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.
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.
“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.
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.
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.
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.
“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.
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.
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.
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.
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.”
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.
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.
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.
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.”
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.
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.
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.
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.
In perhaps the largest national suicide intervention trial ever conducted, researchers at the University of Colorado Anschutz Medical Campus and Brown University found that phone calls to suicidal patients following discharge from Emergency Departments led to a 30 percent reduction in future suicide attempts.
The year-long trial, which involved 1,376 patients in eight locations nationwide, provided suicidal patients with interventions that included specialized screening, safety planning guidance and follow-up telephone calls.
“People who are suicidal are often disconnected and socially isolated,” said study co-author Dr. Michael Allen, MD, professor of psychiatry and emergency medicine at the Helen and Arthur E. Johnson Depression Center at CU Anschutz. “So any positive contact with the world can make them feel better.”
Allen is also medical director of Rocky Mountain Crisis Partners in Denver which has already implemented a similar program where counselors call suicidal patients following their discharge from Emergency Departments (EDs).
Suicide is the 10th leading cause of death in the U.S. In 2015, there were 44,193 deaths by suicide nationally. Over one million people attempt to take their own life every year.
Colorado routinely ranks among the top 10 states for suicide with about 1,000 deaths a year. Last year, it was number seven in the country. The state Legislature has set a goal of reducing suicides by 20 percent by 2024.
Allen said simply handing a suicidal patient a psychiatric referral when discharged isn’t enough.
“We call them up to seven times to check on them after discharge,” he said. “If they aren’t there we leave a message and call again. For many, this telephone call is all they get.”
The crisis center has worked with 17 of Colorado’s 88 EDs and is hoping to increase that number and eventually go statewide.
“We don’t need more brick and mortar buildings, we can reduce suicide risk by simply calling people on the phone,” Allen said.
His colleague and study collaborator Dr. Emmy Betz agreed.
“Telephone follow-up programs offer a great way to help bridge an ED visit to outpatient mental health care and hopefully save lives,” said Betz, an associate professor of emergency medicine at CU Anschutz who has conducted extensive research on suicide. “It would be great to see such programs become more widely implemented. Suicide is a leading cause of death, especially in Colorado, and a shortage of inpatient and outpatient mental health care options make innovative approaches like telephone counseling even more attractive.”
The study was led by Brown University and Butler Hospital psychologist Ivan Miller.
Miller, a professor of psychiatry and human behavior at the Warren Alpert Medical School of Brown University, said he was encouraged that they were able to impact suicide attempts among this population with a relatively limited intervention.
While suicide prevention efforts such as hotlines are well known, published controlled trials of specific interventions are much rarer, Miller said.
“We were happy that we were able to find these results,” he said.
This report was one of several from the Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE) study led by Miller, Professor Edwin Boudreaux of the University of Massachusetts and Dr. Carlos Camargo of Massachusetts General Hospital and Harvard University.
Dr. Betz was the principal investigator for Colorado’s ED-SAFE site.
The trial took place in three phases to create three comparison groups. In the first phase, 497 patients received each ED’s usual treatment as a control group. In phase two universal screening was implemented and 377 patients received additional attention in the ED. In the third phase, 502 patients received the experimental intervention.
Those patients received the same Phase 2 care including additional suicide screening from ED physicians, suicide prevention information from nurses and a personal safety plan they could fill out to prepare for times when they might begin harboring suicidal thoughts again.
Over the next year, they also received periodic phone calls from trained providers at Butler Hospital in Providence, R.I., who would discuss suicide risk factors, personal values and goals, safety and future planning, treatment engagement, and problem solving.
The number of suicide attempts and the proportion of people attempting suicide declined significantly in the intervention group compared to treatment as usual. The middle group, which received only additional screening, did not show a significant drop compared to the treatment as usual group.
“This is a remarkably low cost, low tech intervention that has achieved impressive results,” Dr. Allen said.
Using a unique microscope capable of illuminating living cell structures in great detail, researchers at the University of Colorado Anschutz Medical Campus have found clues into how a destructive autoimmune disease works, setting the stage for more discoveries in the future.
