News for nerds

Research reveals how osteocytes form critical structures that maintain bone health

Embedded within bone tissue are osteocytes, cells with tree-like projections called dendrites that are important for receiving communication from other cells. The loss of dendrites that occurs during aging contributes to bone fragility and osteoporosis. In a study published in Nature Communications, an international team led by investigators at Massachusetts General Hospital (MGH) has revealed how osteocytes form dendrites—a discovery that might lead to strategies to maintain these projections and therefore help protect individuals’ bone health throughout life.

In their study, the researchers found that deletion of Sp7, a gene linked to both rare and common skeletal diseases, in osteocytes causes severe defects in osteocyte dendrites. This gene codes for a protein called a transcription factor, which controls the expression of other genes. The team found that the Sp7 transcription factor targets a gene called osteocrin, which promotes osteocyte dendrite formation. In mice, turning the osteocrin gene on made up for the absence of Sp7 and reversed defects in osteocyte dendrites.

“In this work, we demonstrate key roles for the transcription factor Sp7 and its target osteocrin in orchestrating a gene regulatory network needed to promote healthy connections between bone cells,” says senior author Marc Wein, MD, Ph.D., an investigator in the endocrine unit at MGH and an assistant professor of medicine at Harvard Medical School. “Understanding how osteocytes maintain this network of connections opens up exciting possibilities for new ways to treat osteoporosis and other diseases where bones are prone to fracture.”

Naloxone shortage could lead to thousands of overdose deaths, experts warn

It was New Year’s Eve. Devin Lyall sat in the back bedroom of her drug dealer’s house.

Her thin fingers fumbled with the syringe. Her fingers weren’t the only frail thing about her—in the past few months she had lost about 40 pounds, leaving her practically skin and bones.

She was using Opana, a strong narcotic, melting the small, circular pills into a liquid that she could inject.

As the dregs of 2012 trickled into the New Year, Lyall didn’t have much hope. It was as if her life was ticking away as quickly as the seconds remaining before midnight.

She was shaking, chills running through her body, yet she was so hot she felt like she was on fire. She kept injecting, hoping it was the relief her body needed.

She woke up later, lying in a hospital bed. Her mother and father stood over her. She wasn’t sure when or how she had gotten there.

Lyall had overdosed.

The drug dealer had called her mother, who rushed her to Wilkes Medical Center. They made it in time for doctors to give Lyall the reversal drug naloxone, saving her life.

“I remember in that moment feeling very helpless, but relieved,” Lyall said. “I was so glad that I wasn’t in that house anymore and that maybe I had an opportunity to do something different. It was the first time in a long time that I thought maybe I can get help.”

She began the new year in the ICU for seven days, a regular room for 10 more, and detox for 14 after that.

The anti-overdose drug

Naloxone blocks the nervous system’s opiate receptors. It is most commonly used for drug overdoses—Narcan is a well-known brand name.

In August, Pfizer halted production of its single-dose injectable naloxone due to a manufacturing issue. This naloxone is used by many grassroots harm reduction coalitions across the state.

Dr. Nabarun Dasgupta, drug and infectious disease scientist at UNC Gillings School of Global Public Health, and others estimate the naloxone interruption could result in about 1 million fewer doses, which could lead to as many as 18,000 avoidable overdose deaths.

In 2012, the year Devin overdosed, naloxone and overdose kits weren’t common in clinics, harm reduction coalitions, or other local organizations. Hardly any individual had them on hand. In a way, Devin was fortunate. She had a dealer who called her mother, and her mother responded. Many who overdosed at the time weren’t as lucky.

Now, naloxone is more accessible—on pharmacy shelves, part of local syringe exchange programs, and often in first responders’ hands. This access is crucial, especially as opioid overdose deaths rose to an all-time high in North Carolina in 2020.

The change is largely a result of North Carolina’s 2016 naloxone standing order, which allows pharmacists to dispense naloxone to those who need it and for community distribution. But addiction recovery experts say the standing order is not doing enough to blunt the rapid rise of opioid addiction.

