Research

Driving Discovery

The latest research highlights from University of Utah Health Sciences. See the News Room for more.

When it Comes to Preventing Clots, Deviating from Recommended Dosing Could Come with a Cost

Steinberg and colleagues found that 13 percent of patients did not receive proper dosing of non-vitamin K antagonist oral anticoagulants (NOACs), a specific kind of blood thinner, doubling risk for death in over dosed patients.

Oxygen Therapy No Benefit to Patients with Moderate COPD

Supplemental oxygen had no effect on delaying the time of death or first hospitalizations among COPD patients with moderate oxygen desaturation.

Richard E. Kanner, M.D.Professor of Internal Medicine, Division of Pulmonology

Physical Abuse More Than Doubles a Woman's Risk for Pelvic Adhesions

Women with a history of physical abuse face more than twice the risk of developing pelvic adhesions as women with no history of abuse, a new study finds.

Gene's Battle with Microbes Promotes Evolutionary Innovation in Humans

The lactoferrin gene arose in early mammals approximately 160 million years ago, and can still be found in the genomes of humans and other primates. New research shows that lactoferrin, whose original function was to transport nutrient metals such as iron, has undergone “rapid” evolution to develop another role – immune defense against microbes that cause potentially deadly diseases of meningitis, pneumonia and sepsis.

Tendon Issues and Rotator Cuff Tears Linked by Genetic and Environmental Factors

People with rotator cuff tears often experience other tendon or nerve problems as well, but it has been unclear whether those associated ailments are influenced by genetics or environment. New research shows strong evidence that those “global” tendinopathies in the shoulders, knees, hips and other areas appear to cluster among blood relatives and spouses of people with torn rotator cuffs, suggesting that both genetic and environmental factors are involved.

Zebrafish Findings Offer Explanation for Variability in Signs of Sepsis

When bacteria or other microbes enter the bloodstream they can trigger the activation of numerous host defenses as part of a process known as inflammation. While inflammation can promote the clearance of the invading microbes, it can also cause collateral damage to the body’s own cells and tissues. In extreme cases, the inflammatory pathways used by the body may spiral out of control, resulting in a life-threatening condition known as sepsis that can lead to organ failure and rapid death. Sepsis kills well over 250,000 people each year in the United States and is the most expensive condition to treat in hospitalized patients. Patients with sepsis are especially difficult to manage because the signs and symptoms of the disease can vary greatly between individuals. In patients with sepsis, the infecting microbes are usually viewed as generic triggers of inflammation while the patients themselves are considered the primary variables that affect disease progression and severity. This viewpoint is challenged by new work published in the April issue of the journal mSphere by researchers in the Department of Pathology at the University of Utah School of Medicine. The study shows that variations in just a single bacterial protein known as flagellin can significantly alter levels of inflammation and the progression of sepsis. Much of this work used a novel zebrafish infection model that mimics many of the key aspects of sepsis seen in human patients. A better understanding of how different flagellin variants differentially affect host inflammatory responses may help researchers develop improved diagnostic and therapeutic tools for sepsis and related diseases. Use of the zebrafish sepsis model may also facilitate the discovery of new treatments that can restore balance to out-of-control inflammatory pathways.

Older People with Low Levels of Bicarbonate at Higher Risk for Dying Prematurely

Otherwise healthy older people with low levels of bicarbonate, a major element in the body that helps maintain proper pH balance, were at a 24 percent higher risk of dying prematurely than those in a study group whose bicarbonate levels were normal or even high. Researchers analyzed information on 2,287 healthy black and white adults 70-79 years old who were part of the Health, Aging, and Body Composition (Health ABC) study, which began in 1997. Survival data were evaluated through February 2014 and study participants were followed for an average of more than 10 years. The analysis showed that people with normal or high bicarbonate levels had a similar risk of dying during the follow-up period, but those with low levels faced a substantially higher risk of dying earlier. Bicarbonate helps maintain proper pH balance, which is important to keep cells and organs working properly. However, the overall pH levels of participants in the study appeared to have no association with early death among people who had low bicarbonate levels. The study findings suggest that physicians might want to take a closer look at the bicarbonate levels in older patients to identify those at risk for dying prematurely.

