Wild orangutan treats wound with pain-relieving plant

Even though there is evidence of certain self-medication behaviors in animals, so far it has never been known that animals treat their wounds with healing plants. Now, biologists from the Max Planck Institute of Animal Behavior, Germany and Universitas Nasional, Indonesia have observed this in a male Sumatran orangutan who sustained a facial wound. He ate and repeatedly applied sap from a climbing plant with anti-inflammatory and pain-relieving properties commonly used in traditional medicine. He also covered the entire wound with the green plant mesh. Thus, medical wound treatment may have arisen in a common ancestor shared by humans and orangutans.

While sick and avoidance behavior can be regularly observed in non-human animals, self-medication in the form of ingestion of specific plant parts is widespread in animals but exhibited at low frequencies. The closest relatives to humans, the great apes, are known to ingest specific plants to treat parasite infection and to rub plant material on their skin to treat sore muscles. Recently a chimpanzee group in Gabon was observed applying insects to wounds. However, the efficiency of this behavior is still unknown. Wound treatment with a biologically active substance has so far not been documented.

In a study published in Scientific Reports, cognitive and evolutionary biologists from the Max Planck Institute of Animal Behavior, Konstanz, Germany and Universitas Nasional, Indonesiareport evidence of active wound treatment with a healing plant in a wild male Sumatran orangutan. The study, led by Caroline Schuppli and Isabelle Laumer, took place at the Suaq Balimbing research site in Indonesia, which is a protected rainforest area home to approximately 150 critically endangered Sumatran orangutans. "During daily observations of the orangutans, we noticed that a male named Rakus had sustained a facial wound, most likely during a fight with a neighboring male," says Isabelle Laumer (MPI-AB), first author of the study.

Three days after the injury Rakus selectively ripped off leaves of a liana with the common name Akar Kuning (Fibraurea tinctoria), chewed on them, and then repeatedly applied the resulting juice precisely onto the facial wound for several minutes. As a last step, he fully covered the wound with the chewed leaves.

Says Laumer: "This and related liana species that can be found in tropical forests of Southeast Asia are known for their analgesic and antipyretic effects and are used in traditional medicine to treat various diseases, such as malaria. Analyses of plant chemical compounds show the presence of furanoditerpenoids and protoberberine alkaloids, which are known to have antibacterial, anti-inflammatory, anti-fungal, antioxidant, and other biological activities of relevance to wound healing."

Observations over the following days did not show any signs of the wound becoming infected and after five days the wound was already closed. "Interestingly, Rakus also rested more than usual when being wounded. Sleep positively affects wound healing as growth hormone release, protein synthesis and cell division are increased during sleep," she explains.

Like all self-medication behavior in non-human animals, the case reported in this study raises questions about how intentional these behaviors are and how they emerge. "The behavior of Rakus appeared to be intentional as he selectively treated his facial wound on his right flange, and no other body parts, with the plant juice. The behavior was also repeated several times, not only with the plant juice but also later with more solid plant material until the wound was fully covered. The entire process took a considerable amount of time," says Laumer.

"It is possible, that wound treatment with Fibraurea tinctoria by the orangutans at Suaq emerges through individual innovation," says Caroline Schuppli, senior author of the study. "Orangutans at the site rarely eat the plant. However, individuals may accidentally touch their wounds while feeding on this plant and thus unintentionally apply the plant's juice to their wounds. As Fibraurea tinctoria has potent analgesic effects, individuals may feel an immediate pain release, causing them to repeat the behavior several times."

Since the behavior has not been observed before, it may be that wound treatment with Fibraurea tinctoria has so far been absent in the behavioral repertoire of the Suaq orangutan population. Like all adult males in the area, Rakus was not born in Suaq, and his origin is unknown. "Orangutan males disperse from their natal area during or after puberty over long distances to either establish a new home range in another area or are moving between other's home ranges," explains Schuppli. "Therefore, it is possible that the behavior is shown by more individuals in his natal population outside the Suaq research area."

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Could a drug prevent hearing loss from loud music and aging?

Researchers have found a gene that links deafness to cell death in the inner ear in humans -- creating new opportunities for averting hearing loss.

A person's hearing can be damaged by loud noise, aging and even certain medications, with little recourse beyond a hearing aid or cochlear implant.

But now, UCSF scientists have achieved a breakthrough in understanding what is happening in the inner ear during hearing loss, laying the groundwork for preventing deafness.

The research, published on Dec. 22, 2023, in the Journal of Clinical Investigation Insight, links animal studies on hearing loss with a rare type of inherited deafness in humans. In both cases, mutations to the TMTC4 gene trigger a molecular domino effect known as the unfolded protein response (UPR), leading to the death of hair cells in the inner ear.

Intriguingly, hearing loss from loud noise exposure or drugs such as cisplatin, a common form of chemotherapy, also stems from activation of the UPR in hair cells, suggesting that the UPR may underly several different forms of deafness.

There are several drugs that block the UPR -- and stop hearing loss -- in laboratory animals. The new findings make a stronger case for testing these drugs in people who are at risk of losing their hearing, according to the researchers.

"Millions of American adults lose their hearing due to noise exposure or aging each year, but it's been a mystery what was going wrong," said Dylan Chan, MD, PhD, co-senior author on the paper and director of the Children's Communication Center (CCC) in the UCSF Department of Otolaryngology. "We now have solid evidence that TMTC4 is a human deafness gene and that the UPR is a genuine target for preventing deafness."

How hair cells in the ear self-destruct

In 2014, Elliott Sherr, MD, PhD, director of the UCSF Brain Development Research Program and co-senior author of the paper, noticed that several of his young patients with brain malformations all had mutations to TMTC4. But laboratory studies of this gene soon presented a conundrum.

"We expected mice with TMTC4 mutations to have severe brain defects early on, like those pediatric patients, yet to our surprise, they seemed normal at first," Sherr said. "But as those animals grew, we saw that they didn't startle in response to loud noise. They had gone deaf after they had matured."