“There’s a third tier of programs around the state that rely on other programs to purchase naloxone for them,” Dasgupta says. “So, these are sponsored programs, programs run by people of color serving people of color, and they are ones that don’t have the official paperwork to buy and purchase naloxone—but have the really critical infrastructure to get it to where it needs to go.”

Getting naloxone to these local harm reduction groups is critical, because this is often where active users—who are most at risk—go for naloxone.

The standing order only covers distribution—not purchasing. Pharmaceutical companies producing naloxone require a prescription. This is where the nuances of the North Carolina order stand in the way of getting naloxone to the organizations where it is most effective.

“The standing order, it’s kind of a sham,” Dasgupta says. “Our legislature came up with a piecemeal, almost useless version of a law that created this standing order, then feel like they’ve done something and wash their hands of it. What would have really helped is for these smaller programs to be able to order naloxone directly from pharmaceutical distributors.”

With rising overdoses, a flawed standing order, and a shortage of Pfizer naloxone, North Carolina faces what could be a nightmare.

People die without naloxone

Louise Vincent is the executive director of the N.C. Urban Survivors Union, a grassroots Greensboro group working to support and assure safety for opioid users in the community through syringe exchanges and by providing naloxone.

“If I didn’t have naloxone I couldn’t go to work'” Vincent says. “I could not look someone in the face and tell them I don’t have naloxone and send them to die—because you’re literally sending someone off to die if you don’t have it.”

This reality landed on national consultant Robert Suarez’s doorstep at Urban Survivors just a few weeks ago. A young woman ran into the center screaming. Her friend was overdosing in her car right outside. Suarez grabbed two bottles of naloxone, ran outside, opened the passenger side door, climbed on top of the overdosing man, and administered the lifesaving drug.

After he injected the naloxone, Suarez said he gave him mouth-to-mouth during the four minutes it took the naloxone to work.

“Four minutes is an eternity when someone isn’t breathing on their own,” Suarez says.

A month into Pfizer’s naloxone shortage, the Urban Survivor’s Union supplies remain sufficient—for now.

But the fear of coming up short is pervasive.

“I’m acutely aware that there’s a shortage, and I want to be mindful,” Vincent says. “I cannot run out. I will not run out. Bottom line is I won’t run out. There’s expired naloxone that I’ve already figured out how to access. We’re pretty scrappy people, I’m going to find it.”

Alternate sources

Another way harm reduction groups are coping with this shortage is by getting naloxone from larger organizations across the state with the ability to purchase from other pharmaceutical distributors.

One of these groups helping provide naloxone is Project Lazarus in Wilkes County. They have a medical director able to order the drug.

“We’ve worked with what stock we have, and every time we have looked at getting naloxone it wasn’t just for ourselves,” says Fred Brason, executive director and founder. “I’ve given Louise Vincent naloxone, I’ve given it to Twin Cities Harm Reduction.”

Brason explains that studies show that people who go to a pharmacy for naloxone are usually family members or friends of users, rather than the users themselves.

“Within the harm reduction circle there is a huge concern—there never has been the full access that is necessary to make the difference naloxone can,” Brason says. “Any reduction from what was already not sufficient is going to create major problems.”

A waitress saves a life

Tracy Coins, a waitress in Greensboro, relies on the Urban Survivors Union for naloxone.

“The circle of people that I travel in wouldn’t go anywhere else but Urban Survivors,” Coins says. “They don’t want to walk into places like CVS or Walgreens because those people are so judgmental.”

In August, Coins saved someone overdosing right in front of her with the naloxone she had on hand.

She was with a group of people at a friend’s house, and they were all doing heroin. Suddenly, one man curled up, his body as tense as a rubber band stretched to its limits, his arms and legs locked up. Coins looked around the room and realized that no one had any idea how to help.