Prevention Program Eliminates Bloodstream Infections in Burn Trauma Unit Patients

By implementing a program to prevent bloodstream infections associated with central-line catheters, the University of Utah Health Care Burn Trauma Intensive Care Unit eliminated those hazards entirely, a multidisciplinary committee of the health care system’s nurses and physicians reported in JAMA Surgery. Central-line catheters are inserted into patients’ veins to serve as a main port for delivering medications, antibiotics and other IV fluids, eliminating the need to insert new catheters each time a patient requires fluids or drugs. Such lines, however, can attract germs and lead to bloodstream infections in patients, an especially important issue in burn trauma intensive care units. The prevention program focuses on key elements to prevent central-line infections, such as ensuring that lines are inserted according to federal Agency for Healthcare Research and Quality recommendations, using alcohol-impregnated caps and following updated central-line care standards. The physicians and nurses looked at de-identified records of 478 patients who received central lines in University of Utah Hospital’s Burn Trauma Intensive Care Unit (BTICU) between April 1, 2011, and March 31, 2015. Study patients were divided into two groups: those who received burn care before Oct. 1, 2013, when the prevention program was started, and those who received burn care after that date. In the 30 months before the program started, 11 patients got central-line infections in the BTICU. But in the 18 months following the program’s inception until the end of the review period, the patient records showed no such infections, the researchers reported.  

Prevention Program Eliminates Bloodstream Infections in Burn Trauma Unit Patients

By implementing a program to prevent bloodstream infections associated with central-line catheters, the University of Utah Health Care Burn Trauma Intensive Care Unit eliminated those hazards entirely, a multidisciplinary committee of the health care system’s nurses and physicians reported in JAMA Surgery. Central-line catheters are inserted into patients’ veins to serve as a main port for delivering medications, antibiotics and other IV fluids, eliminating the need to insert new catheters each time a patient requires fluids or drugs. Such lines, however, can attract germs and lead to bloodstream infections in patients, an especially important issue in burn trauma intensive care units. The prevention program focuses on key elements to prevent central-line infections, such as ensuring that lines are inserted according to federal Agency for Healthcare Research and Quality recommendations, using alcohol-impregnated caps and following updated central-line care standards. The physicians and nurses looked at de-identified records of 478 patients who received central lines in University of Utah Hospital’s Burn Trauma Intensive Care Unit (BTICU) between April 1, 2011, and March 31, 2015. Study patients were divided into two groups: those who received burn care before Oct. 1, 2013, when the prevention program was started, and those who received burn care after that date. In the 30 months before the program started, 11 patients got central-line infections in the BTICU. But in the 18 months following the program’s inception until the end of the review period, the patient records showed no such infections, the researchers reported.  

Prostate Cancer Incidence Declines

The incidence of prostate cancer among U.S. men declined by nearly 20 percent beginning in 2011, a study of data from 2007 through 2012 shows. Researchers looked at prostate cancer diagnoses by age, race, stage of the disease and Gleason score–the most common system doctors use to grade prostate cancer cells based on the likelihood that a tumor will spread–and found that the decline in the disease occurred among all age groups of men. The incidence of low-grade tumors dropped by an estimated 29 percent, while that of high-grade tumors declined by nearly 11 percent. Stage I/II and III tumor incidences went down by 24 percent and almost 17 percent, respectively. Prostate cancer is the most commonly diagnosed cancer in U.S. men. Beginning in the 1980s, PSA tests became the standard for detecting prostate cancer. The incidence rate peaked in 1992 but has gradually declined since then. In May 2012 the United States Preventive Services Task Force recommended against giving PSA tests, citing research showing limited benefits and potential risks associated with prostate cancer screening.

Brain Circuits Disrupted in Mice Missing a Gene Implicated in Autism, Intellectual Disabilities

Alterations to brain circuits underpinning intellectual disability, autism and other neuropsychiatric disorders appear to be related to subtle cellular changes that occur when a gene is disrupted in the hippocampus–a major part of the brain needed for learning and memory, new research with mice has shown. Variations in the Kirrel3 gene are associated with autism spectrum disorder, intellectual disability and Jacobsen syndrome, a rare developmental disorder. In light of this association, Utah researchers studied how changes in Kirrel3 damage brain circuits that people need for learning and memorization. Their study found that the gene helps form part of the mossy fiber synapse, a large synapse in the hippocampus. Synapses are connectors that help brain cells, or neurons, to communicate through electrical and chemical signals. Any cognitive task a person undertakes–from tying shoelaces, to memorizing the alphabet, to solving complex problems–requires neurons to communicate with each other. The researchers found that in developing mice lacking the Kirrel3 gene part of the mossy fiber synapse was malformed, causing the hippocampus to become overactive. It has long been thought that intellectual disabilities arise from altered brain functions following even tiny changes to synapses. But what we do still do not understand, is exactly where these tiny changes occur. according to Megan Williams, Ph.D., assistant professor of neurobiology and anatomy and lead author on the study. In addition to the hippocampus, Kirrel3 is expressed in other areas of the brain that may also have impaired synapses that could contribute to neurodevelopmental disorders. Autism spectrum disorder, which affects the social and intellectual development of an estimated one in 68 U.S. children, according to recent studies.

