If you go see a doctor about these symptoms, and there is no evidence of a cardiac cause of the chest pain, you could be diagnosed as having some sort of disorder of the esophagus.

Peppermint can help with the difficulty swallowing and non-cardiac chest pain experienced by some patients with disorders of the esophagus, report investigators at the Medical University of South Carolina (MUSC) in Digestive Diseases & Sciences. Of the 38 patients enrolled in the MUSC pilot study, 63 percent overall reported improvement of symptoms. Patients were recruited from the Esophageal Disorders Clinic at the MUSC Health Digestive Disease Center.

“Peppermint oil is an established agent in the treatment of irritable bowel syndrome. We tried to examine its effect on patients with swallowing and chest pain issues with no apparent cause,” says Mohamed Khalaf, M.D., an esophageal disorders research fellow at the MUSC Health Digestive Disease Center and first author on the article.

“Our findings suggest that peppermint may help prevent these symptoms by relaxing the smooth muscle in the lower esophagus,” says Donald O. Castell, M.D., a professor emeritus in the MUSC College of Medicine, a nationally recognized gastroenterologist, and senior author on the article.

Peppermint oil has been known to have therapeutic effects in multiple disorders due to its muscle-relaxing properties. However, only two previous studies have investigated its role in the upper digestive tract.

The MUSC study found that patients who took peppermint oil tablets before eating felt better after meals than those who did not. Those with both non-cardiac chest pain and unobstructed difficulty swallowing saw the most benefits: 73 percent of them reported feeling better. Of patients with just one of the symptoms, those with non-cardiac chest pain had a more positive response from the peppermint oil (63 percent) than those with difficulty swallowing (53 percent).

The results were even better among patients with spastic disorders of the esophagus: 83 percent reported feeling better or slightly better. Although less well-known than esophageal disorders such as acid reflux, spastic disorders of the esophagus can also disrupt a patient’s life. In these disorders, the esophagus undergoes painful spasms that can interfere with eating. Because the spasms occur only from time to time, these disorders are difficult to diagnose and treat.

Current standard of care calls for these disorders involves trying multiple drugs, including tricyclic antidepressants and calcium channel blockers, and hoping that one works.

Peppermint offers an attractive first line of defense for these patients, who experience intermittent symptoms, because they can take it freely as symptoms occur.

“In this study, patients who had experienced difficulty swallowing took two pieces of a commercially available peppermint right before meals. Those with chest pain took the peppermint tablets as needed,” says Khalaf.

This study highlights the effects of the so-called Charleston Approach, which advocates a “start low and go slow” treatment strategy. The Charleston Approach differs from current standard of care in that it uses peppermint oil as a first attempt to relieve symptoms.

Castell and Khalaf caution that patients must first be examined by a doctor to rule out heart disease and undergo a procedure known as an endoscopy to rule out obstruction before they are offered peppermint as a first-line treatment. Endoscopy involves inserting a flexible tube fitted with a light and camera into the esophagus.

One of the drawbacks of the study was that researchers did not know the precise dosage of peppermint being given since it was a commercial candy (only one type of which was effective) with a proprietary recipe. Another was the study relied on self-reporting by patients to determine whether symptoms improved.

Although the preliminary findings of this study are promising, they need to be confirmed in a trial that compares outcomes in patients who receive a specific dose of peppermint oil and those who receive only a placebo.

In the meantime, however, patients who have been diagnosed as having spastic disorders of the esophagus and who have no heart disease or obstruction can try using peppermint to see if it relieves their symptoms.

“Given the safety profile, low cost, and widespread availability, there are no risks from empirical use of peppermint oil,” says Khalaf.

“We concluded that because this technology both creates a selection pressure on the viruses to evolve more quickly, and also provides the viruses a means to evolve, it resulted in a virus mutant that is resistant to our interventions,” explained Devang Mehta, postdoctoral fellow in the Department of Biological Sciences. CRISPR-Cas9 is found in nature, where bacteria use it to defend against viruses, however the researchers found that the technology results in very different outcomes in plants — and researchers are stressing the importance of screening against these sorts of unintended results in the future.

The cassava plant, the object of the study, is a starchy root vegetable that is consumed for food throughout the tropics. Cassava is a primary staple crop grown in South America, Africa, and Asia, from which 1 billion people get most of their calories each day. Each year, cassava crops are plagued by cassava mosaic disease, which causes 20 per cent crop loss. It is the mosaic disease that Mehta and his colleagues endeavoured to engineer against.

