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University of Arizona valley fever research seeks why some get sicker

Arizona Daily Star

​​By: Stephanie Innes Arizona Daily Star – Apr 16, 2017

Researchers at the University of Arizona hope a $2.27 million federal grant will help them build a genetic profile of people who get severely ill from valley fever.

Some genetic factors are already known to put people at higher risk for the potentially deadly respiratory disease — gender, blood type and ethnicity. Other risk factors include a compromised immune system and pregnancy.

The biggest risk factor is geography: More than 65 percent of all valley fever cases in the U.S. occur in Arizona, and 30 percent occur in California. Most other cases occur in Nevada, Utah and New Mexico. Nearly 6,200 cases of valley fever were recorded in Arizona last year, including 54 deaths, preliminary state health data show.

But UA researchers want to focus on the specific genetics of those who get very sick with the disease and are neither pregnant nor immunocompromised, said Dr. John Galgiani, director of the UA’s Valley Fever Center for Excellence.

“It’s a major commitment to understanding why some people get really bad (valley fever) disease,” Galgiani said. “I can’t remember funding for that from the NIH in a long time.”

200 PATIENTS

The UA researchers are hoping to include about 200 patients in their study, which is called “Immuno-Genetic Basis for Human Disseminated Coccidioidomycosis.” Coccidioidomycosis is the scientific name for valley fever.

One result could be the ability to tell a patient with a particular DNA sequence that if they were to get valley fever, it would disseminate. When valley fever disseminates, that means it goes to the bloodstream, moving from the lungs to the skin, bones and joints, the spinal cord, and brain.

Or if that same patient were to get pneumonia and get a valley fever diagnosis, then medical providers may have to be more aggressive about treating it.

The four-year grant is from the National Institutes of Health (NIH) and technically amounts to $2.7 million, Galgiani noted, as the NIH will do part of the work and has been awarded $500,000 for its role.

NIH researcher Dr. Steven Holland will be a co-investigator along with the UA team, which includes Galgiani and Dr. Yves Lussier, who is the associate vice president and director of the Center for Biomedical Informatics and Biostatistics at UA Health Sciences as well as associate director of the UA’s BIO5 Institute.

SEVERE ILLNESS

Current research shows one of every three people who inhales a coccidioides fungal spore gets sick enough to go to a doctor. In one of every 200 people who get sick, the valley fever disease disseminates.

Studies have already found higher rates of disseminated valley fever in men than in women, and in African Americans and Filipinos versus other ethnic groups. Also, certain blood groups — B and AB — have been identified in studies as more likely to get the disseminated version of the disease.

But Galgiani said the UA researchers are looking for more specifics.

“We want to know the mechanisms. …We have associations but we don’t actually know what differences drive those associations,” he said. “The associations are not all-or-none. African Americans have a higher rate of severe disease, but most African Americans still don’t get severe disease.”

Galgiani is hoping researchers might also understand whether any genetic factors might prevent a vaccine from working on people with disseminated valley fever.

“An underlying question about vaccines is would they actually help the people who would benefit the most?,” Galgiani said. “We’re going to address that. It could be the vaccine works only for people who don’t get disseminated cocci.”

In a separate project, UA researchers are working with a veterinary startup on developing a live vaccine against valley fever made from a mutant fungal spore. The research team, which has applied for a separate NIH grant for the vaccine development, is hopeful the vaccine will work on both humans and dogs.

DEATH FROM VALLEY FEVER

Sue Medinger, who lost her husband to disseminated valley fever Aug. 24, says anything that will focus more on valley fever awareness and prevention is a step in the right direction.

The Medingers divided their time between Tucson and San Antonio, and Sue is certain her husband contracted valley fever in Tucson, where the couple owned a townhome. Her husband, Joseph David Medinger, was an avid UA Wildcats fan. The couple got engaged in front of Old Main in 1966 and were married here in 1968.

Yet no one in the family, nor the doctors they saw in Texas, suspected valley fever until it was too late, Sue said. Her husband, who also had diabetes, was admitted to the emergency room with what appeared to be severe pneumonia just days before he died at the age of 71. Initially, doctors thought he might have tuberculosis, she said.

“It is hard to know he might have been saved if we’d had the right information,” Sue said. “There’s just not enough awareness.”

Galgiani said awareness and the purpose of the latest grant are not mutually exclusive.