Physical Therapy May Help Speed Lower Back Pain Recovery, But Problem Often Resolves Over Time

It’s estimated that 70 percent of people will experience low back pain (LBP) at some point in their lives. People with LBP often visit their primary care doctor in search of a prescription to end their pain. Sometimes this involves Physical Therapy (PT). University of Utah researchers found that while PT may hasten recovery somewhat, for many the problem will resolve itself with time. In a trial with 220 people with LBP, the researchers found that 108 patients who underwent physical therapy soon after the problem appeared received limited, short-term improvement in disability compared with 112 who received usual care–meaning no PT. When participants were evaluated at the end of three months, the early physical therapy group showed a slight improvement in the ability to carry out daily tasks and were somewhat more likely to be satisfied with their progress compared to the no-PT group. But a follow-up at 12 months showed no significant functionality difference between the two groups, nor was there a difference in pain intensity at four-week, three-month or one-year follow-ups with patients. Overall, patients in each group improved rapidly and the modest difference in disability relief between those who received early physical therapy and those who didn’t was not considered clinically important. While the overall difference in ability to function between the two groups was not significant, PT did benefit some patients, the study found. The researchers concluded that PT may be helpful for patients who want or need a little assistance in recovering from LBP, but patients can be optimistic that they will improve with time even if they do not receive PT.  

Pharmacist-led Telemonitoring Aids Diabetes Patients in Lowering A1C

Diabetes patients whose disease management was overseen by a pharmacist via telemonitoring significantly lowered their A1C levels compared to those who received standard diabetes care, a study with 150 patients has shown. The researchers divided the study participants into two groups of 75 patients each. The group whose care was led by a pharmacist via telemonitoring saw an A1C decline of 2.07 percent from their baseline levels compared to a 0.66 percent baseline decrease in the standard-care group. The study lasted six months. Telemonitoring sessions were held once a day Monday through Friday and lasted five to 10 minutes. Telemonitoring patients received one of two devices for the study. They used their own glucometers to measure A1C levels as well as a digital scale provided to them to monitor their weight and blood pressure monitors that came with the telemonitoring device or were given to them. A1C and LDL levels, as well as weight and blood pressure readings, were transmitted electronically to the pharmacist, who checked to ensure they were within ranges determined to be acceptable at the outset of the study. Patients also answered several questions during each telemonitoring session, incuding whether they had taken their medication. While A1C levels in the telemonitoring group decreased significantly at the end of six months, declines in blood pressure and LDL (low density lipoprotein) cholesterol were not statistically significant between the two groups. Studies by other researchers have shown, however, that pharmacist-led care can result in lower blood pressure. Patients also received weekly diabetes care education sessions. The study showed not only that pharmacist-led diabetes care could result in better disease management but also that diabetes patients could improve their own management of the disease.

Chlamydia Associated with Fourfold Risk of Gastroschisis in Newborns

Positive antibody tests for chlamydia trachomatis in pregnant women were associated with almost a fourfold higher risk for gastroschisis in their newborns, a pilot study found. The study included 33 pregnant women whose prenatal ultrasounds showed their fetuses had gastroschisis (cases), a protrusion of the intestine, and sometimes other organs, through a hole in the abdominal wall, and a group of 66 pregnant women (controls) whose ultrasounds showed no fetal abnormalities. Evidence of a recent chlamydia infection in the mothers-to-be was confirmed by blood tests. The researchers also found that cases were significantly more likely to be younger than controls, less educated, smoke cigarettes, report having a previous sexually transmitted disease and, among those who’d been pregnant before, report a different sexual partner with their current pregnancy. Cases also reported a lower median age when they became sexually active and a greater number of sexual partners than controls, putting them at greater risk for getting a sexually transmitted disease.  Chlamydia is the most common sexually transmitted disease. It can cause infertility and is becoming a public health issue as its occurrence increases. This study was the first step to better understanding the relationship between chlamydia infections and gastroschisis. Future research will investigate chlamydia-related inflammation. 

Rotator Cuff Tear? For Some People It's in the Genes

Hundreds of thousands of people experience rotator cuff tears every year, and it appears that some of them might well be able to blame the painful condition on two gene variations. In a study that looked at 311 cases of people with confirmed rotator cuff tears and 2,641 genetically matched controls without the problem, researchers identified two gene variations—SAP30BP and SASH1—that had significant associations with the condition. Called a genome-wide association study, the research examined more than 250,000 genetic variations, or SNPs, to look for any that were associated with rotator cuff tears. SAP30BP and SASH1 respectively reside on chromosomes 17 and 6, and each of the variations plays a role in apoptosis, or cell death. Prior research, including work by the authors of this study, suggested that rotator cuff tears had a genetic origin, but no specific genes had been identified until now. Rotator cuff tears have been associated with various associated factors, including trauma, overuse in sports (such as tennis), inflammation and aging. This study is the first attempt by genome-wide association to identify genetic factors influencing rotator cuff tears.

