Exploring potential adverse effects of marijuana use during pregnancy

In one of the most comprehensive examinations to date of marijuana use during pregnancy, Torri D. Metz, MD, MS, a University of Utah Health associate professor of obstetrics and gynecology, will evaluate the drug’s effects on the health of both mother and child throughout gestation.

The study, supported by the National Institute on Drug Abuse, will focus on the risk of adverse outcomes for newborns, including placenta dysfunction and inhibited fetal growth in the womb. It will also assess whether marijuana increases the probability of preeclampsia and gestational hypertension among expectant women.

Marijuana is the most commonly used drug during pregnancy, but little is known about its potential effects on mother and child. Previous studies have found substantial evidence that the drug can lower birth weights. However, these studies have relied on self-reporting from mothers-to-be or clinical toxicology testing rather than evaluating biological samples directly.

To remedy that problem, Metz and her colleagues will study biological samples previously collected from more than 9,200 women who participated in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be. They will evaluate urine samples from the first, second, and third trimester of pregnancy. They will also assess a segment of umbilical cord to look for marijuana metabolites.

“In this study, we will be able to more rigorously evaluate the relationship between marijuana use and adverse pregnancy outcomes by testing for marijuana metabolites in biological samples across the course of pregnancy,” Metz says. “Not only will we be able to examine if any use influences outcomes but we can also look at whether timing and amount of use is important.”

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Study reinforces drug’s potential to treat hypertrophic cardiomyopathy

Research at Washington State University sheds new light on one molecule that may be used to treat a heart condition that can lead to stroke, heart attack and other forms of heart disease.

That molecule is mavacamten. Scientists at WSU’s Integrative Physiology and Neuroscience department discovered it suppresses excessive force generated by hyper-contractile muscle cells in the human heart.

The research, published in the British Journal of Pharmacology, is especially significant for those with hypertrophic cardiomyopathy, a genetic condition where the left ventricle wall of the heart is enlarged. If left untreated, hypertrophic cardiomyopathy can lead to cardiac fibrosis, stroke, heart attack, heart failure, other forms of heart disease and a condition known as sudden arrhythmic death syndrome.

“Too much contraction leads to thicker, stiffer hearts, where the heart contracts so much it is unable to properly fill with blood as the heart relaxes,” said Peter Awinda, first author on the paper and scientific manager in Bertrand Tanner’s laboratory at WSU. “This ends up pushing less blood out of the heart with each heartbeat and, in turn, less blood pumped throughout the body like it is supposed to be.”

Hypertrophic cardiomyopathy affects men and women equally. About 1 out of every 500 people have the disease.While there are some genetic markers to detect it, most people only discover their condition after a cardiac event that often results in a hospital visit.

The research

The project is a collaboration between the Tanner Laboratory in Pullman and Ken Campbell’s laboratory at University of Kentucky. Campbell manages a human cardiac biobank, where he ships tissue samples frozen in liquid nitrogen to Tanner, who is the principal investigator for the research.

After arriving in Pullman, the cardiac tissue was thawed, ‘skinned’ to remove the cell membrane, and trimmed to the right dimensions for an experiment.

Three micrograms of the drug, mavacamten, were then applied to some of the prepared tissue samples; other samples did not receive the drug and were labeled as controls.

To activate muscle contraction Awinda applied calcium to the tissue.

“As we increase calcium concentration it encourages contraction and the muscle goes from relaxed to contracted, and so we were testing the drug against these different levels of force,” Awinda said.

He found the drug reduces the maximal force of contraction by nearly 20 to 30% compared to the controls.

“The drug is successful because it is an inhibitor of myosin, which is one of the proteins required for the muscle contraction process,” Awinda said. “The research shows this could be a good candidate to treat hypertrophic cardiomyopathy.”

The collaborative study was made possible by organ donors and their families. The work was paid for by a $300,000 grant from the American Heart Association to Tanner and Campbell.

These initial studies helped Tanner and Campbell add an additional $2.8 million grant from the National Institutes of Health to support additional work in this area over the next 4 years.

Next steps

One of the research team’s next goals is to see how mice with a human mutation for hypertrophic cardiomyopathy respond to the drug.

Awinda said researching mice expressing the human gene is significant because it may provide a connection to what is seen in humans.