Sherr partnered with Chan, an expert on the inner ear, to look into what was happening to the mice, which looked like an accelerated version of age-related hearing loss in humans. They showed that mutations to TMTC4 primed hair cells in the ear to self-destruct, and loud noise did the same thing. In both cases, hair cells were flooded with excess calcium, throwing off the balance of other cellular signals, including the UPR.

But they found there was a way to stop this. ISRIB, a drug developed at UCSF to block the UPR's self-destruct mechanism in traumatic brain injury, prevented animals who were exposed to noise from going deaf.

The first adult human deafness gene

In 2020, scientists from South Korea, led by Bong Jik Kim, MD, PhD, connected Chan and Sherr's 2018 findings with genetic mutations they found in two siblings who were losing their hearing in their mid-20s. The mutations were in TMTC4 and matched what Chan and Sherr had seen in animals, although they were distinct from those in Sherr's pediatric neurology patients.

"It's rare to so quickly connect mouse studies with humans," Sherr said. "Thanks to our Korean collaborators, we could more easily prove the relevance of our work for the many people who go deaf over time."

Kim, an otolaryngologist at the Chungnam National University College of Medicine (Korea), facilitated the shipping of cells from those patients to UCSF. Sherr and Chan tested those cells for UPR activity and found that, indeed, this flavor of TMTC4 mutation turned on the destructive UPR pathway in a human context.

When Chan and Sherr mutated TMTC4 only in hair cells in mice, the mice went deaf. When they mutated TMTC4 in cells from individuals in the Korean family who hadn't gone deaf, and in laboratory human cell lines, the UPR drove the cells to self-destruct. TMTC4 was more than a deafness gene in mice -- it was a deafness gene in humans, too.

Translating a discovery to prevent deafness

Understanding TMTC4 mutations gives researchers a new way of studying progressive deafness, since it is critical for maintaining the health of the adult inner ear. The mutations mimic damage from noise, aging or drugs like cisplatin.

The researchers envision a future where people who must take cisplatin, or who have to be exposed to loud noises for their jobs, take a drug that dampens the UPR and keeps hair cells from withering away, preserving their hearing.

The science also suggests that the UPR could be targeted in other contexts where nerve cells become overwhelmed and die, including diseases long thought to be incurable, like Alzheimer's or Lou Gehrig's disease.

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Riding sound waves in the brain

Brain tumours, brain haemorrhages and neurological and psychological conditions are often hard to treat with medication. And even when effective drugs are available, these tend to have severe side effects because they circulate throughout the brain and not just the area they are meant to treat. In light of this situation, researchers have high hopes of one day being able to provide a more targeted approach that would deliver medications to very specifically defined locations. To this end, they are in the process of developing mini-transporters that can be guided through the dense maze of blood vessels.

Researchers at ETH Zurich, the University of Zurich and the University Hospital Zurich have now managed for the first time to guide microvehicles through the blood vessels in the brain of an animal using ultrasound.

Ultrasound instead of magnetism

Compared to alternative navigation technologies such as those based on magnetic fields, ultrasound offers certain benefits.

Daniel Ahmed, Professor of Acoustic Robotics at ETH Zurich and supervisor of the study, explains: "In addition to being widely used in the medical field, ultrasound is safe and penetrates deep into the body."

For their microvehicle, Ahmed and his colleagues used gas-filled microbubbles coated in lipids -- the same substances that biological cell membranes are made of. The bubbles have a diameter of 1.5 micrometres and are currently used as contrast material in ultrasound imaging.

As the researchers have now shown, these microbubbles can be guided through blood vessels.

"Since these bubbles, or vesicles, are already approved for use in humans, it's likely that our technology will be approved and used in treatments for humans more quickly than other types of microvehicles currently in development," Ahmed says.

He was awarded a Starting Grant by the European Research Council ERC in 2019 for his project to research and develop this technology.

Another benefit of the ultrasound-guided microbubbles is that they dissolve in the body once they've done their job.

When using another approach, magnetic fields, the microvehicles have to be magnetic, and it's not easy to develop biodegradable microvehicles.

Moreover, the microbubbles developed by the ETH Zurich researchers are small and smooth.

"This makes it easy for us to guide them along narrow capillaries," says Alexia Del Campo Fonseca, a doctoral student in Ahmed's group and lead author of the study.

Going against the flow

Over the past few years, Ahmed and his group have been working in the lab to develop their method for guiding microbubbles through narrow vessels.

Now, in collaboration with researchers from the University of Zurich and University Hospital Zurich, they have tested this method on blood vessels in the brains of mice.

The researchers injected the bubbles into the rodents' circulatory system, where they are swept along in the bloodstream without any outside help.

However, the researchers managed to use ultrasound to hold the vesicles in place and guide them through the brain vessels against the direction of blood flow.

The researchers were even able to guide the bubbles through convoluted blood vessels or get them to change direction multiple times in order to steer them into the narrowest branches of the bloodstream.

To control the microvehicles' movements, the researchers also attached four small transducers to the outside of each mouse's skull.

These devices generate vibrations in the ultrasonic range, which spread through the brain as waves.

At certain points in the brain, the waves emitted by two or more transducers can either amplify each other or cancel each other out.

The researchers guide the bubbles using a sophisticated method of adjusting the output of each individual transducer.

Real-time imaging shows them what direction the bubbles are moving in.

To create the imaging for this study, the researchers used two-photon microscopy.

In the future, they also want to use ultrasound itself for imaging and plan to enhance ultrasound technology for this purpose.

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Turn up your favorite song to improve medication efficacy

While listening to a favorite song is a known mood booster, researchers at Michigan State University have discovered that music-listening interventions also can make medicines more effective.

"Music-listening interventions are like over-the-counter medications," said Jason Kiernan, an assistant professor in the College of Nursing. "You don't need a doctor to prescribe them."

While previous research studies have used music-listening interventions as a tool to treat pain and anxiety, Kiernan took a novel approach by studying the effects of music-listening interventions on chemotherapy-induced nausea.

"Pain and anxiety are both neurological phenomena and are interpreted in the brain as a state," Kiernan said. "Chemotherapy-induced nausea is not a stomach condition; it is a neurological one."