Sea Snail's Toxic Venom May Bring Relief to People with Chronic Neuropathic Pain

University of Utah researchers identified a new potential pain management medication that has broad implications for the treatment of chronic neuropathic pain due to injury to the nerves, spinal cord or brain. This discovery is the result of a collaborative study of the deadly venom from predatory marine cone snails (Conus generalis) that are indigenous to the South China Sea. The findings were published in the Proceedings of the National Academy of Sciences.

In a study with rats, the U researchers and colleagues at identified a peptide, GeXIVA alphaO-contoxin, found in the venom of the cone snails  appears to relieve pain without impairing motor skills, suggesting it does not cross the blood-brain barrier as most narcotic pain medications do. In addition, the analgesic effects of GeXIVA occur at much lower doses with greater than or equal effects of the opioid morphine. “This new information may lead to a new treatment for chronic and debilitating pain in millions of people around the world,” says J. Michael McIntosh, Ph.D., professor of psychiatry at the University of Utah. “We have identified a previously unrecognized peptide, GeXIVA, for the treatment of persistent pain.”

Neuropathic pain can result from damage to nerves from diabetes, degenerative disc disease, and tumors pressing on the nerves, infection, repetitive motion disorders and many other conditions. In some cases doctors cannot find an exact cause of the pain but it is constant and can be intense. There is no completely effective treatment for this type of severe incessant pain. But identifying this novel mechanism for pain management opens the door for further research and future clinical trials of medications.

The U researchers collaborated with colleagues from Hainan University, Haikou Hainan, China; the University of Queensland, Brisbane, Australia; Russian Academy of Sciences, Moscow; Kirksville College of Osteopathic Medicine, Kirksville, Mo.

Understanding a Crucial Process in Mitochondrial Health

Mitochondria are the powerhouses inside cells – they harness oxygen to produce the energy cells need to perform their normal activities.  In addition, mitochondria act as important sentinels monitoring cellular health, and can trigger programmed cell death (known as apoptosis) if cells are not functioning normally.  However, mitochondria themselves can become dysfunctional, releasing toxic factors that damage the cells that contain them, resulting in diseases such as diabetes, non-alcoholic fatty liver disease and a variety of neurological conditions such as Parkinson's disease, ALS, and Alzheimer's disease.  Therefore, understanding how mitochondrial health can be maintained could provide breakthrough strategies for preventing or treating many conditions.

When mitochondria grow old or become damaged, they are normally "rounded up" and delivered to lysosomes, a part of the cell that functions as a trash disposal and recycling facility.  Lysosomes contain acid and enyzmes that breakdown cellular components allowing them to be recycled or used for making energy.  This process is known as 'mitophagy' (Greek for 'eating of mitochondria'), and there is increasing evidence that many diseases associated with accumulation of damaged or dyfunctional mitochondria are caused in part by defective mitophagy.

Until recently, studies of mitophagy were very laborious, requiring researchers to analyze one cell at a time to determine how effectively cells are recycling their old and damaged mitochondria.  A team led by Timothy Graham, M.D., associate professor of internal medicine in the Molecular Medicine Program at the Utah Diabetes and Metabolism Center, and Ashot Sargsyan, a graduate student in biological chemistry, recently reported development of a ground-breaking method that enables researchers to measure mitophagy in tens of thousands of cells in just a few seconds.  They made use of a newly developed fluorescent protein probe that they attached to mitochondria inside cells.  When mitochondria are delivered to lysososomes the probe changes color indicating that mitophagy is occurring.  By coupling this method with high-throughput cell analyzers this method will allow researchers to screen thousands of drugs or gene therapies a day to identify new approaches to enhancing mitophagy in cells, or inhibiting process that lead to deficient mitophagy.

