hijacked this pathway that is part of our body’s immune response,” Cliffe said. “it highlights how some viruses have evolved to take advantage of what should be part of our infection-fighting machinery.”

The scientists say that more research will need to be done to fully understand the potential factors which play into herpes simplex disease. It may vary depending on the virus strain or the type of neuron infected, even. And it is still unknown if the virus alters how neurons respond to cytokines such as Interleukin 1 beta. But the new insights help doctors better understand what is happening in neurons and the immune system, and that could lead to ways to prevent unwanted outbreaks, the researchers hope.

“A better understanding of what causes HSV to reactivate in response to a stimulus is needed to develop novel therapeutics,” Cliffe said. “Ultimately, what we hope to do is target the latent virus itself and make it unresponsive to stimuli such as Interleukin 1 beta.”

Findings Published

The researchers have published their findings in the scientific journal eLife. The research team consisted of Sean R. Cuddy, Austin R. Schinlever, Sara Dochnal, Philip V. Seegren, Jon Suzich, Parijat Kundu, Taylor K. Downs, Mina Farah, Bimal N. Desai, Chris Boutell and Cliffe.

The work was supported by the National Institutes of Health’s National Institute of Neurological Disorder and Stroke, grant R01NS105630; the National Institute of Allergy and Infectious Diseases, grant T32AI007046; the National Eye Institute, grant F30EY030397; the National Institute of General Medical Sciences, grants T32GM008136, T32GM007267, GM108989 and GM007055and Medical Research Council grant MC_UU_12014/5.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.

AC_LatinoCovid by Allison Christensen for 360 Magazine

Antibody Cocktail May Prevent Symptomatic COVID-19 Infections

An antibody cocktail being tested at UVA Health and other sites was able to block 100% of symptomatic COVID-19 infections among people exposed to the virus, early results from the clinical trial suggest.

In addition, those who developed asymptomatic infections accumulated far less virus in their bodies than usual and saw their infections resolve within a week, according to interim data released by the cocktail’s manufacturer, Regeneron Pharmaceuticals.

“This is the first treatment shown to prevent COVID-19 after a known exposure, and offers protection for unvaccinated individuals caring for a family member with COVID-19,” said UVA Health’s William Petri Jr., MD, PhD, one of the leaders of the trial at UVA. “We expect that Regeneron will file for Emergency Use Authorization from the FDA so that this drug can be used outside of the context of a clinical trial.”

Antibodies for COVID-19

The phase 3 clinical trial aims to determine if the antibodies will prevent COVID-19 infection in people who have been exposed but not yet developed the disease. This is known as “passive immunization.”

Regeneron’s new analysis, which has not yet been published in a scientific journal, looked at outcomes in approximately 400 trial participants. Of 186 people who received the antibodies, none developed symptomatic COVID-19. Of the 223 who received a placebo, eight developed symptomatic COVID-19, the company reports.

Asymptomatic infections occurred in 15 of the antibody recipients and in 23 of the placebo recipients. Overall rates of infection, including both symptomatic and asymptomatic infections, were approximately 50% lower in the antibody group.

Among those who developed infections, placebo recipients had, on average, a peak viral load (the amount of virus in the body) that was more than 100 times greater than antibody recipients. The antibody group also recovered more quickly–all the infections resolved within seven days, while 40 percent of infections in the placebo group lasted three to four weeks, Regeneron said.

The cocktail also appears to shorten the duration of viral shedding, the time when the virus is being manufactured in the body. The viral shedding period was nine weeks among antibody recipients and 44 weeks among the placebo recipients. While people with COVID-19 are not infectious for this entire time, reducing the duration of viral shedding may shorten the period when they can spread the disease.

There were more adverse events reported among placebo recipients than among antibody recipients – 18 percent and 12 percent, respectively. Regeneron attributed this to the larger number of COVID-19 infections in the placebo group.

There was one death and one COVID-19-related hospitalization in the placebo group and none in the antibody group. Injection-site reactions were reported among 2 percent of both groups.