The small pilot study included 12 patients undergoing chemotherapy treatment who agreed to listen to their favorite music for 30 minutes each time they needed to take their as-needed anti-nausea medication. They repeated the music intervention anytime nausea occurred over the five days beyond their chemotherapy treatment. The patients in the study provided a total of 64 events.

"When we listen to music, our brains fire all kinds of neurons," Kiernan said.

While Kiernan did see a reduction in the ratings of patients' nausea severity and their distress (how much it bothered them to be nauseous), he cautions that it is difficult to isolate whether it was the gradual release of the medication doing its job or the increased benefit of the music. For future studies, Kiernan is drawing inspiration from another previously published study that measured the amount of serotonin, a neurotransmitter, that was released by platelets in the blood after listening to unpleasant and pleasant music.

"Serotonin is the major neurotransmitter that causes chemotherapy-induced nausea," Kiernan said. "Cancer patients take medications to block serotonin's effects."

During that previous study, researchers found that patients who listened to pleasant music experienced the lowest levels of serotonin release, indicating that the serotonin stayed in the blood platelets and was not released to circulate throughout the body. Results also showed that after listening to music they found unpleasant, patients experienced greater stress and increased levels of serotonin release.

"This was intriguing because it provides a neurochemical explanation and a possible way to measure serotonin and the blood platelet release of serotonin in my study," Kiernan said. "In 10 to 20 years, wouldn't it be neat if you could use a nonpharmacological intervention like listening to 10 minutes of your favorite music to complement a medicine?"

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Mild fever helps clear infections faster, new study suggests

It may be better to let a mild fever run its course instead of automatically reaching for medication, new University of Alberta research suggests.

Researchers found that untreated moderate fever helped fish clear their bodies of infection rapidly, controlled inflammation and repaired damaged tissue. "We let nature do what nature does, and in this case it was very much a positive thing," says immunologist Daniel Barreda, lead author on the study and a joint professor in the Faculty of Agricultural, Life & Environmental Sciences and the Faculty of Science.

Moderate fever is self-resolving, meaning that the body can both induce it and shut it down naturally without medication, Barreda explains. The health advantages of natural fever to humans still have to be confirmed through research, but the researchers say because the mechanisms driving and sustaining fever are shared among animals, it is reasonable to expect similar benefits are going to happen in humans.

That suggests we should resist reaching for over-the-counter fever medications, also known as non-steroidal anti-inflammatory drugs, at the first signs of a mild temperature, he says. "They take away the discomfort felt with fever, but you're also likely giving away some of the benefits of this natural response."

The study helps shed light on the mechanisms that contribute to the benefits of moderate fever, which Barreda notes has been evolutionarily conserved across the animal kingdom for 550 million years. "Every animal examined has this biological response to infection."

For the study, fish were given a bacterial infection and their behaviour was then tracked and evaluated using machine learning. Outward symptoms were similar to those seen in humans with fever, including immobility, fatigue and malaise. These were then matched to important immune mechanisms inside the animals.

The research showed that natural fever offers an integrative response that not only activates defences against infection, but also helps control it.The researchers found that fever helped to clear the fish of infection in about seven days -- half the time it took for those animals not allowed to exert fever. Fever also helped to shut down inflammation and repair injured tissue.

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Parkinson's medication improved blood pressure in teens with Type 1 diabetes

Teens with Type 1 diabetes (T1D) who took bromocriptine, a medication used to treat Parkinson's disease and Type 2 diabetes, had lower blood pressure and less stiff arteries after one month of treatment compared to those who did not take the medicine, according to a small study published today in Hypertension, an American Heart Association journal.

High blood pressure and stiff arteries contribute to the development of heart disease. People with T1D, a lifelong, chronic condition in which the pancreas doesn't produce enough insulin to control blood sugar levels, have a higher risk of developing heart disease than those without the condition. Those diagnosed with T1D as children have even higher risks for heart disease than people diagnosed in adulthood. Therefore, researchers are interested in ways to slow down the onset of vascular disease in children with T1D.

"We know that abnormalities in the large vessels around the heart, the aorta and its primary branches, begin to develop in early childhood in people with Type 1 diabetes," said lead study author Michal Schäfer, Ph.D., a researcher and fourth-year medical student at the University of Colorado School of Medicine in Aurora, Colorado. "We found that bromocriptine has the potential to slow down the development of those abnormalities and decrease the risk for cardiovascular disease in this population."

The multidisciplinary team conducted this study to examine the impact of bromocriptine on blood pressure and aortic stiffness compared with a placebo in adolescents with Type 1 diabetes. Bromocriptine is in a class of medications called dopamine receptor agonists. It increases levels of dopamine, a chemical in the brain, which leads to an increase in the body's responsiveness to insulin, called insulin sensitivity. Bromocriptine has been FDA-approved since 2009 to treat adults with Type 2 diabetes due to its effect on insulin sensitivity.

The study included 34 participants (13 male, 21 female) ages 12 to 21 years who had been diagnosed with Type 1 diabetes for at least a year, and their HbA1c (glycosylated hemoglobin -- a measure of blood glucose) was 12% or less. An HbA1c level of 6.5% or higher indicates diabetes. They were randomly divided into two groups of 17, with one group receiving bromocriptine quick-release therapy and the other receiving a placebo once daily. The study was conducted in two phases. Participants took the first treatment or placebo for 4 weeks in phase 1, then had no treatment for a 4-week "wash-out" period, followed by phase 2 with 4 weeks on the opposite treatment. In this "crossover" design, each participant served as their own control for comparison.

Blood pressure and aortic stiffness were measured at the start of the study and at the end of each phase. Aortic stiffness was determined by assessing the large arteries with cardiovascular magnetic resonance imaging (MRI) and a measurement of the velocity of the blood pressure pulse called pulse wave velocity.