The scientists were trying to visualize antibodies that cause neuromyelitis optica (NMO), a rare autoimmune disorder that causes paralysis and blindness. Using a custom STED (Stimulated Emission Depletion) microscope built at CU Anschutz, they were able to actually see clusters of antibodies atop astrocytes, the brain cell target of the autoimmune response in NMO.
“We discovered that we could see the natural clustering of antibodies on the surface of target cells. This could potentially correspond with their ability to damage the cells,” said Professor Jeffrey Bennett, MD, PhD, senior author of the study and associate director of Translational Research at the Center for NeuroScience at CU Anschutz. “We know that once antibody binds to the surface of the astrocyte, we are witnessing the first steps in the disease process.”
When that domino effect begins, it’s hard to stop. But Bennett said the ability to see the antibodies on the brain cells offers a chance to develop targeted therapies that do not suppress the body’s immune system like current treatments for the disease do.
“By applying this novel approach we can see firsthand how these antibodies work,” said the study’s lead author, John Soltys, a current student in the Medical Scientist Training Program at CU Anschutz. “We are looking at the initiation of autoimmune injury in this disease.”
The breakthrough was made possible with the STED microscope, a complex instrument that uses lasers to achieve extreme precision and clarity. It was built by physicist Stephanie Meyer, PhD, at CU Anschutz. This is the first time it has been used in a research project here.
“This would have been impossible to see with any kind of normal microscope,” said study co-author Professor Diego Restrepo, PhD, director of the Center for NeuroScience. “We are inviting other scientists with research projects on campus to use the STED microscope.”
According to Meyer, lower resolution microscopes are blurrier than the STED due to diffraction of light. But the STED’s lasers illuminate a smaller area to acquire a higher resolution image . Unlike electron microscopes, STED users can see entire living cells at super high resolution, as they did in this study.
Restrepo said there are only a handful of STEDs in the nation and just one in Colorado.
The researchers said the discovery is the result of a unique partnership between clinical neurology, immunology and neuroscience coming together to solve a fundamental question of how antibodies can initiate targeted injury in an autoimmune disease.
“These are the building blocks that we can use to carry our research to the next level,” Bennett said.
The study was published this week in Biophysical Journal.
The new study, published online recently in the Journal of the American Academy of Dermatology, summarizes the current literature on the subject and concludes that pharmaceuticals containing cannabinoids may be effective against eczema, psoriasis, atopic and contact dermatitis.
Currently, 28 states allow comprehensive medical cannabis programs with close to 1 in 10 adult cannabis users in the U.S. utilizing the drug for medical reasons. As researchers examine the drug for use in treating nausea, chronic pain and anorexia, more and more dermatologists are looking into its ability to fight a range of skin disease.
“Perhaps the most promising role for cannabinoids is in the treatment of itch,” said the study’s senior author Dr. Robert Dellavalle, MD, associate professor of dermatology at the University of Colorado School of Medicine.
He noted that in one study, eight of 21 patients who applied a cannabinoid cream twice a day for three weeks completely eliminated severe itching or pruritus. The drug may have reduced the dry skin that gave rise to the itch.
Dellavalle believes the primary driver in these cannabinoid treatments could be their anti-inflammatory properties. In the studies he and his fellow researchers reviewed, they found that THC (tetrahydrocannabinol) the active ingredient in marijuana, reduced swelling and inflammation in mice.
At the same time, mice with melanoma saw significant inhibition of tumor growth when injected with THC.
“These are topical cannabinoid drugs with little or no psychotropic effect that can be used for skin disease,” Dellavalle said.
Still, he cautioned that most of these studies are based on laboratory models and large-scale clinical trials have not been performed. That may change as more and more states legalize cannabis.
Dellavalle said for those who have used other medications for itch and skin disease without success, trying a cannabinoid is a viable option especially if it has no psychotropic effect. He did not recommend such medications for cancer based on current evidence.
