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Researchers say climate change may accelerate infectious disease outbreaks

Aside from inflicting devastating natural disasters on often vulnerable communities, climate change can also spur outbreaks of infectious diseases like Zika , malaria and dengue fever, according to a new study by researchers at the University of  Colorado Anschutz Medical Campus.

“Climate change presents complex and wide-reaching threats to human health,” said Cecilia Sorensen, MD, lead author of the study and the Living Closer Foundation Fellow in Climate and Health Policy at CU Anschutz. “It can amplify and unmask ecological and socio-political weaknesses and increase the risk of adverse health outcomes in socially vulnerable regions.”

When natural disasters strike such places, she said, the climatic conditions may make the public health crisis significantly worse.

Dr. Cecilia Sorensen, lead author of the study and the Living Closer Foundation Fellow in Climate and Health Policy at CU Anschutz.
Dr. Cecilia Sorensen, lead author of the study and the Living Closer Foundation Fellow in Climate and Health Policy at CU Anschutz.

The researchers said these vulnerabilities can happen anywhere. After Hurricane Katrina hit New Orleans, cases of West Nile disease doubled the next year. Climate change in Africa appears to be increasing cases of malaria. And the recent destruction in Houston, Florida and Puerto Rico due to hurricanes may usher in more infectious diseases in the years ahead.

The study focused specifically on a magnitude 7.7 earthquake that struck coastal Ecuador in April 2016, coinciding with an exceptionally strong El Niño event. El Niños are associated with heavy rainfall and warmer air temperatures. They are also linked to outbreaks of dengue fever.

Sorensen, a clinical instructor in emergency medicine at CU Anschutz, was in Ecuador with her co-authors working with the Walking Palms Global Initiative. They were operating a mobile health clinic after the disaster.

“We were seeing all of these viral symptoms in the wake of the quake,” she said. “We noticed a huge spike in Zika cases where the earthquake occurred. Prior to this, there were only a handful of Zika cases in the whole country.”

In fact, the researchers found the number of Zika cases had increased 12-fold in the quake zone.

Zika virus is transmitted by mosquitos. Symptoms are usually mild but the infection can cause major abnormalities and even death in a developing fetus.

Warmer temperatures and increased rainfall from the El Niño, along with a devastated infrastructure and an influx of people into larger cities, likely caused the spike in Zika cases, Sorensen said.

Natural disasters like Hurricane Katrina can spur outbreaks of infectious disease.
Natural disasters like Hurricane Katrina can spur outbreaks of infectious disease.

“We saw so many people affected by the earthquake that were sleeping outside without any shelter from mosquitoes, so we were worrying that the region’s changing climate could facilitate the spread of diseases,” she said. “Natural disasters can create a niche for emerging diseases to come out and affect more people.”

Sorensen’s team reviewed the existing research on the link between short-term climate changes and disease transmission. They applied those findings to explain the role of the earthquake and El Niño in the Zika outbreak.

They suggest El Niño created ideal conditions for Zika-carrying mosquitos to breed and make more copies of the Zika virus. The warmer temperatures and increased rainfall from El Niño have previously been associated with a higher likelihood of dengue outbreaks. Warmer temperatures can also accelerate viral replication in mosquitoes and influence mosquitos’ development and breeding habits.

At the same time, the El Niño event brought warmer sea-surface temperatures, which have been shown to correlate with outbreaks of mosquito-transmitted diseases. Estimates from remote sensing data in coastal Ecuador show that sea-surface temperatures were higher than average from 2014-2016.

The team also believes an increase in water scarcity after the earthquake indirectly benefited mosquito development. The quake damaged municipal water systems, forcing people to store water in open containers outside their homes. These served as additional habitats for mosquito larvae.

The new findings could be used by governments to identify and protect vulnerable communities before natural disasters happen, Sorensen said.

“One idea is to develop disease models that can use existing climate models to predict where these vectors will show up due to climate variability,” she said. “Applying these new models to areas that have pre-existing social vulnerabilities could identify susceptible regions, allowing us to direct healthcare resources there ahead of time.”

The study was published October 12 in GeoHealth, a publication of the American Geophysical Union.

The co-authors of the study from CU Anschutz include Emilie Calvello-Hynes, MD, assistant professor of emergency medicine and Jay Lemery, MD, associate professor of emergency medicine and chief of wilderness and environmental medicine.

The other co-authors include: Mercy J. Borbor-Cordova, Faculty of Naval Engineering, Oceanic Sciences and Natural Resources, Escuela Superior Politecnica del Litoral, Guayaquil, Ecuador; Avriel Diaz, Dept. of Evolution, Ecology and Environmental Biology, Columbia University; Anna M. Stewart-Ibarra, Department of Public Health and Preventative Medicine, SUNY Upstate Medical University, Syracuse, NY.

This paper is a collaboration of the University of Colorado Consortium for Climate Change and Health.