The study found:
 

• Compared to placebo, blood pressure was significantly decreased with bromocriptine. On average, bromocriptine therapy resulted in a systolic blood pressure decrease of 5 mm Hg and a diastolic blood pressure decrease of 2 mm Hg at the end of 4 weeks of treatment.
• Aortic stiffness was also reduced with bromocriptine therapy. The improvement in aortic stiffness was most pronounced in the ascending aorta with a lowered pulse wave velocity of about 0.4 meters/second, and an increase in distensibility, or elasticity, of 8%. In the thoraco-abdominal aorta, bromocriptine was associated with a lowered pulse wave velocity of about 0.2 meters/second, with a 5% increase in distensibility.

"A stiff aorta predisposes a patient to other health issues, such as organ dysfunction or atherosclerosis and higher stress or strain on cardiac muscle," Schäfer said. "We were able to take it a notch further and show, using more sophisticated metrics, that these central large arteries are impaired, and impairment among adolescents and young adults with Type 1 diabetes may be decelerated with this drug."

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Infants, young children finally get relief from eczema's terrible itch

The first study to treat moderate-to-severe eczema in infants and children 6 months to 5 years old with a biologic drug (monoclonal antibody) rather than immune-suppressing medications shows the drug was highly effective in reducing the signs and symptoms of moderate-to-severe eczema, report researchers involved in a new multi-site international phase III study led by Northwestern Medicine.

A 16-week course of dupilumab, a medication that targets a key immune pathway in allergies, resulted in more than half the children having at least a 75% reduction in signs of eczema and highly significant reductions in itch with improved sleep.

This is the first large-scale, randomized, placebo-controlled trial of a monoclonal antibody in any skin disease, including eczema, in children as young as 6 months. The study, which included 31 sites in Europe and North America, will be published Sept. 15 in The Lancet.

"Preschoolers who are constantly scratching, awake multiple times a night with their parents, irritable and markedly curtailed in their ability to do what other children their ages can do improved to the extent that they sleep through the night, change their personalities and have a normal life -- as babies and children should," said lead study author Dr. Amy Paller, chair of dermatology at Northwestern University Feinberg School of Medicine and an attending physician at Ann & Robert H. Lurie Children's Hospital of Chicago.

Eczema, also known as atopic dermatitis, is a chronic inflammatory skin disorder characterized by red, dry, often oozing skin and itch that can profoundly affect the lives of affected patients and their families.

An estimated 19% or more of all children under 6 years of age have eczema and 85 to 90% of individuals affected overall with eczema have the onset of disease during the first five years of life.

The children's debilitating itch leads to sleep disturbance, poor neurocognitive development and, on average, a full night of sleep lost per week.

"The ability to take this drug will significantly improve the quality of life for infants and young children who suffer tremendously with this disease," Paller said. "Atopic dermatitis or eczema is so much more than just itchy skin. It is a devastating disease. The quality of life of severe eczema -- not only for the child but also parents -- is equivalent to many life-threatening diseases."

As a result of this study, this medication is now available to infants and preschoolers as young as 6 months of age. It has "an outstanding safety profile" and does not even require any laboratory tests before starting the medication, Paller said.

Although one-half to two-thirds of young children with eczema have mild symptoms, which can be handled with steroid ointment and moisturizers, the other one-third or more have moderate-to-severe disease and require more aggressive management.

"Up to now, all we have had to treat more severe eczema is immune-suppressing medications, such as oral steroids, which we try to avoid in children, because they are associated with so many side effects and thus are not a preferred treatment for a chronic skin disease," Paller said. "The potential long-term impact on the development of the immune system in young children is also of concern with these immunosuppressants."

During the past few years, a new medication has become available called dupilumab, which is the first "biologic" drug to treat eczema in a targeted manner, meaning a narrow attack on just what scientists have found is causing the manifestations of the disease in skin. This medication was found to be effective and safe in studies with adults, then adolescents, then other school-aged children.

"But the group in whom we worry the most about safety -- those under 5 -- had not been tested and were unable to get this medication," Paller said.

The parent or a health care provider gives the child a monthly shot to administer the medication.

"The effect for most of these younger children is dramatic and at least as good as we've seen with the risky immunosuppressant medications," Paller said.

Potential added benefit by treating associated allergies

This medication has also been shown to be effective for treating asthma, gastrointestinal manifestations of allergy and other allergy-mediated problems but is not yet approved for these indications in infants and young children.

In fact, 66% of children in this trial had developed their eczema during the first six months of life and, by the time of initiating the dupilumab, more than 80% had already developed at least one allergic disorder, such as asthma or food allergy.

"By treating more aggressively to calm the immune system activation in these young children with early, severe eczema, we may also reduce the risk of their developing a range of allergic problems, changing their life beyond improving eczema," Paller said. "These associated allergic issues most often begin after the eczema starts."

Children were randomized to receive either a placebo injection or the dupilumab (weight-based dosing) every four weeks for 16 weeks. Only children who were not responding adequately to topical medications were allowed to enroll, and they had to be of a high severity, even with the topical medications.

As a result of the study, Paller said, scientists and physicians can start to better understand the relationships between eczema and a variety of allergic disorders and can consider the possibility of using this medication for other disorders that affect these very young children.

Read more at Science Daily

How the brain changes during depression treatment

For the first time, researchers have shown what happens to the brain when a person receives a depression treatment known as repetitive transcranial magnetic stimulation (rTMS). The results were published today in the American Journal of Psychiatry.

rTMS is a depression treatment typically used when other approaches -- such as medications -- haven't been effective for a patient. It is estimated that approximately 40 per cent of people with major depression do not respond to antidepressants.

During an rTMS session, a device containing an electromagnetic coil is placed against a patient's scalp. The device then painlessly delivers a magnetic pulse that stimulates nerve cells in a region of the brain involved in mood control -- called the dorsolateral pre-frontal cortex.

Although proven to be effective, the mechanisms behind how rTMS affects the brain have not been well understood.

"When we first started this research, the question we were asking was very simple: we wanted to know what happens to the brain when rTMS treatment is being delivered," says Dr. Fidel Vila-Rodriguez, an assistant professor in UBC's department of psychiatry and researcher at the Djavad Mowafaghian Centre for Brain Health (DMCBH).