“We are profoundly grateful to the nurses and staff of the UVA COVID-19 clinic, led by Dr. Debbie-Anne Shirley,” Petri said. “Their day-to-day support made our participation in this trial possible.”

About the Clinical Trial

Phase 3 clinical trials, such as the one under way at UVA, examine the safety and effectiveness of new drugs and treatments in large numbers of people. Positive results in the phase 3 trial could spur the federal Food and Drug Administration to make the antibody cocktail available for post-exposure COVID-19 prevention.

The antibody cocktail is not a vaccine and is not expected to provide permanent immunity to COVID-19.

The team conducting the study at UVA is led by Petri and Shirley and includes Gregory Madden, MD; Chelsea Marie, PhD; Jennifer Sasson, MD; Jae Shin, MD; Cirle Warren, MD; Clinical Research Coordinator Igor Shumilin; assistant Rebecca Carpenter; and COVID-19 Clinic nurses Michelle Sutton, Elizabeth Brooks, Danielle Donigan, Cynthia Edwards, Jennifer Pinnata, Samantha Simmons and Rebecca Wade.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.

Science Tech Illustration by Gabrielle Archuleta

Blood Discovery Research x UVA

Blood Discoveries Advance Effort to Grow Organs, Battle Cancer 

New Research Reveals Important Insights Into How Our Bodies Make Blood 

CHARLOTTESVILLE, V.A.– Pioneering research into how our bodies manufacture the cells that make blood has moved us closer to regrowing tissues and organs. These findings also may let doctors grow the cells for transplantation into people to battle cancer, blood disorders and autoimmune diseases.

Researcher Karen K. Hirschi, PhD, of the Department of Cell Biology and Cardiovascular Research Center at the University of Virginia School of Medicine, has developed a simple and efficient way to generate “hemogenic endothelial cells.” These cells are the first step in the production line of blood cells, and Hirschi’s new findings provide a blueprint for creating them outside of the body.

“By studying how hemogenic endothelial cells develop normally, we gain the insight needed to generate them in the lab,” Hirschi said. “Now that we have established a method to produce human hemogenic endothelial cells outside of the body, we will continue to improve their production and function as we learn more about the mechanisms that promote their normal development.”

Building Blood-Making Factories

Hirschi’s latest work, published in a pair of scientific papers, offers important insights into how hemogenic endothelial cells form, and how they ultimately give rise to the cells that directly manufacture blood.

Writing in the prestigious journal, Science, she and her team reveal a key trigger that causes the endothelial cells to “transdifferentiate,” or turn into blood-making factories, during embryonic development. These blood-making (i.e. hemogenic) endothelial cells generate hematopoietic stem and progenitor cells (HSPCs) that have long been used for the treatment of cancer and other diseases. Typically, they are taken from sources such as an individual’s bone marrow, but doctors would like to be able to manufacture them quickly and easily for patients on demand. “Generating human hemogenic endothelial cells in the lab from each patient that needs HSPC is the first step toward patient therapies for blood disorders,” Hirschi said.

In a paper published nearly simultaneously in Cell Reports, Hirschi unveils a blueprint for creating the hemogenic endothelial cells, the source of HSPCs, outside of the body. The secret is a substance called retinoic acid. You may have heard of retinoic acid in association with beauty products, but in this case its responsibilities include triggering genes to cause “hematopoietic transition”–to put more vascular endothelial cells in the business of making blood by producing HSPCs.

The new insights provided by the work “will improve our ability to apply developmental insights to the generation of distinct endothelial cell subtypes for tissue engineering and regenerative medicine,” the researchers write in their new paper. “In addition, our system could likely be developed further to optimize the generation of transplantable HSPCs from human hemogenic endothelial cells for clinical therapies.”

The approach offers several advances over existing means, including being quicker and less expensive, the researchers note.

“We hope our continued efforts will move us closer to treating both vascular and blood disorders,” Hirschi said. “These studies highlight the importance of basic cell and developmental biology research as a foundation for devising strategies for patient-specific clinical therapies.”

Hirschi was recruited from Yale in 2019 to join the faculty in the Department of Cell Biology, which has long been interested in addressing how embryos develop and applying this basic knowledge to the repair and regeneration of damaged tissues and organs.