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New oral diabetes drug shows promise

A University of Colorado Anschutz Medical Campus study finds sotagliflozin helps control glucose and reduces the need for insulin in patients with type 1 diabetes.

Principal results were published today in the New England Journal of Medicine of a global Phase 3 clinical trial in patients with type 1 diabetes treated with sotagliflozin. Sotagliflozin is an investigational new oral drug for patients with type 1 diabetes that has shown promise in improving glucose control without any increase in severe hypoglycemia or diabetic ketoacidosis compared to insulin alone.

Garg
Dr. Satish Garg

Among 1,402 trial participants given the drug, sotagliflozin showed clinically meaningful and statistically significant effects on glucose control. Concentrations of hemoglobin A1C, a measure of plasma glucose, were improved. Patients experienced a lower rate of confirmed severe hypoglycemia than observed in patients on placebo and also had weight loss.

According to lead investigator Satish Garg, MD, professor of medicine and pediatrics at the Barbara Davis Center for Diabetes at the University of Colorado Anschutz Medical Campus, no oral medication has ever been approved for the treatment of type 1 diabetes and sotagliflozin has the potential to become the first new treatment innovation in nearly a century since insulin.

Most patients do not achieve optimal glycemic control with insulin alone. A1C concentrations, hypertension and reduction in body weight are critical issues which significantly impact people living with type 1 diabetes.

“If approved by the FDA, sotagliflozin may be the first oral drug that helps patients with type 1 diabetes in improving their glucose control without any weight gain or increase and severe hypoglycemia,” Garg said. “If long-term use continues to show similar metabolic improvements in patients with type 1 diabetes, it is likely that the long-term complications of diabetes would be significantly reduced.”

Sotagliflozin would be used in conjunction with insulin. Trial participants taking the drug as an oral pill alongside traditional insulin treatments experienced significant improvements in glucose control, a drop in systolic and diastolic blood pressure and weight loss.

Sotagliflozin is a unique dual inhibitor that works by inhibiting two sodium-glucose transporters: SGLT1 and SGLT2. Each modulates glucose levels. SGLT1 regulates the uptake of glucose in the gut while SGLT2 regulates the re-uptake of glucose in the kidney, according to the authors.

“Sotagliflozin added to insulin therapy can potentially help patients with type 1 diabetes improve their glucose control and hopefully manage the disease with fewer complications,” Garg said. “This would not be a replacement for insulin; it is an adjunctive therapy. However, because it works in the gut and the kidneys, it doesn’t require insulin to have an effect.”

The inTandem3 study was a double-blind, placebo controlled and randomized Phase 3 trial including adults with type 1 diabetes at 133 sites worldwide. In conjunction with this publication, the data were announced today at the 53rd Annual Meeting of the European Association Study for Diabetes in Lisbon, Portugal.

The 24-week trial evaluated the safety and efficacy of sotagliflozin at 400mg per day in randomized patients treated with any insulin regimen – pumps or injections. Eligible patients included men and nonpregnant women aged 18 and older, and they were required to self-monitor blood glucose.

The study met its primary endpoint with statistical significance, demonstrating the superiority of sotagliflozin 400 mg compared to placebo in the proportion of patients with A1C less than seven percent at week 24, no episode of severe hypoglycemia and no episode of diabetic ketoacidosis after randomization.

The outcome on every secondary endpoint favored sotagliflozin over placebo, achieving statistical significance for all four secondary endpoints, including change from baseline in A1C, body weight, systolic blood pressure in patients with baseline SBP less than or equal to 130 mm Hg and bolus insulin dose. Sotagliflozin significantly reduced A1C compared to placebo after 24 weeks of treatment.

“As is known with sodium glucose cotransporter 2 (SGLT2) inhibitors, patients experienced more episodes of diabetic ketoacidosis in the trial,” Garg said.

Diarrhea and genital mycotic infection also affected participants more than placebo, but less than one percent discontinued the study due to these effects.

“Sotagliflozin may reduce the bad effects of insulin and the dose patients need,” Garg said. “Patients in our study had lower weights, no severe hypoglycemia and better blood pressure.”

Garg is a faculty member at the University of Colorado School of Medicine at the Anschutz Medical Campus and is editor in-chief of Diabetes Technology and Therapeutics Journal.

Garg and his colleagues are working to publish more results on other inTendem1 and 2 phase 3 clinical trials in type 1 diabetes, including data on continuous glucose monitoring in future publications.

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Jankowski awarded NIH funding for bone density study

Approximately 46 percent (21 million) of older women in the United States have low bone mass, a condition that increases the risk of fracture, disability, and death, but may also be reversible. Exercise is recommended to maintain bone health in women, but the benefits of exercise may be limited by low levels of sex hormones after menopause.

Kathy Jankowski of CU College of Nursing
Kathy Jankowski, PhD, FACSM

A new R01 (a type of research project funded by the National Institutes of Health) study, “DHEA Augmentation of Musculoskeletal Adaptations to Exercise in Older Women,” led by CU College of Nursing Associate Professor Kathy Jankowski, PhD, FACSM, will attempt to show whether dehydroepiandrosterone (DHEA) will provide estrogenic and androgenic hormonal responses that will enhance the benefits of exercise on bone and muscle in postmenopausal women.