Diabetes Patients Fare Better When Pharmacist Leads Follow-up Care

Type 2 diabetes patients may do better controlling their blood sugar levels when they receive follow-up primary care from a team of providers led by a clinical pharmacist. Further, a study led by a University of Utah College of Pharmacy faculty found that a pharmacist-led Diabetes Collaborative Care Management Program (DCCM) could better hold the costs of medical care. The researchers conducted the study using de-identified medical records of Type 2 diabetes patients who’d had trouble controlling their blood sugar levels and were treated at patient-centered, community-based primary care clinics in the greater Salt Lake City area. The study looked at patients whose drug management was led by a clinical pharmacist and those whose plan was not managed by a clinical pharmacist and compared health care outcomes, how often they saw their providers and the total health care costs of each group. “A pharmacist-led diabetes collaborative care management program in a patient-centered primary care setting was associated with significantly better follow-up glycemic control relative to comparison patients,” the researchers reported in the June 2015 issue of the Journal of Managed Care & Specialty Pharmacy. The data also suggested that the DCCM program was associated with a less substantial increase in all-cause total costs in patients with uncontrolled Type 2 diabetes relative to the comparison patients. This could help reduce costs of managed care payers, the researchers reported.

'Cold' Comfort: Study Shows Freezing Doesn't Harm Epinephrine

Millions of people use epinephrine to fend off potentially life-threatening anaphylactic reactions because of allergies to medications, foods, insect stings and other triggers. People susceptible to anaphylactic reactions experience swelling, hives, low blood pressure, dilated blood vessels and other symptoms, which, if not treated immediately, can be fatal. The most common treatment is the use of a needle-and-syringe auto injector that delivers epinephrine into the body to relieve the symptoms. In the backcountry, the drug can be exposed to extremely cold temperatures when people ski, climb mountains and backpack during winter. The maker of a widely used auto injector of epinephrine, EpiPen, recommends replacing the device if it gets frozen. Researchers at the University of Utah School of Medicine and two physicians in Jackson Hole, Wyo., wanted to find out if epinephrine can remain effective even if it freezes. In a study published in Wilderness and Environmental Medicine, they report that after freezing and thawing vials of epinephrine over a period of seven days–to temperatures as low as 13 below zero Fahrenheit–the solution maintained a concentration within limits considered safe for use in emergency situations. The study, although small, provides evidence that epinephrine does not degrade after freezing and thawing, the researchers report. This information is beneficial to those who recreate in the backcountry and have the potential for severe allergic reactions.

Smokers Fare Worse Than Nonsmokers After Spine Surgery

Along with its many other harmful effects, smoking cigarettes appears to adversely affect the outcomes and total costs of patients who undergo surgery for spinal disease.

University of Utah School of Medicine researchers looked at the de-identified records of 122,608 non-smokers and 13,903 smokers treated in hospitals belonging to the University HealthSystem Consortium (UHC). The study looked at patients in the four largest diagnostic groups: fracture, dorsopathy (deviation from or interruption of the normal structure or function of the spine), congenital spine disease and spinal curvature. Outcomes were based on five categories—length of stay; ICU admissions; hospital readmissions, complications and total cost.

The researchers found that compared to nonsmokers patients who smoke tobacco had longer hospital stays, higher admission rates to ICUs, higher hospital readmission rates, more complications and worse outcomes in three of the four diagnostic groups—fracture, spinal dorsopathy and spinal curvature. Smoking patients also had higher total hospital costs than non-smokers in all groups, with increases of 23 percent and 36 percent, respectively, among smokers in the two largest diagnostic groups, dorsopathy and fractures. Outcomes across all categories on those two groups were worse among smokers. 

While more studies are needed to better define the association between smoking tobacco and worse outcomes in spine surgery patients, the authors advise surgeons to encourage spine surgery patients to enroll in formal smoking cessation programs before undergoing an operation.

Study Finds Smoking Is Not a Primary Risk Factor for Multiple Myeloma

The connection between cigarette smoking and various cancers long has been established, but whether the habit is a risk for multiple myeloma has been an open question. A new study by the International Multiple Myeloma Consortium (IMMC) has found that smoking appears not to be a primary risk factor for the cancer.
 
Health systems and academic medical centers from across the United States, Canada and Europe, including the University of Utah, studied 2,670 individuals  with myeloma and 11,913 controls without myeloma. Smoking histories (current, former, those who tried cigarettes but didn’t take up the habit, and those who had never smoked) were compared between the myeloma cases and the controls. Their analysis found that the multiple myeloma cases were not enriched for smokers when compared to controls.
 
Nicola Camp, Ph.D., U of U genetic epidemiologist, professor of medicine and co-author on the study, contributed data from myeloma cases and controls in Utah that were ascertained through the Utah Cancer Registry, Huntsman Cancer Institute Clinics and the Utah Population Database.
 
The only consistently and currently recognized increased risk factors for multiple myeloma are aging and being male or African American, according to Camp. More research is needed to understand risk to this cancer. In particular there is good evidence for genetic risk factors and her work focuses on the identification of these.
 
Gabriella Andreotti of the National Cancer Institute (NCI) in the National Institutes of Health  (NIH) is the corresponding author on the study, and Mark Purdue, also of the NCI and NIH is the senior author.

