US Pharm. 2024;49(3):38-42.
Asthma Rates Climb in High Schoolers as Cannabis Use Grows
Asthma is more common among high school students who use cannabis compared with those who do not, and the prevalence of asthma increases with the frequency of its use among the students, according to a study at Columbia University Mailman School of Public Health and the City University of New York. The findings are published in the journal Pediatric Pulmonology.
The paper, titled “Asthma prevalence among US 9th-12th graders who report past 30-day cannabis use in 2019,” sheds light on the correlation between recent cannabis use and asthma prevalence among American high school students, adjusting for demographic characteristics and cigarette use.
Data were drawn from the 2019 Youth Risk Behavior Surveillance System, a CDC national high school survey, which collects data from students in grades 9 to 12 across the U.S. biannually. The research team, led by Renee Goodwin in the Department of Epidemiology at Columbia Public Health, utilized logistical models to examine the prevalence of asthma with past 30-day cannabis use and current cigarette, alcohol, and state-of-residence cannabis legal status, adjusting for sex, race, and ethnicity.
Cannabis use was more common among females (17% vs. 14% male users) and non-Hispanic black and Hispanic youth relative to non-Hispanic white youth (17% and 16%, respectively, vs. 14.6%). Cannabis use was much more common among the students who reported any past 30-day cigarette or alcohol use (45% vs. 6.5% for nonusers). Declines in cannabis use were observed independent of state-level cannabis law from 2013 to 2021, and cannabis-use prevalence did not differ significantly by state-of-residence cannabis legal status among the 24 participating states in 2021.
Commenting on the significance of the research, Dr. Goodwin and colleagues believe that the study adds to the growing body of evidence linking cannabis use to adverse health outcomes among young people. “Understanding these associations is crucial for developing effective prevention and intervention strategies to protect the health and well-being of our youth.”
Dr. Goodwin, who is a clinical psychologist and expert in psychiatric and substance use epidemiology, added, “The findings of this study have important implications for public health, education, and drug prevention programs targeting high school students, although more public health and clinical research is needed. Scientific data that can inform clinical guidelines and public health policy, as well as parents and youth, on the potential relationship between cannabis use and respiratory health among youth, is critical, and we urge that more studies like this one be a priority.”
New Treatment to Reverse Inflammation, Arterial Blockages in RA?
Researchers from Queen Mary University of London, England, have found that the molecule RvT4 enhances the body’s natural defenses against atherosclerosis in patients with rheumatoid arthritis (RA). Studies in mice, undertaken by researchers from Queen Mary University of London’s William Harvey Research Institute and Centre for Inflammation and Therapeutic Innovation, show that increasing levels of the RvT4 molecule in the body improves the ability of the body’s own defense mechanisms (macrophages) to reduce local inflammation and remove blockages in blood vessels.
This breakthrough in understanding the processes involved could lead to better treatments for people with RA, who are at higher risk of developing cardiovascular disease. Alongside the more widely known symptoms of joint inflammation, people with the condition are also twice as likely as others to develop blood vessel disease. This can lead to serious complications and an increased risk of premature death.
One type of blood vessel disease seen in people with RA is atherosclerosis, which is caused by a buildup of plaque along the artery walls. This causes the arteries to harden and narrow, making it more difficult to circulate blood around the body. These blockages can also break free, causing heart attacks and strokes.
Understanding the reasons why RA patients are at increased risk of these cardiovascular problems is critical in developing better treatments for this group and others. To gain a better grasp of the causes of blood vessel disease in patients with RA, researchers explored the role of a group of molecules called 13-series resolvins (RvTs). In experimental arthritis, the levels of one of these molecules, RvT4, are markedly reduced, a phenomenon that associates with a higher degree of blood vessel disease.
The study found that treating arthritic mice with RvT4 reduced blood vessel inflammation by reprogramming macrophages, a group of white blood cells that accumulate in the diseased vessels, to release stored lipids. Researchers observed that these lipids were preventing the macrophages from carrying out their usual work of clearing dead cells and reducing localized inflammation in blood vessels.