“I carry naloxone with me all the time if I can,” she said. “The only place I get it is through Urban Survivors.”

Coins gave him naloxone and mouth-to-mouth until he came to.

Local harm reduction agencies acknowledge that there are people who are going to use drugs. By providing naloxone, and hosting syringe exchanges, they give these people the option to have a safer experience.

From addict to recovery

After Lyall’s near-fatal New Year’s Eve, she got clean. She gradually got her life back—her house, her kids, and she reconnected with her family.

Today, she is the founder and executive director of Wilkes Recovery Revolution.

Wilkes Recovery focuses on helping people overcome addiction, and is a harm reduction center—working to assure users are safe, distributing Nnaloxone, and trying to decrease stigma.

“Syringe exchange programs are truly the people that are boots on the ground,” Lyall says. “We’re the ones intersecting with people who use drugs and serving them on a daily basis, yet we are the last to get naloxone, when I think it should probably the other way around, So, if there’s a shortage, then we’re definitely hurting at the grassroots level, as a syringe exchange.”

Pfizer expects its naloxone shortage to continue through February 2022, leaving harm reduction groups to continue relying on sources whose naloxone supplies are diminishing.

Lyall says she had a wonderful life before her addiction. A supportive, upper middle-class upbringing. A good job and a family of her own.

When she slipped down some icy stairs at a ski resort, shattering her ankle, she had no idea that the pain medicine she would be prescribed would be the start to a crippling addiction.

Now, Lyall reflects on pulling herself out of the depth of her addiction, how difficult this was, and how lucky she was to get naloxone in time to save her life.

At Wilkes Recovery Center, she wants to give people this same chance.

“When I moved back home, my mission was to give other people the opportunities that I had,” she says. “I understand that I was a privileged person and that not everybody gets those same options and opportunities and that I was very lucky to have.”

Newly discovered skin cell may underlie inflammatory skin disease

The surprise discovery of a new type of cell explains how distress to the skin early in life may prime a person for inflammatory skin disease later, according to a new study by UC San Francisco researchers in the Oct. 27 issue of Nature. Knowledge of this new cell type will likely lead to greater insight on how to reverse autoimmune disorders such as scleroderma, and shed light on the nature of inflammatory disease in general, the researchers said.

“The results reinforce the idea that what you’re exposed to initially may have lasting ramifications,” said Michael Rosenblum, MD, Ph.D., principal investigator on the study. “It appears that early exposure to inflammation can, through these cells we discovered, imprint an ability for tissues to develop inflammatory disease later in life.”

The team learned about the new type of cell while investigating the effects of a set of actions known to evoke immune response in mice. One of these actions involved knocking out a group of skin cells that suppress the immune system. In the absence of that regulation, Rosenblum said, the researchers saw the presence of a unique cell that seemed to be acting as a shelter for pathogenic immune cells that aren’t usually seen in skin tissues.

“We had to knock out one cell population to see that they were controlling the growth and capacity of these other, unknown cells,” he said, noting that the new cells became apparent only in the tissue that had been exposed to inflammatory triggers. “What normally would be a deserted island on the skin was now inhabited by all these strangers,” he said.

The team dubbed the strangers “TIFFs” (Th2-interacting fascial fibroblasts) after the Th2 immune cells that they help to house. The location of TIFFs in the skin suggests that they belong to a group of cells that make up fascia, the fibrous connective tissue that surrounds and connects organs throughout the body, said lead author Ian Boothby, a graduate student in Rosenblum’s lab.

“Because most organs have fascia of some sort, what we’re learning about TIFFs in skin may well be widely applicable to the rest of the body, meaning that these cells may play a role in a huge number of inflammatory diseases,” he said.

‘Home for Immune Cells’ Opens Its Doors

Boothby and Rosenblum saw that when the skin lacking regulatory cells is subjected to inflammatory triggers, the population of TIFFs expands like wildfire, and the TIFFs become a sort of holding pen for the Th2 immune cells. Later in life, when even a small insult to the skin presents itself again, Rosenblum said, the TIFFs open their floodgates, letting the Th2 cells out.