To answer this question, Dr. Vila-Rodriguez and his team delivered one round of rTMS to patients while they were inside a magnetic resonance imaging (MRI) scanner. Since the MRI can measure brain activity, the researchers were able to see in real time what changes were happening in the brain.

The team found that by stimulating the dorsolateral pre-frontal cortex, several other regions of the brain were also activated. These other regions are involved in multiple functions -- from managing emotional responses to memory and motor control.

The participants then underwent another four weeks of rTMS treatment and the team assessed whether the activated regions were associated with patients having fewer symptoms of depression when their treatment ended.

"We found that regions of the brain that were activated during the concurrent rTMS-fMRI were significantly related to good outcomes," says Dr. Vila-Rodriguez.

With this new map of how rTMS stimulates different areas of the brain, Dr. Villa Rodriguez hopes the findings could be used to determine how well a patient is responding to rTMS treatments.

"By demonstrating this principle and identifying regions of the brain that are activated by rTMS, we can now try to understand whether this pattern can be used as a biomarker," he says.

Dr. Vila-Rodriguez is now exploring how rTMS can be used to treat a range of neuropsychiatric disorders. He has received funding through the Djavad Mowafaghian Centre for Brain Health Alzheimer's Disease Research Competition to look at rTMS as a way to enhance memory in patients who are showing early signs of Alzheimer's disease. He also received a grant from the Canadian Institutes of Health Research (CIHR) to study whether the rTMS brain activation patterns can be detected by changes in heart rate.

Dr. Vila-Rodriguez says this is type of research will hopefully encourage more widespread adoption and accessibility of rTMS treatments across the country. Despite being approved by Health Canada 20 years ago, rTMS is still not widely available. In British Columbia, there are some private clinics that offer rTMS, but it is not covered by the provincial health plan.

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Combining certain meds with ibuprofen can permanently injure kidneys

Anyone who is taking a diuretic and a renin-angiotensin system (RSA) inhibitor for high blood pressure should be cautious about also taking ibuprofen, according to new research.

Diuretics and RSA inhibitors are commonly prescribed together for people with hypertension and are available under various pharmaceutical brand names. Painkillers such as ibuprofen are available over-the-counter in most pharmacies and stores in popular brands.

Researchers at the University of Waterloo used computer-simulated drug trials to model the interactions of the three drugs and the impact on the kidney. They found that in people with certain medical profiles, the combination can cause acute kidney injury, which in some cases can be permanent.

"It's not that everyone who happens to take this combination of drugs is going to have problems," said Anita Layton, professor of applied mathematics at Waterloo and Canada 150 Research Chair in mathematical biology and medicine. "But the research shows it's enough of a problem that you should exercise caution."

Computer-simulated drug trials can quickly produce results that would take much longer in human clinical trials. Layton and her team use mathematics and computer science to give medical practitioners a head start with issues like drug complications.

The research, in this case, can also speak directly to the many people who are taking drugs for hypertension and may reach for a painkiller with ibuprofen without giving it much thought.

"Diuretics are a family of drugs that make the body hold less water," Layton said. "Being dehydrated is a major factor in acute kidney injury, and then the RAS inhibitor and ibuprofen hit the kidney with this triple whammy. If you happen to be on these hypertension drugs and need a painkiller, consider acetaminophen instead."

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The diabetes medication that could revolutionize heart failure treatment

A medication originally used for patients with diabetes is the first to help people with heart failure and could revolutionise treatment, according to new research from the University of East Anglia.

Early research had shown that Sodium-glucose co-transporter-2 (SGLT2) inhibitors could help around half of heart failure patients -- those with a condition known as reduction ejection fraction.

But new findings published today show that the medication could be beneficial for all heart failure patients -- including those with a second type of heart failure called preserved ejection fraction.

It is the first drug to provide a real benefit in terms of improving outcomes for these patients. And the research team say it will revolutionise treatment options.

Lead researcher Prof Vass Vassiliou, from UEA's Norwich Medical School and an Honorary Consultant Cardiologist at the Norfolk and Norwich University Hospital, said: "Heart failure is a condition where the heart is not pumping as well as it should, and it affects about one million people in the UK.

"There are two types of heart failure. Heart Failure with a reduction in ejection fraction happens when the heart is unable to pump blood round the body due to a mechanical issue. And heart failure with preserved ejection fraction happens when, despite the heart pumping out blood well, it is not sufficient to provide oxygen to all the parts of the body.

"Patients are equally split between the two types of heart failure.

"For many years there was not a single medicine that could improve the outcome in patients with the second type of heart failure -- those patients with preserved ejection fraction.

"This type of heart failure had puzzled doctors, as every medicine tested showed no benefit.

"One class of heart medication, called SGLT2 inhibitors, was initially used for patients with diabetes. However, it was noticed that it also helped patients who had heart failure.

"Previous studies had shown that this medication would be beneficial in heart failure with reduced ejection fraction.

"But we found that it can also help heart failure patients with preserved ejection fraction."

SGLT2 inhibitors are more commonly known under their trade-names Forxiga (Dapagliflozin), Invokana (Canagliflozin), and Jardiance (Empagliflozin).

The research team undertook a meta-analysis of all studies published in the field and brought together data from almost 10,000 patients. They used statistical modelling to show the specific effect of these medicines.

Prof Vassiliou said: "We found that patients taking SGLT2 inhibitors were 22 per cent less likely to die from heart-related causes or be hospitalised for heart failure exacerbation than those taking placebo.

"This is very important because this is the first medication that can provide a benefit to this previously untreatable group of patients -- in terms of heart-related deaths or hospitalisation.

"This is the first medication that can really improve the outcomes for this patient group and it will revolutionise the treatment offered to heart failure patients," he added.

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Leaky sewers are likely responsible for large amounts of medications in streams

Pharmaceutical compounds can harm the environment. However, in waterways that don't receive treated wastewater, these pollutants aren't expected to be present. Now, researchers reporting in ACS' Environmental Science & Technology have found that amounts of some medications carried by a stream in Baltimore were substantial, despite generally low concentrations over the course of a year. Because wastewater plants don't impact this stream, the high loads are likely coming from leaking sewer pipes, they say.