Once freed of their lipid burden, the macrophages were able to move and work much more effectively to reduce the causes of atherosclerosis. The observation that RvT4 restores protective macrophage biological activities is a meaningful finding for people with RA, who also often present with metabolic dysfunction that is thought to exacerbate vascular disease.
The study found that administration of RvT4 to mice engineered to develop characteristics of metabolic dysfunction, advanced atherosclerosis, and arthritis led to an overall decrease in lipoprotein-associated cholesterol in plasma and an increase in the ratio of HDL-associated cholesterol to total cholesterol.
Jesmond Dalli, professor in the Molecular Pharmacology and Lipid Mediator Unit, director at the William Harvey Research Institute, said, “The study is important because it identifies for the first time the loss of RvT4 production as a potential new cause of blood vessel inflammation in the context of arthritis, offering a mechanistic explanation on the cause of this important disease in RA patients. It also showed that RvT4 restores the biological activities of lipid-loaded macrophages by promoting lipid breakdown and efflux from the cells, an observation that can guide the development of new treatments to limit the incidence and/or severity of cardiovascular disease in patients with RA.”
Dysregulation of macrophage biological responses by lipid accumulation is also involved in the onset and development of many other conditions, including obesity. Medicines derived from RvT4 or RvT4-based compounds may therefore be useful to limit inflammation and promote the release of accumulated lipids out of macrophages in patients with a number of other medical conditions.
Different MS Pain Types Can Inhibit Exercise
For patients with multiple sclerosis (MS), a regular exercise routine is important for managing symptoms. Due to different causes of chronic pain, however, physical exercise can be more difficult for some. Research from the University of Michigan published in the Journal of Pain found that widespread pain with nociplastic features (WPNF) can make engaging in physical activity a painful task for some patients with MS.
“WPNF is a chronic and diffuse pain which can be challenging to localize or describe precisely,” said Libak Abou, PhD, a research assistant professor and lead author of the paper.
“In a person with MS, this type of pain arises from altered processing signals within the central nervous system. This is opposed to pain that arises from specific tissue damage, classified as nociceptive pain, or pain related to demyelination and axonal damage, classified as neuropathic pain.”
Dr. Abou and fellow researchers surveyed patients with MS to see if those with a higher indication of WPNF were more likely to be insufficiently active or sedentary compared with their MS counterparts with no chronic pain, nociceptive pain, or neuropathic pain. Each of the participants self-reported data.
The results of the survey showed that those who experienced WPNF in addition to their MS were not sufficiently active due to the chronic pain they were experiencing. “There is a growing need to consider what type of pain MS patients are experiencing before giving them an exercise plan,” said Dr. Abou. “The concept of considering WPNF when creating exercise plans for MS is newer but could help many patients get to an activity level that will help ease symptoms without causing them intense pain.”
In the future, Dr. Abou hopes that clinicians can begin doing screenings for underlying pain mechanisms in patients with MS who are struggling to stay active to help further tailor their physical routines to their personal needs. “The end goal is to help those with MS maintain their functional independence,” he said, adding, “It is also important to remember that these patients will likely need extra support from their physical therapy team to keep them on a path with less pain.”
Early Treatment a Key to HIV Remission
People living with HIV need to take antiretroviral treatment for life to prevent the virus from multiplying in their body. But some people, known as post-treatment controllers, have been able to discontinue their treatment while maintaining an undetectable viral load for several years. Starting treatment early could promote long-term control of the virus if treatment is discontinued.
Scientists from the Institut Pasteur, the CEA, Inserm, Université Paris Cité and Université Paris-Saclay, in collaboration with Institut Cochin and with the support of MSD Avenir and ANRS Emerging Infectious Diseases, used an animal model to identify a window of opportunity for the introduction of treatment that promotes remission of HIV infection: It appears that starting treatment 4 weeks after infection promotes long-term control of the HIV virus following the interruption of treatment after 2 years of antiretroviral therapy.
These results highlight how important it is for people with HIV to be diagnosed and begin treatment as early as possible. The findings were published in the journal Nature Communications.