High-impact research

“This research has high impact and importance for women, who have a longer life expectancy than men, and are more prone to health issues arising from lower bone mineral density,” Jankowski says. The project is federally funded for a five-year period of study at $600,000 per year.

Exercise is recommended for postmenopausal women to maintain or increase areal bone mineral density, to improve muscular fitness and balance, and ultimately to prevent fractures. During exercise, joint-reaction and ground-reaction forces contribute to strain signals that are transduced via a mechanostat to osteocytes, causing region-specific adaptations in bone tissue.

However, age-related declines in anabolic adrenal, gonadal, and somatotropic hormones may blunt this and other musculoskeletal adaptations. DHEA is the major source of estrogen and testosterone in postmenopausal women, but adrenal DHEA production declines with age.

Jankowski’s research project proposes that DHEA therapy, by providing androgenic and estrogenic hormonal support, will augment the effects of bone-loading exercise on areal bone mineral density and fat free mass in women with low areal bone mineral density (i.e., osteopenia). This population is the focus because low area bone mineral density, an indicator of fracture risk, could be corrected with hormonal treatment.

Measuring changes to bone architecture

“There only a few anabolic hormonal therapies approved to increase bone density in women, and these are typically prescribed only for women with osteoporosis,” Jankowski says. “DHEA has the advantage of providing anabolic effects on bone, and is well-tolerated in postmenopausal women. Exercise is the only therapy that provides benefits to muscle and bone. I am looking forward to discovering whether combining exercise with DHEA provides benefits to muscle and bone that exceed that of either DHEA or exercise alone.”

Jankowski’s study will measure changes in bone architecture in addition to bone density. “Small changes in bone architecture can have profound effects on bone strength,” she says. “It is currently not known if DHEA has beneficial effects on bone architecture.”

To learn more about research projects at the CU College of Nursing Office of Research and Scholarship, contact CON.ORS@ucdenver.edu .

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Doping in sports: official tests fail to pick up majority of cases

Doping is remarkably widespread among elite athletes and remains largely unchecked despite the use of sophisticated biological testing methods. This is according to Rolf Ulrich of the University of Tübingen in Germany and Dawn Comstock of the Colorado School of Public Health at the University of Colorado Anschutz Medical Campus. They are lead authors of a study in Springer’s journal Sports Medicine.

The researchers conducted anonymous surveys among athletes competing at two major sports events in 2011. At least 30-45% of athletes at these events acknowledged that they had used banned doping substances or methods in the previous year. This is a serious concern because doping not only compromises fair play, but it is potentially detrimental to the health of athletes.

Biological tests of blood and urine typically detect doping in only 1-3% of competitors at elite international competitions. However, the new study suggests that the true rate of doping is far greater, because cutting-edge doping schemes seem to make it possible for many athletes to beat the biological tests currently in place to detect prohibited doping.

“Given the numerous recent highly publicized doping scandals in major sports, one might guess that the proportion of such undetected cheats is high,” write Ulrich and his coauthors. In their paper, the authors cite several recent commentaries suggesting that technical, human, political and financial factors are all contributing to flawed results from current biological testing techniques.

The research team conducted anonymous tablet-based surveys of the prevalence of doping at two major sports events in 2011. These were the 13th International Association of Athletics Federations World Championships in Athletics (WCA) in South Korea and the 12th Quadrennial Pan-Arab Games (PAG) in Qatar. The surveys used a randomized response technique, a method that visibly guaranteed the anonymity of the respondent, thus permitting the athletes to answer honestly about their doping without fear of exposure. Surveys were completed by 2167 athletes at the two events.

Even after assessing statistically for various possible forms of bias in the results, the authors estimated that at least 30% of athletes at WCA and 45% of athletes at PAG had engaged in doping during the previous year. The statistical analyses suggested that, if anything, these figures may well have underestimated the true prevalence of doping at the two events. By contrast, on biological testing at WCA, only two (0.5%) of the 440 athletes tested positive for illegal substances. At PAG, 24 (3.6%) of the 670 athletes tested showed positive results.

“These findings suggest that biological testing greatly underestimates the true prevalence of doping in elite athletics,” Dawn Comstock, professor of epidemiology at the Colorado School of Public Health at CU Anschutz, said. “It indicates the need for future studies of the prevalence of doping in athletics using randomized response techniques to protect the anonymity of the athletes.”

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Researchers find creosote bush could treat Giardia and brain-eating amoeba infections

Compounds produced by the creosote bush, a desert shrub common to American Southwest, exhibit potent anti-parasitic properties against two deadly parasites responsible for Giardia infections (Giardia lamblia) and the amoeba that causes an often-lethal form of encephalitis (Naegleria fowleri), according to researchers at the Skaggs School of Pharmacy and Pharmaceutical Sciences at CU Anschutz and UC San Diego.