Critical Immune Factors May Haved Adapted to Evade Common Pathogen Inhibitors

A pathogen’s ability to infect new individuals within and across species is largely driven by its capacity to hijack cellular machinery and overcome the immune system. Pathogens have evolved multiple means to evade and shut down host immunity. Typically, mechanisms of inactivation involve direct interactions between host and pathogen factors. To escape inhibition over the course of generations, host factors frequently evolve in a manner that disrupts interactions at specific interfaces with pathogen factors. Likewise, pathogens adapt to restore such interactions, and these genetic tug-of-wars have been described as “molecular-arms races.” University of Utah researchers focused on the adaptation of two critical host immune factors, cGAS and OAS, which share identity in protein structures despite very limited genetic similarity. Their analysis identifies a variety of ways, including amino acid changes on protein surfaces, by which these host factors appear to escape pathogen-mediated inhibition. Surprisingly, some amino acid substitutions are located at equivalent sites suggesting that cGAS and OAS may have adapted to evade common pathogen encoded inhibitors. These data also identify protein surfaces that are targeted by viruses to inhibit host immunity. Taken together the study results indicate the existence of critical, yet-to-be identified viral antagonists of cGAS and OAS.

Mutations in RAG1 Gene Linked to Even More Immunodeficiency Diseases

In a multi-institution study published in the Journal Clinical of Immunology, University of Utah researchers and colleagues have extended the spectrum of diseases caused by mutations in the RAG1 gene to include antibody deficiency diseases. They made the discovery after identifying a deficiency in RAG1 in two patients who were diagnosed with common variable immunodeficiency (CVID), an antibody deficiency disorder that leads to recurrent infections, such as pneumonia, and other complications. Antibodies, also known as immunoglobulins, identify and neutralize infectious agents, and a decrease in antibody production leads to infections.

Various mutations in the RAG1 gene already were know to cause a number of immune deficiencies, such as severe combined immunodeficiency and Omenn syndrome. RAG1-deficient patients are predicted to have high risk of life-threatening infections, therefore the identification of these mutations suggests treatments not usually considered for patients with CVID. The study shows that single-gene testing for most immunodeficiency diseases is not enough and that gene panels, exome sequencing and soon whole genome testing must be used to diagnose them, according to senior author Attila Kumánovics, M.D., of the ARUP Institute for Clinical and Experimental Pathology and assistant professor of pathology at the University of Utah.

The study's first author is David Buchbinder, of the Children’s Hospital of Orange County, Calif., and the National Institutes of Health.

An 'SOS' for Metabolic Stress

Upon viral invasion, the body launches its defenses in an effort to fight the infection. When a protein called PKR binds double-stranded RNA (dsRNA) made by viruses, the act signals that the fight is on. Several years ago, Dr. Gökhan Hotamisligil from Harvard University, a collaborator in this study, reported that mice fed an unhealthy, high-fat diet activated PKR even in the absence of viral infection. This surprising result prompted Dr. Brenda Bass and her team at the University of Utah to search for molecules that activated PKR during metabolic stress. Unexpectedly, they found that this function was performed by small nucleolar RNAs (snoRNAs) from our own bodies, known primarily for their role in modifying RNA. A key question for future studies is whether the interaction between PKR and snoRNAs can be modulated to control the chronic inflammation that occurs in metabolic stress disorders like obesity and diabetes.

Brenda L. Bass, Ph.D.

A Critical Link in the Assembly and Spread of HIV-1

To multiply and spread infections, viruses must enter and exit cells. Once inside a cell, many viruses take over the cell’s machinery to produce new viral particles and release them into the surroundings. Some viruses—including HIV-1—exit the cell in a manner that wraps them in membrane from the host cell. A virus protein called Gag is required for the release of HIV-1 and other retroviruses. In some cases, Gag proteins bind directly to members of the NEDD4 protein family to facilitate virus release. However, the Gag protein from HIV-1 does not appear to interact directly with NEDD4 proteins, so it was not clear how this virus connects to these proteins. In a study with laboratory-grown human cells, University of Utah researchers show that members of another human protein family called the Angiomotins are required to wrap the HIV-1 virus in membrane, act as a link between Gag and NEDD4L (one member of the NEDD4 family), and are necessary for efficient virus release from human cells.