Findings Published

The Science paper was authored by Dionna M. Kasper, Jared Hintzen, Yinyu Wu, Joey J. Ghersi, Hanna K. Mandl, Kevin E. Salinas, William Armero, Zhiheng He, Ying Sheng, Yixuan Xie, Daniel W. Heindel, Eon Joo Park, William C. Sessa, Lara K. Mahal, Carlito Lebrilla, Hirschi and Stefania Nicoli. The work was supported by the National Institutes of Health (grants F32HL132475, U54DK106857, 1K99HL141687, R01HL130246, R56DK118728, R01HL146056. R01HL128064, R01DK118728 and R01GM049077) and the American Heart Association (grants 19PRE34380749 and19TPA34890046).

The research team responsible for the Cell Reports paper consisted of Jingyao Qiu, Sofia Nordling, Hema H. Vasavada, Eugene C. Butcher and Hirschi. That work was supported by NIH grants HL128064, U2EB017103, R01-AI130471 and R01-CA228019; CT Innovations grant 15-RMB-YALE-04; Department of Veterans Affairs Merit Review award I01BX002919; the Swedish Society for Medical Research; and a Stanford Dean’s Fellowship.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog at http://makingofmedicine.virginia.edu.

Alison Christensen, illustrations, pandemic, 360 MAGAZINE

New COVID-19 Stroke Guidelines

Top stroke experts have issued new guidance to ensure stroke patients receive safe, timely care while preventing the transmission of COVID-19.

The guidelines urge the use of telemedicine to speed treatment and advise EMS crews how to determine the best facility to treat the patient’s needs. The recommendations, from the American Heart Association’s Stroke Council, come amid increasing concerns that stroke patients are delaying seeking care because of fear of COVID-19. Such delays can have catastrophic consequences, including death.

“Even during the COVID-19 pandemic, patients should continue to seek immediate care for life-threatening and emergency conditions, and call 911 for any new signs or symptoms of stroke,” said UVA Health stroke expert Andrew Southerland, MD, one of the guidelines’ authors. “As the only certified Comprehensive Stroke Center in Charlottesville and Central Virginia, UVA has the necessary resources to ensure both patient safety and provide the highest level of care for stroke patients. Seeking emergency care for a stroke can help save lives and reduce the risk of long-term neurologic injury and resulting disability.”

The Importance of Speedy Stroke Care

With strokes, every minute counts, and speedy care can be the difference between life and death. It can also prevent lifelong disability. For that reason, Southerland and other telemedicine experts at UVA have worked with local EMS personnel to pioneer the use of the technology for pre-hospital care. They’ve placed tablets inside ambulances to connect first responders with UVA stroke experts, allowing stroke care to begin even before the patient arrives at the hospital. The new guidelines suggest this approach should be used widely.

The COVID-19 pandemic, however, adds an extra layer of complexity for first responders. In addition to the need for appropriate personal protective equipment, EMS crews must assess whether each patient has the coronavirus, the new guidelines note.

When possible, EMS workers should screen patients using free tools available online, the guidelines recommend. Responders should have a protocol in place in case the screening is positive or if the patient is incapacitated and can’t be screened. The receiving hospital should be notified as well.

Stroke patients with COVID-19 are more likely to require a ventilator and intensive care, so emergency crews should consider taking patients to a hospital with the capacity to provide that level of care, the guidelines note. Emergency crews also may need to consider hospital capacity based on the number of cases in their region and they may want to bypass emergency rooms to lessen exposure risk.

“During the COVID-19 pandemic,” the guidelines state, “it is more important than ever to ensure that the patient is transferred to the right hospital the first time around.”

In all of this, communication between emergency crews and the receiving hospitals is key, the guide’s authors say.

“Now more than ever, during the COVID-19 pandemic, we need to work collaboratively and support our emergency medical services providers working day and night on the front lines for our community,” Southerland said. “To achieve this, we must optimize communication and pre-hospital care for patients. Nowhere is this more important than in rural networks like surrounding areas in Central Virginia.”

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