Unsuccessful results

The researchers used a new gene-editing technology called CRISPR-Cas9 to attempt to design cassava plants that could cut the DNA of the mosaic virus and make the plants resistant to its damaging effects. Unfortunately, their results were not successful. To understand what happened, the team sequenced hundreds of viral genomes found in each plant.

“We discovered that the pressure that CRISPR-Cas9 applied to the virus probably encouraged it to evolve in a way that increased resistance to intervention,” said Mehta. Mehta hastens to add that CRISPR-Cas9 has many other applications in food and agriculture that do not pose the same risks.

The research team is keen to share their results with other scientists who are using CRISPR-Cas9 technology to engineer virus-resistant plants, and encourage these groups to test their plants to detect similar viral mutations.

“We need to do more research on these types of applications of CRISPR-Cas9 technology before we proceed with field testing” said Mehta. Mehta, a postdoctoral fellow with Professor Glen Uhrig, began this research during his PhD studies at the Swiss Federal Institute of Technology (ETH) in Zurich.

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MIT engineers have designed tiny robots that can help drug-delivery nanoparticles push their way out of the bloodstream and into a tumor or another disease site. Like crafts in “Fantastic Voyage” — a 1960s science fiction film in which a submarine crew shrinks in size and roams a body to repair damaged cells — the robots swim through the bloodstream, creating a current that drags nanoparticles along with them.

The magnetic microrobots, inspired by bacterial propulsion, could help to overcome one of the biggest obstacles to delivering drugs with nanoparticles: getting the particles to exit blood vessels and accumulate in the right place.

“When you put nanomaterials in the bloodstream and target them to diseased tissue, the biggest barrier to that kind of payload getting into the tissue is the lining of the blood vessel,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, a member of MIT’s Koch Institute for Integrative Cancer Research and its Institute for Medical Engineering and Science, and the senior author of the study.

“Our idea was to see if you can use magnetism to create fluid forces that push nanoparticles into the tissue,” adds Simone Schuerle, a former MIT postdoc and lead author of the paper, which appears in the April 26 issue of Science Advances.

In the same study, the researchers also showed that they could achieve a similar effect using swarms of living bacteria that are naturally magnetic. Each of these approaches could be suited for different types of drug delivery, the researchers say.

Tiny robots

Schuerle, who is now an assistant professor at the Swiss Federal Institute of Technology (ETH Zurich), first began working on tiny magnetic robots as a graduate student in Brad Nelson’s Multiscale Robotics Lab at ETH Zurich. When she came to Bhatia’s lab as a postdoc in 2014, she began investigating whether this kind of bot could help to make nanoparticle drug delivery more efficient.

In most cases, researchers target their nanoparticles to disease sites that are surrounded by “leaky” blood vessels, such as tumors. This makes it easier for the particles to get into the tissue, but the delivery process is still not as effective as it needs to be.

The MIT team decided to explore whether the forces generated by magnetic robots might offer a better way to push the particles out of the bloodstream and into the target site.

The robots that Schuerle used in this study are 35 hundredths of a millimeter long, similar in size to a single cell, and can be controlled by applying an external magnetic field. This bioinspired robot, which the researchers call an “artificial bacterial flagellum,” consists of a tiny helix that resembles the flagella that many bacteria use to propel themselves. These robots are 3-D-printed with a high-resolution 3-D printer and then coated with nickel, which makes them magnetic.

To test a single robot’s ability to control nearby nanoparticles, the researchers created a microfluidic system that mimics the blood vessels that surround tumors. The channel in their system, between 50 and 200 microns wide, is lined with a gel that has holes to simulate the broken blood vessels seen near tumors.

Using external magnets, the researchers applied magnetic fields to the robot, which makes the helix rotate and swim through the channel. Because fluid flows through the channel in the opposite direction, the robot remains stationary and creates a convection current, which pushes 200-nanometer polystyrene particles into the model tissue. These particles penetrated twice as far into the tissue as nanoparticles delivered without the aid of the magnetic robot.

This type of system could potentially be incorporated into stents, which are stationary and would be easy to target with an externally applied magnetic field. Such an approach could be useful for delivering drugs to help reduce inflammation at the site of the stent, Bhatia says.