Genetic Counseling Helps Parents Cope with 'Uncertain' Genetic Test Result in Children

Chromosomal microarray is the recommended first-tier genetic test when a child presents with idiopathic developmental delay, intellectual disability, and/or autism spectrum disorder. This type of testing, which can simultaneously detect genetic abnormalities on all chromosomes, may discover variants of unknown clinical significance (VUS). When a genetic test determines a child’s disability or disorder is “uncertain,” it can cause parental stress and anxiety. In this study, University of Utah researchers surveyed parents of children with a disability or disorder about their understanding of an uncertain genetic test result and its impact on stress and anxiety. Parents reported that this result was important for understanding their child’s diagnosis and they were satisfied with the information. A majority of parents reported high confidence in their ability to explain an uncertain genetic test result to others. Many of them also stated they received support from a genetic counselor. Based on these survey results, uncertain genetic results are important to parents of children with VUS and genetic counseling regarding uncertain results contributes positively to both parental understanding and support. Stephanie Jez, a student in the University of Utah Graduate Program in Genetic Counseling, led the project.

Alveolar Soft Part Sarcoma Thrives on Lactate

Model systems for the study of cancer come in many varieties. Each model transfers some aspect of a human cancer into an experimental setting, such as a culture dish or animal model, to recreate features of the cancer and teach researchers more about its cell biology.  The point of any model's experimental setting is to enable direct testing of cause and effect relationships. Researchers led by Kevin B. Jones, M.D., transferred no more than a single gene from a human cancer called alveolar soft part sarcoma into a mouse. That gene alone then generated a very precise mimic of the original cancer, proving that the gene serves as the central driver of alveolar soft part sarcoma. Further testing with the mice that spontaneously grew these sarcomas further demonstrated that this particular cancer type prefers to grow in tissues with high levels of lactate, a byproduct made when sugar breaks down. By altering the concentrations of lactate to which a tumor was exposed, the investigators were able to alter its growth and behavior. Contrary to old dogma that considered lactate only a waste product, the team proved that these cancers soak in lactate from their surroundings and thrive on it. Work is under way to test means of blocking this use of lactate as a means of stopping tumor growth.

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A single layer of cells acts like a protective skin for the organs in the human body, but this protective layer also is prone to forming tumors. Normally, these protective cells are dividing constantly and when they become too numerous, some are kicked out to die by a process these researchers have found called “extrusion.” Recently, they found that extrusion is defunct in some of the most aggressive tumors—pancreatic and lung carcinomas—and that instead of dying the cells accumulate and are resistant to chemotherapy. Additionally, some cells can pop into instead of out of the tissue, which could enable them to move to other organs and metastasize—an even more deadly prospect. From learning this basic cellular mechanism for how cells should die, the researchers identified a chemical way to bypass the defects seen in pancreatic cancer without affecting the normal tissue, which could provide a new therapy for these deadly tumors.

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Although undocumented residents comprise an estimated 28 percent of the foreign-born U.S. population, their care is less costly and their use of emergency services less frequent than their native-born counterparts. That’s not necessarily good news. Undocumented residents may avoid seeking health care because they are twice as likely to be uninsured or because they fear surveillance or deportation when accessing health services. Their absence from the health care arena partially explains undocumented residents’ health care disparities. “Nurses have an ethical responsibility to advocate for undocumented individuals’ access to care,” wrote Lauren Clark, Ph.D., FAAN, University of Utah professor of nursing and co-author of a piece examining the issue of health care for undocumented residents. “Advocacy might include assuring a qualified interpreter is present for care. Sometimes advocacy is listening to a person’s life experience and humanizing their care during that encounter.” Clark conducted the study with colleagues at the University of South Carolina and University of Arizona.

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As the cost of U.S. health care continues to skyrocket, University of Utah surgeons and other researchers have found a way to both decrease cost and improve outcomes as they treat appendicitis, the most common surgical emergency in children. In a study with 580 patients treated for non-ruptured appendicitis, they found that introducing a protocol to eliminate variability in treatment could reduce the duration of hospital stay and total cost of care by 20 percent, while decreasing the rate of readmission, reoperation and other complications. The protocol standardized everything from the evaluation to diagnose appendicitis to the type, dose, duration and timing of prescribing antibiotics before surgery. David E. Skarda, M.D., the study’s first author, says this shows how applying principles learned in the manufacturing industry to health care is safe, decreases cost and improves outcomes. 

A “Hybrid” Approach to Urine Testing for Compliance with Long-Term Drug Use

Urine drug testing is a common tool for evaluating compliance with long-term, prescribed medications, such as for managing chronic pain, and for assuring abstinence from illegal or non-prescribed medications. This "compliance testing" requires a different approach from the traditional urine drug testing that is common to the workplace, military or among athletes. The approach for compliance testing is not currently standardized. To address this, University of Utah and Associated Regional University Pathologists (ARUP) researchers developed a unique method for urine drug testing that is designed specifically to meet the needs of compliance testing.  The approach is called a "hybrid" because it combines several analytical methods, including high-resolution mass spectrometry and immunoassays, that were selected to optimize quality of testing and time to result, as well as to reduce the overall costs of testing.

