Hopkins Med Newsletter 7

NEWS STORIES IN THIS ISSUE: 

• COVID-19 News: Don’t Let COVID Scare Kids (and Parents) from a Happy, Safe Halloween
• Amyloid Beta and Serotonin May Be Key to Predicting Who Develops Late-Life Depression
• Spines Exposed to Single Radiation Dose More Prone to Breaks Than If Therapy Spread Out
• Study Suggests Youth Who Use Insulin Pumps Less at Risk for Diabetic Retinopathy
• Researchers Find Altering Metabolism in Immune Cells Helps Damage Nerves Recover
• Teen’s Mysterious Condition Leads to Opening of New Johns Hopkins Children’s Center Clinic

COVID-19 NEWS:  Don’t Let COVID Scare Kids (and Parents) from a Happy, Safe Halloween

It’s almost that ghoulish time of year when jack-o’-lanterns light up the night and costumed children venture out in search of treats. This Halloween, Johns Hopkins Children’s Center (JHCC) experts say it’s important to keep up with traditions, but to do so safely in the midst of the continuing COVID-19 pandemic.

“The delta variant of the coronavirus is still very prominent, so families should be cautious,” says JHCC pediatric infectious diseases specialist Aaron Milstone, M.D., M.H.S., who also is a professor of pediatrics at the Johns Hopkins University School of Medicine. “But with many people vaccinated this year against COVID-19, there’s less risk involved than last Halloween.”

Milstone and his JHCC colleagues believe that trick-or-treating will be safer than last year when there were many unknowns and no available vaccine. Experts say it’s OK for kids to go door-to-door for candy as long as they can choose an individually wrapped treat out of a neighbor’s bowl.

“If families do decide to go trick-or-treating or celebrate Halloween in another way, parents of adolescents should consider getting their children vaccinated against COVID-19,” says Allison Agwu, M.D., Sc.M., JHCC adult and pediatric infectious diseases specialist, and a professor of pediatrics at the Johns Hopkins University School of Medicine. “All children should wear face masks if physical distancing can’t be maintained, and wash their hands or use hand sanitizer before digging into sweets.”

She adds that children should stay home if they are not feeling well.

JHCC experts say outdoor activities with a small group, such as hosting a Halloween party or scavenger hunt, or carving pumpkins and decorating the house, are safer ways to celebrate the holiday.

JHCC experts also recommend that, like every year, children stay on the sidewalk and be attentive to drivers on the road while trick-or-treating.

“This has been a challenging year for kids especially, so families should absolutely celebrate Halloween in ways that also keep kids safe and happy,” Milstone says.

Agwu and Milstone are available for interviews.

Amyloid Beta and Serotonin May Be Keys to Predicting Who Develops Late-Life Depression

Looking for ways to image the human brain for the earliest signs of aging and cognitive decline, Johns Hopkins Medicine researchers recently identified a pattern that links the accumulation of amyloid beta (Aβ) proteins (associated with cognitive decline later in life) with a reduction of serotonin, the brain chemical that improves mood. The pattern — seen with a mathematical algorithm using data collected from positron emission tomography (PET) scans in older adults — may help predict if a person is likely to develop depression later in life.

The researchers say their findings, published online Sept. 13. 2021, in the journal Translational Psychiatry, suggest that the more a person expresses this pattern, the more severe the depression might be.

“What’s unique about PET scans is that they enable us to look at chemicals localized in the living brain in relation to Aβ proteins associated with memory loss,” says Gwenn Smith, Ph.D., Richman Professor of Alzheimer’s and Related Dementias in the Department of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine. “This was fundamental for our work because we were able to test hypotheses from past research on mice with dementia for our imaging study in the human brain.”

Late-life depression, one of the most common psychiatric disorders among older people, refers to a major depressive episode — in some cases for the first time. According to the American Geriatrics Society’s Health in Aging Foundation, between 1% and 2% of American adults over age 65 have major depression — with more women than men reporting they are depressed. However, the society suggests that the numbers may actually be higher because older adults are less likely than younger people to admit, or even realize, they are depressed. Late-life depression is associated with greater risk for cognitive decline.

For their study, the researchers analyzed data collected from 40 participants over age 60 who were evenly split between men and women. Of the participants, 20 were unmedicated and were experiencing late-life depression without bipolar or psychotic symptoms. Their data were compared with those from a control group of 20 healthy, nondepressed older adults.

All participants had a series of screenings, including physical and neurological examinations, laboratory and toxicology testing, and psychiatric and neuropsychological evaluations. They also were given a standard Mini-Mental State Exam — a test used to identify cognitive impairment — as well as a psychiatric interview.