Thousands of medications are approved for human use in the U.S., and many of them are harmful to microorganisms, algae and insects when they make their way into lakes and streams through wastewater. The concentrations of pharmaceutical compounds are usually used to determine their impact on organisms living in streams and rivers. However, contaminant concentrations may change quickly from one day to the next, and so singular snapshots do not correctly illustrate their cumulative effects on aquatic life. Instead, load -- the mass of a pollutant that passes through a stream or river over time -- better represents the risks to downstream environments, where the contaminants end up. While loads are used in regulations for traditional pollutants, such as nutrients, they have not been considered for pharmaceuticals. So, Megan Fork and colleagues wanted to get an idea of the yearly load of medicines transported by an urban stream in Baltimore.

The researchers tested water from an urban stream draining into Baltimore's Inner Harbor in Maryland on a weekly basis for a year. At the outflow point, they found 16 pharmaceutical compounds whose presence and amount varied considerably from week to week, ranging from concentrations of parts per trillion to parts per billion. Trimethoprim -- an antibiotic -- was found most regularly, but acetaminophen -- a common pain reliever -- was at the highest concentrations. The team used their weekly measurements to estimate annual loads of pharmaceuticals, calculating that the equivalent of 30,000 doses of antidepressants, 1,700 doses of antibiotics and 30,000 tablets of acetaminophen entered the Inner Harbor through the stream. Interestingly, this watershed did not receive wastewater treatment plant effluent, so it's likely these compounds are coming from leaky sewer pipes. Improvements to aging infrastructure could reduce this source of harmful compounds to urban streams and other waterways, the researchers say.

From Science Daily

New study details enzyme that allows coronavirus to resist antiviral medications

The coronavirus that causes COVID-19 has demonstrated a stubborn ability to resist most nucleoside antiviral treatments, but a new study led by an Iowa State University scientist could help to overcome the virus's defenses.

The study, published recently in the peer-reviewed journal Science, details the structure of a critical enzyme present in SARS-CoV-2, the coronavirus that causes COVID-19. This enzyme, known as the proofreading exoribonuclease (or ExoN), removes nucleoside antiviral medications from the virus's RNA, rendering most nucleoside analogs-based antiviral treatments ineffective. The new study presents the atomic structures of the ExoN enzyme, which could lead to the development of new methods for deactivating the enzyme and opening the door to better treatments for patients suffering from COVID-19.

"If we could find a way to inhibit this enzyme, maybe we can achieve better results to kill the virus with existing nucleoside antiviral treatments. Understanding this structure and the molecular details of how ExoN works can help guide further development of antivirals," said Yang Yang, lead author of the study and assistant professor in the Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology at Iowa State University.

SARS-CoV-2 is an RNA virus, which means its genetic material is composed of ribonucleic acid. When the virus replicates, it must synthesize RNA. But the virus's genome is unusually large when compared to other RNA viruses, which creates a relatively high likelihood that errors arise during RNA synthesis. These errors take the form of mismatched nucleotides, and too many errors can prevent the virus from propagating.

But the ExoN enzyme acts as a proofreader, recognizing mismatches in the virus RNA and correcting errors that occur during RNA synthesis, Yang said. The enzyme is present only in coronaviruses and a few other closely related virus families, he said.

The same process that eliminates replication errors also eliminates antiviral agents delivered by the treatments commonly used to fight other RNA viruses, such as HIV, HCV and Ebola virus, which partially explains why SARS-CoV-2 has proven so difficult to treat, Yang said.

But Yang and his colleagues utilized cryogenic electron microscopy, a technique in which samples are flash cooled to cryogenic temperatures in vitreous ice to preserve their native structures, to detail the structure of the enzyme. Understanding that structure could allow for the development of molecules that bind to the enzyme and disable it. Yang said that's the next step for his laboratory and his colleagues. Finding such a molecule could make the virus more susceptible to newly developed antivirals, Yang said. Or, it could allow for the optimization of current antivirals, such as Remdesivir.

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5-minute breathing workout lowers blood pressure as much as exercise, drugs

Working out just five minutes daily via a practice described as "strength training for your breathing muscles" lowers blood pressure and improves some measures of vascular health as well as, or even more than, aerobic exercise or medication, new CU Boulder research shows.

The study, published June 29 in the Journal of the American Heart Association, provides the strongest evidence yet that the ultra-time-efficient maneuver known as High-Resistance Inspiratory Muscle Strength Training (IMST) could play a key role in helping aging adults fend off cardiovascular disease -- the nation's leading killer.

In the United States alone, 65% of adults over age 50 have above-normal blood pressure -- putting them at greater risk of heart attack or stroke. Yet fewer than 40% meet recommended aerobic exercise guidelines.

"There are a lot of lifestyle strategies that we know can help people maintain cardiovascular health as they age. But the reality is, they take a lot of time and effort and can be expensive and hard for some people to access," said lead author Daniel Craighead, an assistant research professor in the Department of Integrative Physiology. "IMST can be done in five minutes in your own home while you watch TV."

Developed in the 1980s as a way to help critically ill respiratory disease patients strengthen their diaphragm and other inspiratory (breathing) muscles, IMST involves inhaling vigorously through a hand-held device which provides resistance. Imagine sucking hard through a tube that sucks back.

Initially, when prescribing it for breathing disorders, doctors recommended a 30-minute-per-day regimen at low resistance. But in recent years, Craighead and colleagues have been testing whether a more time-efficient protocol -- 30 inhalations per day at high resistance, six days per week -- could also reap cardiovascular, cognitive and sports performance improvements.

For the new study, they recruited 36 otherwise healthy adults ages 50 to 79 with above normal systolic blood pressure (120 millimeters of mercury or higher). Half did High-Resistance IMST for six weeks and half did a placebo protocol in which the resistance was much lower.