Chemical Warfare: Cone Snails Use Insulin as Weapon to Disable Fish

Cone snails lack the speed and other advantages that most predators use, but they’ve made up for it by evolving a venom cocktail that disables fish and, a new study reveals, includes a weaponized form of insulin. A synthetic form of the insulin caused blood glucose levels to plummet when injected into zebrafish and also disrupted swimming behavior in fish exposed to it through water contact. The researchers propose that adding the insulin to the cone snail’s venom cocktail enables some types of the predatory snails to disable entire schools of fish with hypoglycemic shock. The snail insulin potentially can aid researchers in studying how the human body controls blood sugar and energy metabolism.

Multiple C-sections Linked to Ectopic Pregnancies

Women who delivered two or three babies through cesarean section were at a substantially higher risk for a subsequent ectopic pregnancy compared with women who gave vaginal birth or had one C-section, University of Utah researchers report in a recent study. Using the Utah Population Database, a unique storehouse of genealogical, health and public records, the researchers evaluated 255,082 women who gave live birth in Utah between 1996 and 2011. They found that those with two of two, two of three, or three of three prior C-sections were 1½ to 3½ times more likely to have ectopic pregnancies than women who’d never had a C-section. Women who had one prior cesarean section delivery faced no greater risk than women who’d given vaginal birth.  These findings underscore another downstream risk of the increasing rate of cesarean delivery.

Retinal Swelling Sensor Identified as Possible Target for Treating Eye and Brain Diseases

Researchers identified the cellular mechanism that controls swelling in retinal cells, a discovery with implications for treating brain and eye diseases and traumas resulting from swelling. Their study brings three new insights: First, it identifies an ion channel (TRPV4) as the retina’s swelling sensor and shows it is activated and regulated differently in neurons versus glial cells (the most numerous cells in the central nervous system.)  Second, it determines the molecular link between glial swelling and inflammatory signaling by linking TRPV4 activation to a fatty acid known to exacerbate brain pathology during swelling. Third, it shows that calcium signaling in retinal neurons and glial cells is required in the cells’ response to swelling and mechanical stress. These discoveries mean the TRPV4 ion channel might be targeted to treat brain and eye diseases related to swelling.      

Scalpel or Scope? Costs Influence Consumers

Consumer price comparison is almost nonexistent in the U.S. health care system, but University surgeons show in a study that when given the choice between a less costly "open" operation or a pricier laparoscopy for their children's appendicitis, parents were almost twice as likely to choose the less expensive procedure - when they were aware of the cost difference.

The study, shows that providing pricing information upfront can influence patient choice of surgical procedures and potentially lead to cost savings in health care, a sector of the economy that accounts for more than 17 percent of the U.S. Gross Domestic Product, says Eric R. Scaife, M.D., senior author, associate professor of surgery and chief of pediatric surgery. Surgery resident Katie W. Russell, M.D., is the study's first author.

Mouse Model Provides Window into the Working Brain

University of Utah scientists developed a genetically engineered line of mice that is expected to open the door to new research on epilepsy, Alzheimer's and other diseases.

The mice carry a protein marker, which changes in degree of fluorescence in response to different calcium levels. This will allow researchers to study many cell types, including astrocytes and microglia, in a new way. John White, Ph.D., professor of bioengineering and executive director of the Brain Institute, is corresponding author of the study. Peter Trvdik, Ph.D., a fellow in human genetics, is senior author, and J. Michael Gee, who is pursing and M.D. and graduate degree in bioengineering, is first author.

8,000-Year-Old Mutation Key to Human Life at High Altitude

Researchers long have known of a connection between mitochondrial function and distribution and neural disease, but they hadn’t been able to tell whether a defect occurs because mitochondria isn’t functioning properly or isn’t getting to the right.

Biochemistry professor Janet Shaw, Ph.D., and M.D./Ph.D. student Tammy T. Nguyen led a study that addressed that question and found that when mitochondria weren’t distributed along the spinal cord and axons in mouse models they developed, the animals developed symptoms of neurodegenerative diseases.

If Mitochondria Don't Move, Motor Neuron Disease May Develop

Researchers long have known of a connection between mitochondrial function and distribution and neural disease, but they hadn’t been able to tell whether a defect occurs because mitochondria isn’t functioning properly or isn’t getting to the right.

Biochemistry professor Janet Shaw, Ph.D., and M.D./Ph.D. student Tammy T. Nguyen led a study that addressed that question and found that when mitochondria weren’t distributed along the spinal cord and axons in mouse models they developed, the animals developed symptoms of neurodegenerative diseases.

Janet Shaw