In a series of tests using radiotracers — short-acting radioactive molecules that “light up” in a PET scan — the researchers looked at both sets of participants for the amounts of Aβ and serotonin transporter (5-HTT), a protein that regulates the amount of serotonin in nerve cells. 

The data collected from the PET scans were then analyzed using a mathematical formula that identified a pattern showing how Aβ accumulation relates to 5-HTT.

The pattern, Smith says, was significantly higher in the late-life depression group, indicating that a decrease in 5-HTT is linked to higher levels of Aβ in different areas of the brain — and in turn, to depression.

The researchers also examined the relationship between the mathematically derived pattern and the severity of depression. For all study participants, the more that the decreased serotonin/increased Aβ pattern was seen, the greater were the depressive symptoms.

Lower serotonin levels, say the researchers, were previously linked to depression. Therefore, selective serotonin reuptake inhibitors — antidepressants that increase the amount of the brain chemical to a more normal level — have been prescribed for treatment of major depressive disorders, anxiety disorders and other psychological conditions.

“Our work reinforces the role of serotonin in late-life depression and the proteins associated with memory loss,” says Smith.

Smith says further research is needed to understand how these findings can best be applied to help people with depression. “Our aim is to use this as a diagnostic tool to predict who will respond best to antidepressants and who may be at risk for memory decline,” she says.

Smith is available for interviews.

Spines Exposed to Single Radiation Dose More Prone to Breaks Than If Therapy Spread Out

In an animal study published Oct. 1, 2021, in the International Journal of Radiation Oncology, Biology and Physics, Johns Hopkins Medicine researchers have provided evidence that treating spinal tumors with “fractionated” radiation therapy — doses given in a series of sessions rather than a single treatment — helps prevent vertebral compression fractures.

Timothy Witham, M.D., director of the Johns Hopkins Medicine Spinal Fusion Laboratory; Alexander Perdomo-Pantoja, M.D., a postdoctoral fellow at the Johns Hopkins University School of Medicine; and Christina Holmes, Ph.D., a former Johns Hopkins Medicine postdoctoral fellow who is now at Florida State University, worked together with colleagues on this research to explore the effects of radiation therapy on spinal bone structure.

“Radiation and tumors can weaken the bones in the spine,” says Witham. “When bones fracture, it can further complicate care and quality of life for patients, so we wanted to find the ideal way of delivering radiation to attack the tumor while minimizing the effects on bone strength and quality.”

The team looked at two ways to deliver radiation in rabbit models. One group of rabbits received a single radiation dose of 24 Gray (Gy — a typical chest X-ray is 1/10,000 of a Gy), while a second group had the total treatment spread out over three 8 Gy doses. A control group of rabbits received no radiation.

Next, the researchers analyzed the microstructure and morphology of the bones in the irradiated areas, tested the spinal biomechanics (stiffness and fracture load) of the exposed vertebrae and examined the bone cellular features from those sites.

Based on their findings, Witham and his colleagues concluded that bone is less impacted if high-dose radiation treatment is broken up into fractions rather than administered in a single dose.

“The beauty of this model is that we can look at the three-dimensional structure of the bone to measure its quality, its density and the interconnectedness of its structure,” says Holmes.

“This model was specifically designed to better understand how localized radiation leads to vertebral changes that ultimately cause fractures in patients,” says Perdomo-Pantoja. “Our team found bone samples receiving a single high dose of radiation broke easier than ones given smaller doses in separate sessions, which correlated with the microstructural and cellular damage we observed in that group.”

 The researchers next plan to study the timeline of bone fractures during radiation to better understand how and why they occur. They say that insight will enable them to start considering preventive therapies.

 “When we make a discovery in the lab and try to make it have a direct impact on patient care, it can take a long time,” says Witham. “Our current project took a few years, but the results are directly clinically translatable. Based on this study, we can immediately recommend that oncologists use fractioned radiation dosage in their practices and hopefully, prevent further suffering.”

Witham is available for interviews.

Study Suggests Youth Who Use Insulin Pumps Less at Risk for Diabetic Retinopathy

In one of the largest and most racially diverse studies to date of American children and adolescents with type 1 and type 2 diabetes, researchers at Johns Hopkins Medicine, Baylor College of Medicine and the University of Wisconsin have identified the clinical and demographic factors associated with pediatric diabetic retinopathy. The disorder, a leading cause of vision loss worldwide, is characterized by damage to the small blood vessels lining the retina (the eye’s light-focusing area).

The researchers say the most important finding from the study — posted online Sept. 27, 2021, in JAMA Network Open — is that insulin pump users among those with type 1 diabetes are less likely to develop diabetic retinopathy, independent of other risk factors, compared with youth who get their insulin through multiple daily injections.