Daniel LaBarbera, PhD, associate professor of drug discovery and medicinal chemistry at Skaggs School of Pharmacy and Pharmaceutical Sciences.
Daniel LaBarbera, PhD, associate professor of drug discovery and medicinal chemistry at Skaggs School of Pharmacy and Pharmaceutical Sciences.

The findings, published online this month in PLOS Neglected Tropical Diseases, may give scientists the chance to widen their arsenal of antimicrobial agents effective against deadly parasitic infections. The current standard treatment for both infections involve antibiotics and anti-parasitic drugs.

The World Health Organization estimates giardiasis, a diarrheal illness, is linked to approximately 846,000 deaths worldwide each year. Infection usually occurs through ingestion of contaminated water or food. Though rarely lethal in the United States, it’s estimated there are more than a million cases of giardiasis in the country annually. Infections due to N. fowleri, sometimes called the `brain eating amoeba,’ are much less common than Giardia.

Compounds from the creosote bush may fight two deadly parasitic infections.
Compounds from the creosote bush may fight two deadly parasitic infections.

“However, it is a far deadlier parasite that is found in warm fresh waters and infects the central nervous systems of their victims through the nasal passages causing lethal brain damage known as primary amoebic meningoencephalitis (PAM),” said principal investigator Dan LaBarbera, PhD, associate professor of drug discovery and medicinal chemistry at the Skaggs School of Pharmacy and Pharmaceutical Sciences at CU Anschutz.

Due to its rapid infection cycle and high mortality rate, the CDC has been given special approval to provide the drug miltefosine to clinicians as a treatment option for N. fowleri infection. But it is still not FDA approved and has limited availability in the U.S. This new compound potentially provides a less expensive, more effective treatment option.

Scientists from CU Anschutz and UC San Diego collaborated as part of the Skaggs Scholars program, which matches investigators from Skaggs-funded schools of pharmacy with complementary expertise to discover potential drug breakthroughs. UC San Diego scientists provided expertise in parasitology, while the CU Skaggs School of Pharmacy provided expertise in natural products, compound libraries and active compounds from plants. The researchers investigated these tropical diseases because of their occurrence in Mexico and South America and found indigenous peoples treating infections with creosote compounds.

“The significance and intrigue about our study is that it shows the value of prospecting for new medicines from plants traditionally used by indigenous people as medicine,” said co-principal investigator Anjan Debnath, Ph.D., an assistant adjunct professor at Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego.

The creosote bush (Larrea tridentata), is a tough evergreen bush with small waxy leaves, yellow flowers and a distinctive turpentine-like scent. Native Americans in both the United States and Mexico have long used the plant for a variety of ailments, including intestinal complaints. There is also an existing body of scientific work documenting the plant’s pharmacologically active compounds, notably nordihydroguaiaretic acid (NDGA). NDGA has antiviral, antibacterial, anti-inflammatory and anticancer properties.  The study is the first to show that NDGA and five other compounds are active against both pathogenic parasites.

In other studies, NDGA has been shown to be a neuroprotective agent. It protects human monocytes and other cells and tissues through its powerful antioxidant activity.

“In our study the creosote natural product, NDGA, proved to be a more potent anti-parasitic agent against N. fowleri compared to miltefosine,” LaBarbera said. “Therefore, NDGA may lead to a more effective drug therapy option for N. fowleri infection.”

This research was funded in part, by a grant from The ALSAM Foundation and National Institutes of Health.

 

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Major communication gaps between doctors and home health care nurses revealed

Researchers at the University of  Colorado Anschutz Medical Campus have found serious gaps in communication between physicians and home health care agencies (HHC) responsible for caring for often elderly patients discharged from hospitals. The problem, the study said, can contribute to hospital readmissions.

The research, published today in the Journal of General Internal Medicine, cites an array of communication challenges between HHC agencies and physicians following hospital discharge.

Dr. Christine Jones, assistant professor of medicine and lead author of the study.
Dr. Christine Jones, MD, MS, assistant professor of medicine and lead author of the study.

The study cited frequent discrepancies in medication lists, confusion over who was responsible to write patient care orders, inaccessible hospital records and resistance from clinicians and staff for accountability.

Led by Christine D. Jones, MD, MS, assistant professor at the University of Colorado School of Medicine, the researchers conducted six focus groups with HHC nurses from six different agencies in Colorado to ask about their general experience with caring for patients after discharge from any of their referring hospitals.

“We found that communication breakdowns can have consequences for patients,” said Jones, lead author of the study. “These are some of our most fragile patients, most are over 65, and more seamless communication is needed.”

Some of the HHC nurses interviewed complained of a lack of accountability, medical errors and difficulty in reaching doctors.

“As a general rule, I’ve been told you’re not to contact the hospitals. I actually got in trouble for contacting the hospital, trying to find out, get more information, trying to track a doctor down,” one nurse said in a focus group.