Bacterial swarms

The researchers also developed a variant of this approach that relies on swarms of naturally magnetotactic bacteria instead of microrobots. Bhatia has previously developed bacteria that can be used to deliver cancer-fighting drugs and to diagnose cancer, exploiting bacteria’s natural tendency to accumulate at disease sites.

For this study, the researchers used a type of bacteria called Magnetospirillum magneticum, which naturally produces chains of iron oxide. These magnetic particles, known as magnetosomes, help bacteria orient themselves and find their preferred environments.

The researchers discovered that when they put these bacteria into the microfluidic system and applied rotating magnetic fields in certain orientations, the bacteria began to rotate in synchrony and move in the same direction, pulling along any nanoparticles that were nearby. In this case, the researchers found that nanoparticles were pushed into the model tissue three times faster than when the nanoparticles were delivered without any magnetic assistance.

This bacterial approach could be better suited for drug delivery in situations such as a tumor, where the swarm, controlled externally without the need for visual feedback, could generate fluidic forces in vessels throughout the tumor.

The particles that the researchers used in this study are big enough to carry large payloads, including the components required for the CRISPR genome-editing system, Bhatia says. She now plans to collaborate with Schuerle to further develop both of these magnetic approaches for testing in animal models.

The research was funded by the Swiss National Science Foundation, the Branco Weiss Fellowship, the National Institutes of Health, the National Science Foundation, and the Howard Hughes Medical Institute.

“Unfortunately, treatment with blood thinners does not prevent all cases of blood clotting in APS,” says Jason Knight, M.D., Ph.D., an assistant professor of rheumatology at Michigan Medicine. APS is an autoimmune condition characterized by blood clots in both genders and pregnancy loss in women.

“And those blood thinners do very little to impact the neurologic, hematologic and cardiac complications that regularly affect patients with the condition,” he adds.

Knight’s lab is currently pursuing the idea that anti-inflammatory treatment might provide a more targeted way to treat APS and give patients better control of the condition with fewer side effects.

“Specifically, we have been interested in the role that neutrophils, the most abundant white blood cells in circulation within the body, play in APS,” Knight says. “We’ve had prior studies demonstrate that neutrophils release sticky, spider web-like structures called neutrophil extracellular traps, also called NETs, that trigger the blood to clot in patients with APS.”

Now, Knight and team are building upon that prior work in a new study, published in Nature Communications, that investigated two drugs and their effects on NETs in mice with APS.

“We explored a new strategy for inhibiting those neutrophils, using experimental drug CGS21680 and an approved drug called dipyridamole,” says Knight, senior author of the study.

Testing potential treatments

Using mouse models with APS, the research team first administered CGS21680 and found that it reduced the levels of NETs in their blood.

“The drug works by activating adenosine receptors on the neutrophil surface,” says Ramadan Ali, Ph.D., a member of Knight’s lab and lead author of the study. “Adenosine is best known for its role in energy metabolism, but also has anti-inflammatory effects when released outside of cells. This appears to be a natural pathway for turning off inflammation.”

The research team observed that the drug also dramatically reduced the tendency of the mice to form blood clots in large veins.

“Testing this specific drug allowed us to show that activation of adenosine receptors is an effective strategy for preventing NET release in APS, and potentially other contexts as well,” Ali says. “We also found that the adenosine-receptor pathway can be exploited to prevent the formation of blood clots.”

Because CGS21680 is not approved for use in humans, the research team also decided to test the stroke drug dipyridamole, which has been shown previously to activate adenosine receptors.

“It was very gratifying to see that dipyridamole copied the results of the experimental drug that we began the study with,” Ali says. “It reduced both NET release and the tendency of the mice with APS to form clots.”

Translating from bench to bedside

While all of the work was preclinical, the research team believes it could be translated to patients with APS.

“This is what’s exciting,” Knight says. “We have identified a pathway here that is already influenced by a number of drugs approved for use in humans. Beyond dipyridamole, drugs like apremilast, used in patients with psoriasis and psoriatic arthritis, and methotrexate, used to treat rheumatoid arthritis and certain types of cancer, can also modulate adenosine-receptor signaling.”

He adds, “Translating these findings to a clinical trial in patients could therefore be very straightforward.”

Based on their findings, the research team plans to move forward with a pilot clinical trial in patients with APS.

“We’re very motivated to provide safer, more effective and more individualized treatments for patients with APS we see in our clinic,” Knight says. “The hope is that by continuing to pursue anti-neutrophil therapeutics, we will be treating APS closer to its source and thereby neutralize all aspects of the condition.”