After six weeks, the IMST group saw their systolic blood pressure (the top number) dip nine points on average, a reduction which generally exceeds that achieved by walking 30 minutes a day five days a week. That decline is also equal to the effects of some blood pressure-lowering drug regimens.

Even six weeks after they quit doing IMST, the IMST group maintained most of that improvement.

"We found that not only is it more time-efficient than traditional exercise programs, the benefits may be longer lasting," Craighead said.

The treatment group also saw a 45% improvement in vascular endothelial function, or the ability for arteries to expand upon stimulation, and a significant increase in levels of nitric oxide, a molecule key for dilating arteries and preventing plaque buildup. Nitric oxide levels naturally decline with age.

Markers of inflammation and oxidative stress, which can also boost heart attack risk, were significantly lower after people did IMST.

And, remarkably, those in the IMST group completed 95% of the sessions.

"We have identified a novel form of therapy that lowers blood pressure without giving people pharmacological compounds and with much higher adherence than aerobic exercise," said senior author Doug Seals, a Distinguished Professor of Integrative Physiology. "That's noteworthy."

The practice may be particularly helpful for postmenopausal women.

In previous research, Seals' lab showed that postmenopausal women who are not taking supplemental estrogen don't reap as much benefit from aerobic exercise programs as men do when it comes to vascular endothelial function. IMST, the new study showed, improved it just as much in these women as in men.

"If aerobic exercise won't improve this key measure of cardiovascular health for postmenopausal women, they need another lifestyle intervention that will," said Craighead. "This could be it."

Preliminary results suggest MST also improved some measures of brain function and physical fitness. And previous studies from other researchers have shown it can be useful for improving sports performance.

"If you're running a marathon, your respiratory muscles get tired and begin to steal blood from your skeletal muscles," said Craighead, who uses IMST in his own marathon training. "The idea is that if you build up endurance of those respiratory muscles, that won't happen and your legs won't get as fatigued."

Seals said they're uncertain exactly how a maneuver to strengthen breathing muscles ends up lowering blood pressure, but they suspect it prompts the cells lining blood vessels to produce more nitric oxide, enabling them to relax.

The National Institutes of Health recently awarded Seals $4 million to launch a larger follow-up study of about 100 people, comparing a 12-week IMST protocol head-to-head with an aerobic exercise program.

Meanwhile, the research group is developing a smartphone app to enable people to do the protocol at home using already commercially available devices.

Read more at Science Daily

Blood pressure medications help even the frailest elderly people live longer

Taking blood pressure medication as prescribed helped even the frailest elderly people (65 and older) live longer, and the healthiest older people had the biggest survival boost, according to a large study in northern Italy published today in Hypertension, an American Heart Association journal.

"We knew that high blood pressure medication was protective in general among older people, however, we focused on whether it is also protective in frail patients with many other medical conditions who are usually excluded from randomized trials," said Giuseppe Mancia, M.D., lead study author and professor emeritus at the University of Milano-Bicocca in Milan, Italy.

Researchers reviewed data on almost 1.3 million people aged 65 and older (average age 76) in the Lombardy region of northern Italy who had 3 or more high blood pressure medication prescriptions in 2011-2012. Examining the public health care database, researchers calculated the percentage of time over the next seven years (or until death) that each person continued to receive the medications. Because almost all medications are free or low-cost and dispensed by the public health service, this corresponds roughly to people's adherence in using the medication in Italy.

To look separately at outcomes among older people with various medical conditions, researchers used a previously developed score that accounts for 34 different health factors and has a close relationship with mortality.

Researchers compared roughly 255,000 people who died during the 7-year follow-up with age-, gender-, and health-status-matched controls who survived and divided them into four groups of health status: good, medium, poor or very poor.

The probability of death over 7-years was 16% for people rated in good health at the beginning of the study. Mortality probability increased progressively to 64% for those rated in very poor health.

Compared with people with very low adherence to blood pressure medications (dispensed pills covered less than 25% of the time period), people with high adherence to blood pressure medications (more than 75% of the time period covered) were:

    44% less likely to die if they started in good health; and

    33% less likely to die if they started in very poor health.

A similar pattern was seen with cardiovascular deaths. The greatest survival benefit was among the people who started in good health, and the most modest survival benefit was in those who started in very poor health.

"Our findings definitely suggest that even in very frail people, antihypertensive treatment reduces the risk of death; however, the benefits may be smaller in this group," Mancia said.

No matter what a person's initial health status, survival benefits were greatest in those who received blood pressure medication to cover more than 75% of the follow-up period, compared with those with intermediate (25-75%) or low levels (less than 25%) of coverage, highlighting the importance of consistent use of blood pressure medications.

"Do your best to encourage and support patients to take their medications, because adherence is crucial to getting the benefits. Medications do nothing if people don't take them," Mancia said.

Read more at Science Daily

Aspirin may halve air pollution harms

Aspirin pills

A new study is the first to report evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin may lessen the adverse effects of air pollution exposure on lung function. The team of researchers from the Columbia Mailman School of Public Health, Harvard Chan School of Public Health, Boston University School of Medicine published their findings in the American Journal of Respiratory and Critical Care Medicine.

The researchers analyzed a subset of data collected from a cohort of 2,280 male veterans from the greater Boston area who were given tests to determine their lung function. The average age of participants was 73 years. The researchers examined the relationship between test results, self-reported NSAID use, and ambient particulate matter (PM) and black carbon in the month preceding the test, while accounting for a variety of factors, including the health status of the subject and whether or not he was a smoker. They found that the use of any NSAID nearly halved of the effect of PM on lung function, with the association consistent across all four weekly air pollution measurements from same-day to 28 days prior to the lung function test.

Because most of the people in the study cohort who took NSAIDs used aspirin, the researchers say the modifying effect they observed was mainly from aspirin, but add that effects of non-aspirin NSAIDs are worthy of further exploration. While the mechanism is unknown, the researchers speculate that NSAIDs mitigate inflammation brought about by air pollution.