“We knew from previous studies that insulin pump use is associated with better glycemic control [management of blood sugar level] and lower hemoglobin A1c level [HbA1c is the amount of sugar attached to hemoglobin in red blood cells and a measure of blood sugar level], so we expected that it also would be associated with a reduced risk of complications from diabetes, such as diabetic retinopathy,” says study co-senior author Risa Wolf, M.D., Johns Hopkins Children’s Center pediatric endocrinologist and assistant professor of pediatrics at the Johns Hopkins University School of Medicine. “What surprised us was that insulin pump users appear to be more ‘protected’ against retinopathy regardless of their A1c levels.”

“Another benefit of insulin pumps shown by our study is that pump users had significantly fewer admissions for diabetic ketoacidosis, a serious condition that can lead to a diabetic coma or death,” says retina specialist Roomasa Channa, M.D., study co-senior author and assistant professor of ophthalmology and visual sciences at the University of Wisconsin School of Medicine and Public Health. “This finding — along with our evidence that pump use protects against retinopathy — suggests clinicians should encourage children and adolescents with type 1 diabetes to use this technology.”

To get their results, the researchers at the three participating institutions looked at 1,640 children and adolescents with either type 1 (74%) or type 2 (26%) diabetes. The average age was nearly 16, with females making up 53% of the group. There was a diverse mix of races and ethnicities: 40% non-Hispanic white, 31% Hispanic, 23% non-Hispanic Black and 6% other (American Indian or Alaska Native, Asian, Native Hawaiian or Pacific Islander, and unspecified or undeclared).

Overall, 558 of 1,216 patients (46%) with type 1 diabetes and five of 416 patients (1.2%) with type 2 diabetes used an insulin pump. Diabetic retinopathy was found in 57 of the total 1,640 participants, or 3.5%.

“Among those with type 1 diabetes, insulin pump use was associated with a lower likelihood of diabetic retinopathy, after adjusting for four other factors: race and ethnicity, insurance status [those with private health insurance have greater access to a pump], diabetes duration and HbA1c level,” says Wolf.

“Our data also initially showed that Black youth were 2.1 times more likely to develop diabetic retinopathy than white youth,” says Channa. “However, the difference between the two groups was no longer significant after we adjusted for insurance status, diabetes duration, HbA1c level, and insulin pump use for those with type 1 diabetes.”

Wolf and Channa says that the one disparity that remained after controlling for other factors was insulin pump use.

“Pump users were more likely to be white [59%, compared with 27% of Black youth] and have private or commercial insurance,” says Wolf. “This highlights the importance of making sure state-of-the-art technology is available to all children with diabetes — with a focus on identifying barriers to access and increasing pump use in minority populations.”

Wolf is available for comment.

Researchers Find Altering Metabolism in Immune Cells Helps Damage Nerves Recover

Peripheral nerves — the nerves outside the brain and spinal cord — have the capacity for regeneration, but the rate of renewal is so slow that many nerve injuries lead to incomplete recovery and permanent disability for patients. Johns Hopkins Medicine researchers have determined that macrophages — white blood cells that surround and kill microorganisms, remove dead tissues and stimulate the action of other immune system soldiers — can be modified to support and accelerate the regeneration of peripheral nerves in mice following injury.

In a study published Sept. 7, 2021, in the Journal of Clinical Investigation, Brett Morrison M.D., Ph.D., associate professor of neurology at the Johns Hopkins University School of Medicine; Mithilesh Kumar Jha, Ph.D., postdoctoral research fellow at Johns Hopkins; and colleagues investigated whether altering the metabolism of macrophages in mice would impact the recovery from nerve injury.

Using genetic manipulations on the macrophages, the researchers determined that removing a specific metabolic transporter (a protein that facilitates movement of metabolites across membranes) — monocarboxylate transporter 1 (MCT1) — delayed recovery from nerve injury. This was accompanied by alterations in several macrophage cellular functions, including the ability to collect foreign or dead cells, and to secrete specific cytokines (proteins produced by cells in the immune system) that communicate with other immune cells to coordinate the immune system’s overall response to injury. 

Of even greater clinical interest, say the researchers, was their discovery that increasing MCT1 in macrophages led to improved recovery following neve injury in mice.

“It was surprising how effective it was,” says Morrison. “We were able to accelerate the recovery from nerve injury by increasing MCT1. This opens up new avenues for potentially treating severe nerve injuries that can occur from traumas such as a motor vehicle accident or gunshot wounds.”

Jha says another exciting advance from the study was the demonstration that macrophages that were purified outside the body and intravenously injected into mice could impact nerve recovery.

“This finding could lead to a treatment for peripheral nerve injuries — for which no medical therapy currently exists — where a person could receive an injection of their own macrophages with upregulated levels [higher amounts from increased production] of MCT1,” he explains.