“Knowledge is valuable. If we know exactly, we might be able to replace what’s missing, or suppress what’s too much therapeutically and prevent you from disseminating,” he said. “If you know it’s broken, you can more likely fix it.”

It may turn out that people with disseminated valley fever have a slow immune response to the disease, Galgiani said.

“The reason that is so important is that means that a vaccine actually would prevent it. If you vaccinate them and bring up that immunity way before they see the infection, they are now immune.

“So this work has real practical value. We’re trying to help patients with this. That’s why the NIH funded it.”

Resources: Innes, S. (2017, April 16). University of Arizona valley fever research seeks why some get sicker. Retrieved February 26, 2018, from http://tucson.com/news/university-of-arizona-valley-fever-research-seeks-why-some-get/article_0656d381-0654-5a80-b5cb-c0317c50441f.html 

Plant Toxin Causes Biliary Atresia in Animal Model, According to Penn Study – 

Rare disease of developing liver most common reason for liver transplant in children

​​By: Karen Kreeger – Wednesday, May 6, 2015

​A study in this week’s Science Translational Medicine is a classic example of how seemingly unlikely collaborators can come together to make surprising discoveries. An international team of gastroenterologists, pediatricians, natural products chemists, and veterinarians, working with zebrafish models and mouse cell cultures have discovered that a chemical found in Australian plants provides insights into the cause of a rare and debilitating disorder affecting newborns. This ailment, called biliary atresia (BA), is the most common indication for a liver transplant in children.

The team isolated a plant toxin with a previously uncharacterized chemical structure that causes biliary atresia in zebrafish and mammals, noted collaborators Michael Pack, MD, a professor of Medicine in the Gastroenterology Division and the department of Cell and Developmental Biology, and Rebecca Wells, MD, an associate professor of Medicine in the Gastroenterology Division and the department of Pathology and Laboratory Medicine, both at the Perelman School of Medicine, University of Pennsylvania.

BA is a rapidly progressive and destructive disorder that affects the cells lining the extra-hepatic bile duct. The cells within this large duct, which carries bile from the liver to the small intestine, are damaged as the result of an as-yet-unidentified environmental insult, a toxin or infection, resulting in scarring (fibrosis) that obliterates the duct, thus preventing bile flow.  

The incidence of BA is 1/10,000 to 15,000 live births. It occurs worldwide and is one of the most rapidly progressive forms of liver cirrhosis and liver failure. Fortunately, a life-saving treatment for BA is available for babies, a surgical procedure called a Kasai portoenterostomy, in which a small segment of intestine is connected directly to the liver, to restore bile flow. Most babies, though, eventually develop cirrhosis of the liver and ultimately liver failure, leading to the need for a transplant either in infancy, childhood or adolescence. 

Working with pediatric gastroenterologists Elizabeth Rand, MD and David Piccoli, MD and other colleagues at the Fred and Suzanne Biesecker Pediatric Liver Center at The Children’s Hospital of Philadelphia, Pack and Wells became interested in a naturally occurring BA model reported by veterinarians in Australia. During years of extreme drought over the last four decades, sheep and cows grazed in unusual pastures had given birth to offspring with a BA-like syndrome that was essentially identical to human BA. Field veterinarian Steve Whittaker, BVSc, and veterinary scientist Peter Windsor, DVSc, PhD, who diagnosed BA in lambs during a drought in 2007, correlated the outbreaks with ingestion of plants in the genus Dysphania, including a plant called pigweed, that grew on lands normally under water, suggesting a toxic cause of the animal BA 

“The 2007 drought persisted through 2008, enabling us to harvest Dysphania species plants from a pasture implicated in the 2007 episode,” recalls Wells, who initiated the collaboration by contacting Whittaker soon after the 2007 outbreak and arranged to have the plant harvested and imported into the U.S. “With the plant in hand, we knew we had a chance to identify the responsible biliary toxins, guided by a zebrafish bioassay devised in my laboratory,” adds Pack. 

To continue reading this article go to https://www.pennmedicine.org/news/news-releases/2015/may/plant-toxin-causes-biliary-atr

Resource: Kreeger, K. (2015, May 6). Plant Toxin Causes Biliary Atresia in Animal Model, According to Penn Study – PR News. Retrieved from https://www.pennmedicine.org/news/news-releases/2015/may/plant-toxin-causes-biliary-atr 

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