Another nurse said even if they reach a primary care physician, they often say they didn’t know the patient was in the hospital and they don’t have a report on them.

“The communication between the hospital and the primary care providers is just as bad as it is for us because the PCP’s don’t have the information,” the nurse said.

Dr. Jones said another complicating factor is that insurance often requires doctors to order HHC services. So if a nurse practitioner is providing primary care for a patient, obtaining HHC immediately becomes more difficult.

The researchers found another serious problem when it came to ordering medication. HHC nurses and staff said most of the medication lists they receive are incorrect due to the number of doctors and specialties involved.

“As hospitalists, we need to think about what happens beyond the hospital walls and how we can support our patients after discharge, especially when it comes to home health care patients who can be very vulnerable.” Jones said.

She noted that the study did not focus on any one specific hospital, but hospitals in general.

The study proposes a series of solutions to these problems including the following:

  • Hospitals and primary care physicians could provide HHC agencies direct access to Electronic Medical Records and direct phone lines to doctors.
  • Enact laws allowing nurse practitioners and physician’s assistants to write HHC orders. A bill was under consideration to do this but was not acted upon by Congress.
  • Clearly establishing accountability for hospital clinicians to manage HHC orders until a primary care physician can see a patient and help HHC nurses with questions.
  • Create better communication methods with PCPs to ensure safer transitions

“Our findings suggest that improvements to accountability and communication could address patient needs and goals, avoid medication discrepancies and ultimately improve safety for patients and HHC nurses,” Dr. Jones said.

 

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Senior Executives from Film and Virtual Reality Industries Join NBHIC

The National Behavioral Health Innovation Center announced today that Rick Rekedal, a former senior executive with DreamWorks Animation, and Dr. Walter Greenleaf, a pioneer and leading authority on virtual reality for medical use, have joined its staff.

Rick Rekedal joins NBHIC as Senior Creative Advisor
Rick Rekedal joins NBHIC as Senior Creative Advisor

“Walter and Rick are recognized internationally as leaders in their fields,” said Matt Vogl, executive director of NBHIC at the University of Colorado Anschutz Medical Campus. “Their knowledge and insight are powerful assets to our mission of finding bold new solutions to the country’s mental health crisis.”

In 2016, Rekedal completed over 20 years with DreamWorks as Chief Creative of franchise development and the global franchise director of the hit movie “Trolls.” Rekedal has also worked on properties such as “How To Train Your Dragon,” “Shrek,” “Kung Fu Panda,” and “The Lost World: Jurassic Park,” developing merchandising, interactive and licensing programs. Rekedal’s work has been recognized with two Annie Awards, two Kids Choice Awards and Toy of the Year. He is a frequent speaker and serves on advisory boards for The Wedgwood Circle; Michael W. Smith Group and Seabourne Pictures; and Belmont University’s film school.

Dr. Walter Greenleaf is NBHIC’s new Director of Technology Strategy
Dr. Walter Greenlef joins NBHIC as Director of Technology Strategy

Rekedal joins NBHIC as Senior Creative Advisor, consulting on how to elevate an open and urgent national conversation on mental health.

Greenleaf is a behavioral neuroscientist and a medical product developer who has been on the cutting edge of virtual reality and augmented reality applications in healthcare for more than 30 years.

In his role as NBHIC’s Director of Technology Strategy, Greenleaf brings his considerable knowledge to the Center’s approach to digital initiatives. He continues to work as a Visiting Scholar at the Stanford University Virtual Human Interaction Lab.

He has developed several clinical product streams, founded medical companies, and served as a scientific advisor and reviewer for the U.S. Public Health Service, National Science Foundation, National Institutes of Health, NASA and the U.S. Department of Education. He holds a PhD in Neuro and Bio-behavioral Sciences from Stanford University.

“Our approach is to seek out unexpected partners as we look beyond the current mental health system for new solutions,” said Vogl. “Walter and Rick fit that approach. Walter’s depth of knowledge in virtual reality and Silicon Valley are leading us to work with new technology partners in developing cutting edge tools for mental health treatments. Rick’s extraordinary creative abilities can help steer powerful human connections to combat the awful stigma that is so harmful to many people in need.”

Guest contributor: Lauren Baker, marketing and communications strategist for the National Behavioral Health Innovation Center at CU Anschutz.

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Immune system may keep body from neutralizing HIV-1 virus

Researchers at the University of  Colorado Anschutz Medical Campus have discovered that a process protecting the body from autoimmune disease appears to prevent it from creating antibodies that can neutralize the HIV-1 virus, a finding that could possibly help lead to a vaccine that stimulates production of these antibodies.

Dr. Raul Torres, professor of immunology and microbiology at CU Anschutz
Raul Torres, PhD, professor of immunology and microbiology at the University of Colorado School of Medicine.

The study, led by Raul M. Torres, PhD, professor of immunology and microbiology at the University of Colorado School of Medicine, was published Tuesday in The Journal of Experimental Medicine.