Research on the VISCONTI cohort, composed of 30 post-treatment controllers, has provided proof of concept of possible long-term remission for people living with HIV. These individuals received early treatment that was maintained for several years. When they subsequently interrupted their antiretroviral treatment, they were capable of controlling viremia for more than 20 years in some cases.
At the time (in 2013), the team leading the VISCONTI study suggested that starting treatment early could promote control of the virus, but this remained to be proven. In this new study, the scientists used a primate model of SIV2 infection. This allowed them to control all the parameters (sex, age, genetics, viral strain, etc.) that may have an impact on the development of immune responses and progression to disease.
They compared groups that had received 2 years of treatment, starting either shortly after infection (in the acute phase) or several months after infection (in the chronic phase), or no treatment. The reproducible results show that starting treatment within 4 weeks of infection (as was the case for most of the participants in the VISCONTI study) strongly promotes viral control after discontinuation of treatment. This protective effect is lost if treatment is started just 5 months later.
“We show the link between early treatment and control of infection after treatment interruption, and our study indicates that there is a window of opportunity to promote remission of HIV infection,” said Asier Sáez-Cirión, head of the Institut Pasteur’s Viral Reservoirs and Immune Control Unit and co–last author of the study. The scientists also demonstrated that early treatment promotes the development of an effective immune response against the virus.
Although the antiviral CD8+ T immune cells developed in the first weeks after infection have very limited antiviral potential, the early introduction of long-term treatment promotes the development of memory CD8+ T cells, which have a stronger antiviral potential and are capable of effectively controlling the viral rebound that occurs after treatment interruption.
“We observed that early treatment maintained for 2 years optimizes the development of immune cells. They acquire an effective memory against the virus and can eliminate it naturally when viral rebound occurs after discontinuation of treatment,” explained Dr. Sáez-Cirión.
These results confirm how important it is for people with HIV to be diagnosed and begin treatment as early as possible. “Starting treatment 6 months after infection, a delay that our study shows results in a loss of effectiveness, is already considered as a very short time frame compared with current clinical practice, with many people with HIV starting treatment years after infection because they are diagnosed too late,” noted Roger Le Grand, director of Infectious Disease Models for Innovative Therapies and co–last author of the study.
“Early treatment has a twofold effect: individually, as early treatment prevents diversification of the virus in the body and preserves and optimizes immune responses against the virus; and collectively, as it prevents the possibility of the virus spreading to other people,” added Dr. Sáez-Cirión.
Finally, these results should guide the development of novel immunotherapies targeting the immune cells involved in the remission of HIV infection.
Epilepsy Drug Shows Promise in Slowing Osteoarthritis
Yale University researchers have identified a drug target that may alleviate joint degeneration associated with osteoarthritis, a debilitating condition that afflicts as many as 30 million people in the United States alone. Their findings were published in the journal Nature.
Pain relievers and lifestyle changes, such as exercise and reduced excess weight, have long been the therapies most used to treat the joint stiffness and pain caused by degenerative disease. There is a pressing need for therapies, however, that can prevent joint breakdown that occurs in osteoarthritis.
It is known that specialized proteins known as sodium channels found in cell membranes produce electrical impulses in “excitable” cells within muscles, the nervous system, and the heart. In previous research, Yale’s Stephen G. Waxman identified the key role of one sodium channel, called Nav1.7, in the transmission of pain signals.
The laboratories of Chuan-Ju Liu, the Charles W. Ohse Professor of Orthopedics, and Dr. Waxman, the Bridget M. Flaherty Professor of Neurology and professor of neuroscience and pharmacology, both at Yale School of Medicine, have found that the same Nav1.7 channels are also present in nonexcitable cells that produce collagen and help maintain the joints in the body.
Osteoarthritis, the most common form of arthritis, is a degenerative disease caused by the breakdown of cartilage that eases friction between the joints, occurring most commonly in the hands, hips, and knees. In the new study, the researchers deleted Nav1.7 genes from these collagen-producing cells and significantly reduced joint damage in two osteoarthritis models in mice. The researchers also demonstrated that drugs used to block Nav1.7, including carbamazepine, a sodium channel blocker currently used to treat epilepsy and trigeminal neuralgia, also provided substantial protection from joint damage in mice.