“All you need to do is push the immune system just a little bit, with a wound or with stress, to unleash all the pathogenic cells living in these TIFFs and create an exaggerated inflammatory response,” he said.

That exaggerated response, the researchers hypothesize, may manifest as the creation of fibroses in the fascia, the driving force behind inflammatory skin diseases such as scleroderma, which affects about 50,000 Americans.

The team’s next move was to confirm the presence of TIFFs in human skin. They obtained samples from volunteers with eosinophilic fasciitis (EF), a rare inflammatory disorder in which white blood cells called eosinophils build up in the skin fascia, the fibrous tissue which lies between the skin and the muscles below it.

When they compared the EF samples to those of healthy skin, the researchers found TIFFs in both types of skin sample, but the two looked completely different. In healthy skin, the fascia forms a thin, spidery network between fat cells, while in the EF skin sample, the cells had expanded to form thick bands of fibrous tissue.

Solving the Mysteries Underlying Inflammation

It turns out that TIFFs are present in every organ of the body, said Rosenblum. They’re usually found in the fascia that surrounds our major organs and serve a role in maintaining structure. They’re also prone to interacting with immune cells. He postulates that TIFFs might have evolved as a sort of emergency brigade in case of injury, able to jump-start repair in the case of internal injury.

“In patients with scleroderma or other fibrosing diseases like EF, that repair program may be kind of co-opted, resulting in this chronic wound-healing response,” said Rosenblum. “If we can understand the biology of these cells, we can come in with drugs that revert them back to what they’re supposed to be doing.”

Taking that approach is vital to addressing the broad array of inflammatory diseases for which there are often no good treatments.

“There are lots of therapies that reduce inflammation, but we don’t have good ways of restoring the affected organs to full health,” he said. “So, learning about how cells like these TIFFs interact with immune cells to drive inflammatory disease is critical to developing treatments that address its cause, rather than its symptoms.”

Tobacco-free nicotine’ claims could lead non-smokers to try E-cigarettes

“Tobacco-free nicotine” claims may reduce young adults’ perception of the health risks of e-cigarettes, according to a Rutgers study
Young adults who do not use tobacco products report higher intentions of using Puff Bar, a leading e-cigarette brand that has a “tobacco-free nicotine” claim, than products with the regular claim of containing nicotine, according to a Rutgers study.

The study, published in the journal Tobacco Control, also found that the claim may reduce young adults’ perception that the products might cause health risks and may prompt the use of the Puff Bar brand over other e-cigarette brands and types.

E-cigarettes that contain nicotine derived from tobacco are subject to FDA regulation and many local tobacco control policies as tobacco products, but products made with synthetic nicotine currently fall into a regulatory gap.

“Many e-cigarette brands now are marketed with ‘tobacco-free nicotine’ or ‘synthetic nicotine’ claims to circumvent local and federal tobacco control measures, such as flavored e-cigarette sales restrictions and the minimum tobacco purchasing age of 21,” said co-author Julia Chen-Sankey, a researcher at the Center for Tobacco Studies at Rutgers University and an assistant professor at Rutgers School of Public Health.

The online study asked 1,822 people aged 18 to 29 who either never used tobacco or who only had experimented with it to view depictions of Puff Bar e-cigarettes with either the claim that the product contains “tobacco-free nicotine,” as it is marketed, or simply “contains nicotine.” They were then asked if they would use these products if they had the opportunity, how harmful they think they are to health, whether they felt positive or negative if they used these products and if they would be more or less likely to use the Puff Bar product versus another e-cigarette brand.