Torres and his team sought to better understand how the body’s own immune system might be getting in the way of neutralizing the HIV-1 virus.

They knew that some patients infected with HIV-1 developed what are known as ‘broadly neutralizing antibodies,’ or bnAbs, that can protect against a wide variety of HIV-1 strains by recognizing a protein on the surface of the virus called Env. But the patients only develop these antibodies after many years of infection.

Because of shared features found in a number of HIV-1 bnAbs, researchers suspected the inability or delayed ability to make these type of protective antibodies against HIV was due to the immune system suppressing production of the antibodies to prevent the body from creating self-reactive antibodies that could cause autoimmune diseases like systemic lupus erythematosus.

At the same time, patients with lupus showed slower rates of HIV-1 infection. Scientists believe that’s because these autoimmune patients produce self-reactive antibodies that recognize and neutralize HIV-1.

The process by which the body prevents the creation of antibodies that can cause autoimmune disease is known as immunological tolerance.

Torres wanted to break through that tolerance and stimulate the production of antibodies that could neutralize HIV-1.

“We wanted to see if people could make a protective response to HIV-1 without the normal restraint imposed by the immune system to prevent autoimmunity,” Torres said.

The researchers first tested mice with genetic defects that caused lupus-like symptoms. They found that many of them produced antibodies that could neutralize HIV-1 after being injected with alum, a chemical that promotes antibody secretion and is often used in vaccinations.

Next, they treated normal mice with a drug that impairs immunological tolerance and found that they began producing antibodies capable of neutralizing HIV-1. The production of these antibodies was increased by alum injections. And if the mice were also injected with the HIV-1 protein Env, they produced potent broadly neutralizing antibodies capable of neutralizing a range of HIV-1 strains.

In every case, the production of these HIV-neutralizing antibodies correlated with the levels of a self-reactive antibody that recognizes a chromosomal protein called Histone H2A. The researchers confirmed these antibodies could neutralize HIV-1.

“We think this may reflect an example of molecular mimicry where the virus has evolved to mimic or look like a self protein,” Torres said.

Torres suggested that the difficulty in developing a vaccine against HIV-1 may be because of the ability of the virus to camouflage itself as a normal part of the body.

“But breaching peripheral immunological tolerance permits the production of cross-reactive antibodies able to neutralize HIV-1,” Torres said.

Since the research was done on animals, scientists must still determine its relevance for HIV-1 immunity in humans.

“The primary consideration will be determining whether immunological tolerance can be temporarily relaxed without leading to detrimental autoimmune manifestations and as a means to possibly elicit HIV-1 bnAbs with vaccination,” he said.

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Researchers to study neurological effects of Zika virus in young children

Researchers at the University of  Colorado Anschutz Medical Campus and the Baylor College of Medicine will join with Guatemalan investigators in a major study examining the clinical outcomes of children infected with the Zika virus after being born, focusing on long-term brain development.

“We now know the severe effects of Zika in the fetus and the unborn child if the mother gets the infection during pregnancy,” said Edwin Asturias, MD, co-principal investigator of the study and director of Latin American Projects at the Center for Global Health at the Colorado School of Public Health. “But if the virus is able to affect the developing brain of an infant or a child, this will have enormous consequences to a generation of children in areas where the virus has spread.”

Dr. Edwin Asturias of the Center for Global Health at the Colorado School of Public Health.

 

The study, funded by the National Institutes of Health, has been approved by the Ministry of Health in Guatemala and will take place in the rural southwestern coast of that country. Along with the Zika virus, the region is also endemic for the dengue and chikungunya virus transmitted by the same mosquito that carries Zika.

“We are enrolling infants in the first year of life and children up to 5 years of age who will be followed over one year to see if they become infected with Zika virus, and then we will be looking at the effects of the infection in the infants’ and children’s neurodevelopment,” said Dr. Flor M. Muñoz, associate professor of pediatrics in the section of infectious diseases at Baylor and principal investigator of the study. “We will look for neurologic or neurodevelopmental effects specifically, including effects on hearing and eye problems, because we know that the virus has the potential to cause central nervous manifestations.”

Zika virus has been known to affect babies in utero when the mother is infected during pregnancy, but little is known about what happens when infants are infected in early life, Muñoz said.

“Our concern is that a developing brain in early life can be impacted significantly,” she said. “It’s an important question to address not just for children that live in the endemic areas, but also for children who travel to these areas.”

Recruitment for the study will take place through a clinic created by the University of Colorado’s Center for Global Health in Guatemala. The goal is to follow 500 infants and their mothers for one year to determine if they become infected by the Zika virus. Neurologic exams and age-appropriate neurodevelopmental testing will be run for the duration of the study to identify changes in children infected with Zika virus.

Researchers will also be enrolling 700 children between the ages of 1 and 5 years, including 300 children known to have been exposed to dengue or Zika viruses while participating in a previous dengue study, and 400 who are siblings of the infants in this study. They will be tested periodically and evaluated for symptoms of flavivirus-like illness to determine if they have been infected by Zika, dengue or chikungunya viruses. Investigators will monitor serial neurologic examinations and developmental milestones in the children to determine if the Zika virus infection is associated with any neurologic or developmental changes.