“These diseases cause a lot of problems for people and have a direct impact on their quality of life,” he said. “The treatments are currently being bought over the internet and we need to educate dermatologists and patients about the potential uses of them.”
The other authors of the study include Jessica S. Mounessa, BS, Julia A. Siegel, BA and Cory A. Dunnick, MD.
The grants come from the Gates Grubstake Fund, which backs scientists at CU Anschutz who research regenerative medicine and stem cell technologies. The name of the fund comes from the Gold Rush. Investors would give prospectors seed money known as grubstakes to buy food and supplies so they could survive while they searched for gold. In exchange, the investors would get a share of future profits.
The Gates Center and CU Innovations hope the grants do something similar for recipients, said Heather Callahan, the Gates Center’s entrepreneur-in-residence and a portfolio manager with CU Innovations. The grants are for projects that are in the early stages of work and will provide support for researchers until they are ready to seek larger grants and potentially money from investors.
“This amount of money can hopefully bring researchers to an inflection point or a point where they are able to get additional funding to move on to the next step,” Callahan said.
In the big picture, the Gates Grubstake Fund will support innovation at CU Anschutz and lead to the development of new therapies or devices that help patients. Researchers could commercialize their discoveries by working with private companies or create spin-off companies, Callahan said.
The program is open to researchers affiliated with the University of Colorado. There were 26 applications for grants this year, up from three applications last year. Callahan said the number and quality of applications are good indications of the work being done at CU Anschutz.
“It made it clear that we have a pipeline, and there’s robust research in regenerative medicine,” she said.
The three winning projects could lead to treatments for multiple sclerosis, age-related macular degeneration, and the wounds and skin ulcers that are a complication of diabetes.
Protecting the nervous system
David Wagner, PhD, is an associate professor at the CU School of Medicine (SOM) whose research could lead to new therapies that regenerate parts of nerve cells. One application for his research could be treating multiple sclerosis (MS), an autoimmune condition in which immune cells called T cells attack the nerves, specifically the myelin sheath that protect neurons. Wagner’s lab has identified a T-cell type that attacks the brain and spinal cord, as well as a drug candidate that might stop the disease and undo the damage.
“People with MS have such debilitating problems because myelin loss causes severe damage in brain and spinal-cord control centers,” Wagner said. “Controlling the inflammation may restore myelin, but should restore some or all of the damaged areas. Theoretically, this will re-establish normalcy.”
The therapy is in the early stage of development. A drug candidate has been identified, and it would take many years of clinical testing before a medication is available, Wagner said.
Jeffrey Olson, MD, is an associate professor of ophthalmology in SOM who is developing a medical device that could treat age-related macular degeneration, which is the leading cause of blindness in the industrialized world. The tiny device would be implanted in patients’ eyes and trap and destroy the proteins that cause the blindness.
Olson said he has done preliminary studies using prototypes and seen positive results. If the device comes to market, it would be a breakthrough for patients—only about 10 percent of people with macular degeneration have the form of the disease that can be stopped before it causes blindness. The current treatment requires patients to receive monthly injections in their eyes to treat the disease. Olson thinks the device could work in most patients with the condition and remove the need for continuing injections.
It could also lead to major savings for patients and Medicare. Current treatments cost about $22,000 per year per patient, which adds up to $5 billion annually. Medicare spends more money on that treatment than any other medication, Olson said.
Healing wounds with nanoparticles
Kenneth Liechty, MD, is a SOM professor who researches wound healing and regenerative medicine. His grant is for research on nanoparticles, which are nanometers in size and smaller than human cells. Liechty is trying to show that nanoparticles can decrease the inflammation around wounds, which slows the healing process. His lab is testing a conjugate of cerium oxide and regulatory microRNA, which he’s named Nanoceria.
Liechty has focused on the slow-healing open sores and wounds from which many diabetic patients suffer. His lab has shown that chronic inflammation accompanies diabetic wounds and impairs the healing process. Tests on mice with diabetes have shown the nanoparticle can correct the impaired wound healing. Liechty said it could take three to five years before human trials could begin as additional optimization and toxicity studies are needed.