“The function of sodium channels in non-excitable cells has been a mystery,” Dr. Waxman said. “This new study provides a window on how small numbers of sodium channels can powerfully regulate the behavior of non-excitable cells.”
“The findings open new avenues for disease-modifying treatments,” added Wenyu Fu, a research scientist in the Liu laboratory and first author of the study.
Cholesterol-Lowering Therapy May Hinder Aggressive Colorectal Tumors
Hard-to-detect colorectal precancerous lesions known as serrated polyps, and the aggressive tumors that develop from them, depend heavily on the ramped-up production of cholesterol, according to a preclinical study from researchers at Weill Cornell Medicine. The finding points to the possibility of using cholesterol-lowering drugs to prevent or treat such tumors.
In the study, published in Nature Communications, the researchers analyzed mice that develop serrated polyps and tumors, detailing the chain of molecular events in these tissues that leads to increased cholesterol production.
They confirmed their findings in analyses of human serrated polyps and tumors. In mouse models that replicate human cancer, the scientists showed that blocking cholesterol production prevented the progression of these types of intestinal tumors.
“Serrated-type polyps and tumors currently are not treated differently from other colorectal neoplasias, but as our work shows, they have this specific metabolic vulnerability that can be targeted,” said study co–senior author Jorge Moscat, a Homer T. Hirst III Professor of Oncology in Pathology, vice-chair for Cell and Cancer Pathobiology in the Department of Pathology and Laboratory Medicine, and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
The other co–senior author is Maria Diaz-Meco, also a Homer T. Hirst III Professor of Oncology in Pathology and a member of the Meyer Cancer Center at Weill Cornell Medicine. The study’s first author is Yu Muta, a postdoctoral associate in the Moscat/Diaz-Meco laboratories.
Cholesterol is generally considered a progrowth molecule, a building block for cell membranes and having other growth-supporting functions. Prior studies have linked high blood cholesterol levels to various cancers, including colorectal cancers. It has not been clear, however, that lowering cholesterol, for example with common statin drugs, can prevent development of colorectal cancers.
“Trials of statins to prevent colorectal cancer have had conflicting results,” Dr. Diaz-Meco said. “Our findings suggest that this is because targeting cholesterol has a preventive but selective effect only against polyps and tumors of this serrated type.”
Serrated polyps, which have a sawtooth appearance under a microscope, are flatter than ordinary colorectal polyps and can often be missed during colonoscopies. Yet, the tumors into which they develop, which account for roughly 15% to 30% of colorectal cancers, contain many “metaplastic” cells that are particularly invasive and resistant to treatments.
Several years ago, the Moscat/Diaz-Meco team linked serrated polyps and tumors to low levels of two enzymes known as aPKCs.
Older Organs Accelerate Aging in Transplant Recipients
Most organ transplantations involve supply from older donors to younger recipients. Aging cells can become senescent, a condition in which they stop multiplying and secrete chemicals that negatively affect neighboring cells. Senescent cells accumulate in older donor organs and have the potential to compromise transplant outcomes.
A study led by researchers from Brigham and Women’s Hospital found that in preclinical models, transplanting older organs can trigger senescence in younger recipients. They observed that young and middle-aged mice that received heart transplants from older mice had impaired physical capacity, with reduced running times and grip strengths. Middle-aged mice that received older hearts also showed increased anxiety-related behavior, impaired memory, and poorer learning performance.
The authors found that the accelerated aging-related effects in younger recipients were driven by the release of senescence-associated factors and mitochondrial DNA from older transplants. Treating older donor mice with senolytics, or senescence-inhibiting drugs, before organ extraction reduced symptoms of senescence in the recipient mice.
“Currently, due to insufficient supply in clinical organ transplantation, donor and recipient ages differ substantially,” said principal investigator Stefan G. Tullius, MD, PhD, of the Division of Transplant Surgery. “Our results suggest that senolytic treatments can be a potential therapeutic approach for improving the outcomes of older organs.
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