Dr. Edwin Asturias examining children in Guatemalan clinic.
Dr. Edwin Asturias examining a child in Guatemalan clinic.

Muñoz and Asturias will collaborate with colleagues from the Fundacion para la Salud Integral de los Guatemaltecos (FUNSALUD) clinic in Guatemala. The clinic, affiliated with the Colorado School of Public Health and Children’s Hospital Colorado, is led by Dr. Antonio Bolaños. It has a full complement of local investigators, nurses and laboratory technicians along with Emory University’s Vaccine Treatment and Evaluation Unit (VTEU) research laboratory led by Dr. Mark Mulligan.

Neurodevelopmental testing will be conducted by three local psychologists under the leadership of Dr. Amy Connery of Children’s Hospital Colorado in Aurora, Colo. The study will last three years and results will be reported throughout the study. More information can be found at the NIH Zika website.

 

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Study puts mechanical hearts in spotlight

For more than two decades, Jim Walsh’s heart has been an uncertain ally.

Like all of us, Walsh, 67, relies on that vital muscle to keep blood pumping to his body. But his can’t do the job alone. Late last year, damage to Walsh’s heart that began more than two decades earlier caught up with him. Two days before Christmas, Walsh lay on an operating table at UCHealth University of Colorado Hospital for a procedure to lend his failing heart a helping hand.

cardio lab at CU Anschutz
William Cornwell, right, performs an echocardiogram on volunteer Scott Ferguson in a CTRC lab as research coordinator Greg Coe looks on. It’s part of Cornwell’s five-year NIH-funded study aimed at better understanding the physiological effects of LVADs.

Cardiac surgeon Joseph Cleveland, MD, implanted a left ventricular assist device (LVAD) called the Heartmate 3, a pump designed to give Walsh’s weakened heart a big boost. Cleveland and his team hoped the LVAD would, in turn, lessen the pressure on Walsh’s pulmonary artery and right ventricle, which are responsible for supplying blood to the lungs for oxygenation.

The procedure happened none too soon. “My progression downward was rapid,” Walsh said. “I had the choice to die rapidly or get an LVAD.”

Long road

Walsh’s lengthy battle with congestive heart failure began in 1995 when tests revealed that the left main stem of his coronary artery had developed an aneurysm – a bulge that weakens the vessel wall and puts it at risk of rupturing. The finding surprised Walsh, who was then a relatively young man who had forged a successful career as an expert in finance for several major companies. He described himself as “asymptomatic” up to that point and added that he regularly jogged and lifted weights.

But the aneurysm worsened and required a surgical graft repair. A London surgeon used a section of Walsh’s mammary artery to bypass the aneurysm, but during recovery the graft failed and Walsh suffered a heart attack. A second graft, using a piece of saphenous vein in his leg, “held true,” but over the next decade his exercise capacity declined steadily, and he required ever-increasing doses of medications, such as diuretics, to manage his condition.

The problem continued to worsen as the years wore on. When he began treatment at the Denver VA Medical Center in 2014, Walsh’s advanced heart failure dangerously increased the pressure on his pulmonary artery. He was admitted to UCH in November 2016 under the care of CU School of Medicine heart failure specialist William Cornwell, MD.  Andreas Brieke, MD, medical director of the Mechanical Circulatory Support Program for CU, also contributed to the case. Considered too great a risk for a transplant, Walsh chose the LVAD implant a month later.

CU Anschutz heart patient Jim Walsh
Jim Walsh is feeling stronger after receiving an LVAD just before Christmas last year. But he’s still working to recover his stamina, even with the help of the pump. Photo courtesy of Jim Walsh.

The surgery was successful, and Walsh is making a slow recovery that he hopes will one day lead to a heart transplant. He makes regular walks around Sloan’s Lake in northwest Denver – about 2.5 miles.

But Walsh’s case points to a larger question about the device that saved his life. Interviewed four months after the LVAD surgery, he said the lake walk still leaves him breathless, especially if he tries to talk at the same time.

The problem of the pump

Why hasn’t the LVAD pump been able to restore Walsh’s ability to normally complete this routine activity? That’s a question that intrigues Cornwell and his colleagues at CU. Cornwell is exploring it with the help of a five-year National Institutes of Health grant that began late last year. He’s equipped a lab in the Clinical and Translational Research Center (CTRC) on the 12th floor of UCH’s Anschutz Inpatient Pavilion to measure exercise capacity in patients with normal hearts, those with mild heart failure and those with LVADs. The work includes frequent measures of patients’ blood pressure, cardiac output, blood flow from the heart to the brain, blood oxygen levels and more while at rest and during exercise.