Morrison says he hopes his team’s research will one day be applied to human clinical trials.

“For the first time, we have demonstrated that manipulating macrophage metabolism can actually accelerate peripheral nerve regeneration,” says Morrison. “This is an exciting pathway that could potentially be manipulated in patients to treat peripheral nerve injuries.”

Morrison is available for interviews.

Teen’s Mysterious Condition Leads to Opening of New Johns Hopkins Children’s Center Clinic

Thirteen-year-old Gregory Rhoden’s condition has been a mystery his entire life. He was born prematurely and his lungs seemed underdeveloped. While he had some respiratory issues growing up, it wasn’t until a running event in kindergarten that he began complaining of chest pain and shortness of breath. A doctor labeled Gregory’s symptoms as asthma and allergies, and referred him to an allergist.

In the fifth grade, the boy’s condition worsened. His mother, Katja Fort Rhoden, says Gregory started coughing up “yucky sputum.” She took him to the emergency department at Johns Hopkins Children’s Center (JHCC), where he was diagnosed with a chest infection.

“It looked like it was walking pneumonia, but his pulmonary function tests [PFTs] were really abnormal — even for a kid with pneumonia,” recalls Fort Rhoden. To shed some light on the mystery, Gregory was referred to JHCC pediatric pulmonologist Christy Sadreameli, M.D., M.H.S., who also is an assistant professor of pediatrics at the Johns Hopkins University School of Medicine.

After reviewing Gregory’s abnormal PFTs, Sadreameli ordered a CT scan of his lungs.  The images revealed unusual findings including emphysema. His mother had a history of chronic variable immune deficiency, an immune system disorder that increases the risk of infections, particularly in the respiratory system. Fort Rhoden’s lung disease had eventually worsened to the point that she needed a double lung transplant.

It was Gregory’s mysterious condition that spurred Sadreameli to begin forming the Childhood Interstitial Lung Disease Clinic (chILD) at Johns Hopkins with a team from JHCC’s neonatology and pulmonology departments to better understand and more successfully treat rare pediatric respiratory diseases.

Sadreameli knew that mother and son shared a similar lung disease, but what was it?

Gregory underwent testing for many known lung disorders including cystic fibrosis, as well as screening for a genetic or an autoimmune cause of his condition.

“I knew that what we were dealing with something that was extremely rare — a lung disease that had not yet been fully documented in the literature,” Sadreameli says.

The genetic workup revealed that Fort Rhoden and her son had the same mutation on the platelet-derived growth factor receptor alpha (PDGFRA) gene. This gene was known to be crucial for lung development, but mutations in the gene had not been linked with any known lung diseases in humans.

With this clue, Sadreameli spoke with her multidisciplinary team members at Johns Hopkins and contacted experts beyond the institution, who agreed that she had a compelling hypothesis — the PDGFRA mutation could explain the lung disease that Fort Rhoden and her son shared.

Sadreameli calls Gregory’s condition a diffuse lung disease of unknown etiology.

“Gregory also has emphysema and a bleeding disorder [pulmonary capillaritis] in his lungs,” she says. “It is uncommon to have both at the same time, and his mom has a very similar disorder.”

She adds that Gregory and his mother likely have a genetic disease that impacts the lungs and immune system.

“He has taught me much over the years as I cared for him clinically, which has impacted the direction of my research program and my current interests,” Sadreameli says. “I really feel that Gregory is the one-of-a-kind patient that changed things for me.”

Sadreameli has received a grant to study the disease at new chILD clinic that she and her colleagues started to better care for patients like Gregory and other patients with unusual pediatric lung disorders. Johns Hopkins also is part of the national registry —established by the Children’s Interstitial Lung Disease Research Network — which collects data about patients with such disorders that can inform research and treatments.

“It’s a clinical research initiative that could open the door to understanding new ways children can get lung disease,” says Sadreameli. “There may be other children like Gregory in the future, so if we can identify their problems, we could discover other new diseases.”

Sadreameli says Gregory may need to have a lung transplant in the future. “My goal is to make that as long from now as possible, or maybe prevent needing it altogether” she says.

Gregory, a fan of video games, model building and science, is aware that he might need a transplant someday. His mother says “he thinks it’s cool.”

Fort Rhoden says that in spite of his lung disease, Gregory attended space camp when he was younger, and now won’t let anything deter his dream of becoming an astrophysicist.

“His condition is a heavy load to carry, and it has disrupted his teenage years a lot,” she says. “But he’s been remarkable in keeping moving. He’s got a really positive outlook as a kid and takes things in stride.”

Sadreameli, Fort Rhoden and Gregory are available for interviews.

See also: Uncovering an Unknown Lung Disease