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Potential target identified for migraine therapy

Migraines affect millions of people worldwide, often lasting days and severely disrupting lives. More than simply super-intense headaches, some migraines actually result from pathological excitation of neurons in the brain. A new study in mice led by Kohichi Tanaka at Tokyo Medical and Dental University (TMDU) shows that susceptibility to migraines could be related to a molecular transporter that normally works to prevent excessive excitation of neurons.

Neurons in the brain communicate with each other by passing along molecules called neurotransmitters. After a neurotransmitter takes care of business, it is transported away from the synapse—the space between two neurons—so that it cannot be used over and over again. This process is called reuptake, and is one of many ways in which over-excitation of neurons in the brain is prevented. Migraines are related to a condition called cortical depression, in which a large wave of hyperactivity spreads across the brain, followed by a wave of inhibition, or depressed brain activity. Tanaka and his team hypothesized that susceptibility to cortical spreading depression is related to disrupted transport of glutamate, the most common excitatory neurotransmitter.

In turns out that mammals have four molecules that transport glutamate, and three of them are in the cerebral cortex. To determine which of these, if any, is related to cortical spreading depression, the researchers created three strains of knockout mice, each of which lacked one of the three cortical glutamate-transporter genes. They found that when mice lacked the GLT-1 transporter, cortical spreading depression occurred more frequently and spread more quickly than in control mice or in the other knockout mice.

“We know that 90% of glutamate is transported by GLT-1 back into astrocytes, not neurons,” says Tanaka. “Our findings thus highlight another important function of glial cells in the brain as they support neuronal function.”

To confirm their findings, the team then measured the amount of glutamate outside of cells using a platinum-iridium electrode coated with glutamate oxidase. When glutamate oxidase interacts with glutamate, it creates a negative current that can be detected by the electrode very quickly, allowing almost real-time measurements of glutamate concentration in the region.

“A fast biosensor is critical,” explains Tanaka, “because cortical spreading depression only lasts about 5 minutes, and the changes in glutamate concentration could never be found using conventional methods that take minutes to hours of sampling.” When testing the three knockout mice, only the GLT-1 knockout mice produced current that differed from that of the control mice. This means that the greater and faster accumulation of glutamate outside of neurons resulted from impaired uptake by astrocytes.

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Two existing drugs point to a potential new target against COVID-19

New lab-based studies show that two existing drugs, including one developed by a researcher at Harvard Medical School and Boston Children’s Hospital, inhibit SARS-CoV-2—the virus that causes COVID-19—from infecting human cells in a dish.

Both drugs, vacuolin-1 and apilimod, originally developed years ago, target a large enzyme called PIKfyve kinase.

Before this study, little was known about this enzyme’s role in COVID-19 infection. The work, which will need to be replicated in human trials, suggests a potential new target for COVID-19 therapies.

Findings were published Aug. 6 in PNAS.

“Our findings show that targeting this kinase through a small-molecule antiviral against SARS-CoV-2 may be an effective strategy to lessen the progression or seriousness of COVID-19,” said study co-senior author Tomas Kirchhausen, professor of cell biology in the Blavatnik Institute at HMS and professor of pediatrics at Boston Children’s.

Kirchhausen discovered vacuolin-1 16 years ago. Apilimod was developed by a company called LAM Therapeutics.

Ebola and beyond

When Kirchhausen first found vacuolin-1, he published a paper describing what it does in a variety of cell types.

Several years later, he began a long collaboration with HMS colleagues in the Center for Excellence in Translational Research focused on small molecules against emerging viruses.

They showed that vacuolin-1 and apilimod, which have a similar chemistry, were both effective inhibitors against the Ebola virus. They did not publish their results at the time.

When COVID-19 began to hit the U.S. hard in early March, Kirchhausen’s lab ramped down like many others in the country. Before turning out the lights, however, he remembered that the kinetics of cell entry of Ebola virus were similar to those of coronaviruses like SARS-CoV-2.

Kirchhausen reached out to co-senior author Sean Whelan, who had been part of the Center for Excellence team at HMS but had since moved to Washington University. The duo performed cell biology studies with SARS-CoV-2 virus in Whelan’s lab.

“Within a week, we knew apilimod worked extremely well in preventing SARS-CoV-2 infection in human cells in the lab,” says Kirchhausen, who initially published this discovery on the bioRxiv pre-print website in April 2020.

That pre-print also included a review of apilimod’s effectiveness against Ebola and SARS-CoV-2.