Cornwell notes that while LVADs are designed to pump 4 to 10 liters of blood per minute to the body, tests show that many patients with the pumps continue to have muscle atrophy and difficulty exerting themselves without their blood pressure and heart rate rising rapidly and fatigue setting in. These are all signs that the pumps might not be delivering a sufficient blood supply to the body’s muscles and organs.

“Many LVAD patients remain functionally incapacitated,” Cornwell said, with low oxygen consumption rates and other clinical symptoms that belie many patients’ subjective reports of feeling better after getting the devices.

In addition, work by Cornwell’s colleague Amrut Ambardekar, MD, CU cardiovascular specialist and medical director of the Cardiac Transplant Program, shows that artery tissue in the hearts removed from transplanted LVAD patients is often stiff and scarred beyond what would be expected with normal aging.

Case of the missing pulse

The problem may lie in the fact that LVAD patients lose something that most of us take for granted: the pulse created by heart contractions. The LVAD’s mechanical pump supplies blood in a continuous flow.

That’s led to known problems. For example, LVAD patients are at higher risk of gastrointestinal bleeding and stroke. The recently approved Heartmate 3 attempted to address the no-pulse problem by regularly speeding up and slowing down the pump rotor – a kind of artificial heart “lub-dub.” But Cornwell said data thus far show that the feature has not decreased the rate of strokes or bleeding.

Losing the pulse has other “subtle but important implications,” Cornwell said. The heart’s contractions stretch a network of sensors in the aorta and carotid arteries called baroreceptors. These sensors communicate with the brain, helping to regulate blood pressure naturally. In LVAD patients, by contrast, the lack of a pulse “revs up” the sympathetic nervous system, which releases adrenaline and increases blood pressure, thus interfering with normal blood flow.

That may help to explain why many LVAD patients such as Walsh don’t see improvement in their capacity to walk at least short distances without fatigue, climb stairs or do regular household chores, Cornwell said. One question to be answered in the lab is whether LVADs can be made to sufficiently increase blood flow to the body during exercise to compensate for the absence of pulse.

Into the lab

Any conclusions await data gathering. Cornwell is now testing healthy patients. Those with mild heart failure and with LVADs will follow. On a recent afternoon, volunteer Scott Ferguson lay on a bed in Cornwell’s lab. An array of lines to measure cardiac output, heart and lung pressure, blood oxygen levels, and other data ran from Ferguson’s arm and neck. A transcranial device fitted around his head would measure the flow of blood to his brain. Cornwell also took an echocardiogram to get an image of Ferguson’s heart.

Lab research at CU Anschutz
Research coordinator Greg Coe fits a breathing tube on volunteer Scott Ferguson while William Cornwell watches. Ferguson completed three stages of steadily demanding cycling to measure the physiological effects on his body.

A team of CTRC nurses assisted with monitoring Ferguson and taking regular blood draws, which would later measure arterial blood gases during periods of rest and exertion. Greg Coe, clinical research coordinator and regulatory specialist at CU, stood before twin towers of computer monitors displaying many fields of colored lines running in peaks and valleys. These were the representations of Ferguson’s body at work: heart and respiration rate, blood pressure, pulmonary artery pressure and much more.

Ferguson, 29, a post-doctoral fellow in cardiovascular physiology at CU, lay calmly on the bed while Cornwell and his team readied him for the tests. Cornwell asked him to breathe in and breathe out, then to bear down for 20 seconds. Coe timed the exercise while monitoring the readings at the two screens.

With that completed, Ferguson stood and mounted a stationary bike. Coe inserted a long breathing tube in his mouth and clipped his nose. Over the next hour or so, he completed three regimens of timed cycling with low, moderate and intense levels of exertion. During each one, nurses drew blood while Ferguson pointed at a clipboard to silently indicate to Coe his level of exertion. Cornwell orchestrated the work while scrutinizing the lines on the computer screens that charted the changes in Ferguson’s physiological functions as he increased his exertions.

Steps ahead

It will be several months before an LVAD patient enters the CTRC lab to provide the same kind of data, Cornwell said. But the work with healthy patients and those with mild heart failure will provide useful comparisons when he and his team examine the responses to exercise of pulseless LVAD patients.

“We’d like to see how much exercise it takes to create a physical pulse using the heart’s natural power,” he said. That might lead to “novel exercise prescriptions,” such as lifting resistance weights or interval training.

“These devices [LVADs] are important, but it doesn’t mean that we stop working,” he said. “Patients improve with them, but they are not out of the woods.”

Walsh is grateful for the lifesaving care he received from the entire CU team at UCH and is ready to do whatever he can to help further. If he is eligible for a transplant, he’s willing to allow study of his damaged heart and said he “absolutely has the same enthusiasm” for Cornwell’s study.

The strongest drive lies close to home: his wife and three daughters, including the youngest, who is just 14 years old.

“My hope is to be here long enough to help her navigate her way through her formative years in high school and, perhaps, even university,” he said. “I’m not afraid of death, but I’d like to think that with the LVAD I have bought more time before the statistics turn against me.”

Tyler Smith is a guest contributor of University Communications. 

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