“The results are concerning given that little is known about the health effects of using tobacco-free nicotine products and regulations are not immediately clear,” said Chen-Sankey. “An increasing number of e-cigarette brands and products are marketed with ‘tobacco-free nicotine’ or similar claims like ‘non-tobacco nicotine’ or ‘synthetic nicotine.’ If such claims increase the likelihood of e-cigarette use among young people who may not otherwise use e-cigarettes as we found, regulatory actions need to be taken immediately to prevent increased use of e-cigarettes among young people.”

Cerebrovascular abnormalities in Alzheimer’s disease: An adrenergic approach

Aging-US has published “Involvement of cerebrovascular abnormalities in the pathogenesis and progression of Alzheimer’s disease: an adrenergic approach” which reported that alzheimer’s disease, as the most common neurodegenerative disease in elder population, is pathologically characterized by β-amyloid plaques, neurofibrillary tangles composed of highly-phosphorylated tau protein and consequently progressive neurodegeneration.

Increasing lines of evidence from both clinical and preclinical studies have indicated that age-related cerebrovascular dysfunctions, including the changes in cerebrovascular microstructure, blood-brain barrier integrity, cerebrovascular reactivity and cerebral blood flow, accompany or even precede the development of AD-like pathologies.

In this review, the authors provide an appraisal of the cerebrovascular alterations in AD and the relationship to cognitive impairment and AD pathologies. Moreover, the adrenergic mechanisms leading to cerebrovascular and AD pathologies were further discussed.

Dr. Song Li and Dr. Jun Tan from Chinareport that “Alzheimer’s disease (AD) is the most common form of neurodegenerative disease in elder population worldwide.”

It is estimated that, by 2060, the number of AD patients in Americans age 65 and older may increase to 13.8 million from 6.2 million today. AD is clinically characterized as cognitive decline and psychiatric manifestations. AD is a progressive neurodegenerative disorder that can start decades before the appearance of clinical symptoms. Although several pathological mechanisms of AD have been identified, the authors believe that no satisfactorily effective therapeutics has been developed. Recently, cerebrovascular dysfunctions, as a possible cause in the development and progression of sporadic AD, have gained increasing attention.

Recent findings further highlighted the prevalence of cerebrovascular disorders in Down syndrome patients and added to a growing body of evidence implicating cerebrovascular abnormalities as a core feature of AD rather than a simple comorbidity.

Moreover, adrenergic system, including /β adrenergic receptors and their downstream molecular signaling process, might serve as the key approach to modulate these cerebrovascular abnormalities and progressive neurodegeneration.

The Li/Tan Research Team concluded that increasing lines of evidence from either preclinical or clinical studies have revealed that the cerebral vascular alterations during early stages of AD may contribute to the pathogenesis and progression of the disease. Cerebral vascular assessment may provide promising tools for AD early diagnosis and cerebral vascular remodeling may yield benefits to AD therapy.

Mother’s weight before pregnancy, not weight gained during pregnancy, has impact on development of allergic diseases

A University of Ottawa-led study of nearly 250,000 children in Ontario over seven years—the largest of its kind—found a mother’s weight before pregnancy may impact their newborn’s risk of developing allergic diseases in early childhood, whereas weight gain during pregnancy did not seem to have the same effect.

Here are the key points from the study, led by Sebastian Srugo, who was a graduate student in the School of Epidemiology and Public Health at the Faculty of Medicine:

No link found between a mother’s weight gain during pregnancy and childhood allergic disease.

Children born to obese mothers in pregnancy were more likely to develop asthma, but slightly less likely to develop dermatitis and anaphylaxis. Specifically, children born to obese mothers before pregnancy had an 8 percent higher risk of developing asthma.

Approximately half of the infants were born to overweight or obese mothers and a third to mothers who gained excess weight during pregnancy.

Mothers are entering pregnancy overweight/obese, gaining excess weight during pregnancy, and many children are developing allergic disease in early childhood.

In Canada, approximately 30% of the population suffers from at least one allergic disease, with an even greater prevalence among children.

Globally, trends in allergic diseases have reached epidemic proportions, becoming the most common and earliest-onset group of chronic disease.