“We found that like apilimod, vacuolin-1 is a very strong inhibitor for viral infection in the lab,” said Kirchhausen.

In an unexpected coincidence, an unrelated group posted a paper showing that, in a screen of 12,000 clinical-stage or FDA-approved small molecules, apilimod was one of the best drugs for inhibiting SARS-CoV-2 virus replication. That paper has since been published in Nature.

Now in clinical trials

Apilimod’s parallel development ultimately landed with AI Therapeutics after it failed to show any benefit in phase I and II clinical trials for treatment of autoimmune conditions, its original purpose.

Although those trials were not successful, apilimod’s clinical testing in 700 healthy volunteers and patients showed it did not produce significant side effects even when given to patients for more than a year at high doses.

This spring, using some of the data from Kirchhausen’s bioRxiv paper as well as information from drug screens by others, AI Therapeutics received FDA approval to see whether apilimod reduces the seriousness of COVID-19.

In late July, AI Therapeutics announced a new randomized, double-blind, placebo-controlled study with apilimod, known as LAM-002 in the study. It will test apilimod’s safety, tolerability and efficacy in reducing the amount of virus in about 140 patients with confirmed early-onset COVID-19.

Looking forward, Kirchhausen hopes to identify other drugs to be given in addition to a PIKfyve kinase inhibitor.

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Untapped potential for TikTok to convey COVID-19 guidance

Research published in DeGruyter’s International Journal of Adolescent Medicine and Health suggests TikTok is rich with untapped educational potential. The platform could play a vital role in conveying important health information alongside lip-syncing videos and viral dance challenges, the paper’s authors say.

Led by researchers at William Paterson University and Columbia University, the new study, “COVID-19 on TikTok: Harnessing an emerging social media platform to convey important public health messages” explores how coronavirus information is being communicated on the platform. This has been a largely unexplored area—until now.

TikTok is a social media platform on which users share short videos. Since its worldwide release in 2018, it has soared in popularity—especially with teenagers and young people. It now has 800 million users worldwide and 37 billion monthly views in the United States alone.

Using a #Coronavirus hashtag, researchers examined and analyzed 117 TikTok videos, 17 of which were created by the World Health Organization (WHO). Altogether, the videos analyzed in the study received more than a billion views.

Fewer than 10% of the videos mentioned how the virus is transmitted, symptoms of COVID-19 and prevention of viral spread. None of the videos—including those uploaded by the WHO—discussed death and death rates, viral incubation time, wearing a face mask or travel restrictions.

The most commonly portrayed topics were anxiety and quarantine, with little focus on transmission and preventing infection. This may stem from the fact that teenagers are facing many social and emotional challenges as a result of lockdown measures—ranging from coping with school closures to the requirement to minimize contact with others.

The researchers behind the study think this indicates a missed opportunity to engage young people with vital health information related to the global pandemic. TikTok could potentially be used to convey messages about controlling the spread of coronavirus by the strict enforcement of social distancing. It is particularly important to impress this information upon the main TikTok audience of teenagers and young adults who can easily pass on the virus to more vulnerable and older family members.

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Researchers find potential treatment for Rett Syndrome

An experimental cancer drug can extend the life of mice with Rett Syndrome, a devastating genetic disorder that afflicts about one of every 10,000 to 15,000 girls within 6 to 18 months after birth, Yale researchers report June 10 in the journal Molecular Cell.

In addition, the drug JQ1 also restores the cellular function of neurons in human models of the disease. Rett Syndrome causes severe deficits in language, learning and other brain functions and eventually leads to death, often during teenage years.

The Yale team—led by senior author In-Hyun Park, associate professor of genetics, and a researcher at Yale’s Child Study Center and Stem Cell Center—wanted to know how a mutation in gene MECP-2 causes the severe disruption to neuronal functions in the cortex of Rett Syndrome patients.

They created a human brain organoid containing this mutation from embryonic stem cells and found severe abnormalities in multiple brain cells. A type of brain cell called interneurons, which regulate the brain’s excitatory neurons, was particularly impacted by the mutation.

The lab then screened a variety of compounds and found that one drug, JQ1, corrected abnormalities found in interneurons of the Rett Syndrome model. The drug has been investigated in several experimental trials as a potential cancer treatment.They then tested the drug in mice models of Rett Syndrome and found that the treated mice lived about twice as long as those not receiving the drug.

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