"Our findings suggest that aspirin and other NSAIDs may protect the lungs from short-term spikes in air pollution," says first and corresponding author Xu Gao, PhD, a post-doctoral research scientist in the Department of Environmental Health Sciences at the Columbia Mailman School. "Of course, it is still important to minimize our exposure to air pollution, which is linked to a host of adverse health effects, from cancer to cardiovascular disease."

"While environmental policies have made considerable progress toward reducing our overall exposure to air pollution, even in places with low levels of air pollution, short-term spikes are still commonplace," says senior author Andrea Baccarelli, MD, PhD, chair of the Department of Environmental Health Sciences at the Columbia Mailman School. "For this reason, it is important to identify means to minimize those harms."

An earlier study by Baccarelli found that B vitamins may also play a role in reducing the health impact of air pollution.

Read more at Science Daily

Aspirin should not be recommended for healthy people over 70

Low-dose aspirin does not prolong disability-free survival of healthy people over 70, even in those at the highest risk of cardiovascular disease. The late breaking results of the ASPREE trial are presented today at ESC Congress 2019 together with the World Congress of Cardiology.

On behalf of the ASPREE Investigators, Professor Christopher Reid of Curtin University, Perth, Australia said: "An ever-increasing number of people reach the age of 70 without overt cardiovascular disease (CVD). This analysis suggests that improved risk prediction methods are needed to identify those who could benefit from daily low-dose aspirin."

European guidelines on the prevention of CVD do not recommend aspirin for individuals free from CVD due to the increased risk of major bleeding. This advice was subsequently supported by results in moderate risk patients (ARRIVE), diabetic patients (ASCEND), and in people over 70 (ASPREE) which demonstrated that modest reductions in CVD risk were outweighed by the increased bleeding hazard.

The primary finding from the ASPREE randomised trial was that in people aged 70 years or over with no known CVD, there was no effect of 100 mg of daily aspirin on the composite primary endpoint of disability-free survival (defined as those not reaching a primary endpoint of dementia or persistent physical disability or death). The primary endpoint was chosen to reflect the reasons for prescribing a preventive drug in an otherwise healthy elderly population.

This analysis examined whether the results for the primary endpoint of disability-free survival might vary by the baseline level of CVD risk. Analyses were also conducted for the secondary endpoints of all-cause mortality, major haemorrhage, and prevention of CVD (defined as fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalisation for heart failure).

The investigators calculated ten-year CVD risk probabilities at baseline for the 19,114 ASPREE participants using the Framingham score (up to 75 years) and the atherosclerotic cardiovascular disease (ASCVD) pooled cohort risk equations (up to 79 years) and divided them into thirds. As there are no CVD risk scores available beyond the age ranges specified in the equations, they also classified participants according to the presence of 0 to 1, 2 to 3, or more than 3 CVD risk factors. Overall rates of disability-free survival, mortality, major bleeding and CVD were examined for each risk group and outcomes were compared for those treated with aspirin or placebo.

For participants in the lowest third of CVD risk, by both Framingham and ASCVD scores, there was no disability-free survival or cardiovascular benefit from aspirin. This group also had the highest likelihood of bleeding.

In contrast, those in the highest third of CVD risk, by both Framingham and ASCVD scores, had significantly lower CVD event rates on aspirin with similar rates of bleeding. Hazard ratios for CVD reduction with aspirin version placebo were 0.72 (95% confidence interval [CI] 0.54-0.95) for the group classified as high risk by the Framingham score and 0.75 (95% CI 0.58-0.97) for those defined as high risk by the ASCVD equations.

However, this reduction in CVD did not translate to a significantly improved disability-free survival. Hazard ratios for disability-free survival with aspirin versus placebo were 0.86 (95% CI 0.62-1.20) for the group designated high risk by the Framingham score and 0.89 (95% CI 0.62-1.28) for those considered high risk by the ASCVD equations.

Prof Reid said: "The findings emphasise that the risk-benefit trade-off for aspirin use in healthy older men and women varies across levels of cardiovascular risk. It also indicates that the reduction in CVD events in the highest risk groups using current stratification methods does not identify individuals in whom this advantage translates into longer disability-free survival."

New ways to identify groups at increased CVD risk, beyond the use of conventional risk factors and current prediction models, will be investigated in the ASPREE longitudinal follow-up study. Genetic and biomarker information will be included from the ASPREE biobank.

Read more at Science Daily

Music can be a viable alternative to medications in reducing anxiety before anesthesia

Music is a viable alternative to sedative medications in reducing patient anxiety prior to an anesthesia procedure, according to a Penn Medicine study published today in the journal Regional Anesthesia & Pain Medicine.

A peripheral nerve block procedure is a type of regional anesthesia -- done in the preoperative area under ultrasound guidance -- that blocks sensations of pain from a specific area of the body. The procedure is routinely performed for a variety of outpatient orthopedic surgeries, such as hip and knee arthroscopies and elbow or hand surgeries. To reduce anxiety, which can lead to prolonged recovery and an increase in postoperative pain, patients commonly take sedative medications, like midazolam, prior to the nerve block procedure. Yet, the medications can have side effects, including breathing issues and paradoxical effects like hostility and agitation. In this study, researchers found a track of relaxing music to be similarly effective to the intravenous form of midazolam in reducing a patient's anxiety prior to the procedure.

"Our findings show that there are drug-free alternatives to help calm a patient before certain procedures, like nerve blocks," said the study's lead author Veena Graff, MD, an assistant professor of Clinical Anesthesiology and Critical Care. "We've rolled out a new process at our ambulatory surgical center to provide patients who want to listen to music with access to disposable headphones. Ultimately, our goal is to offer music as an alternative to help patients relax during their perioperative period."

While research has shown music can help reduce a patient's anxiety prior to surgery, previous studies have primarily focused on music vs. an oral form of sedative medications, which are not routinely used in the preoperative setting. In this study -- the first to compare music medicine with an intravenous form of sedative medication -- researchers aimed to measure the efficacy of music in lowering a patient's anxiety prior to conducting a peripheral nerve block.

The team randomly assigned 157 adults to receive one of two options three minutes prior to the peripheral nerve block: either an injection of 1-2 mg of midazolam, or a pair of noise canceling headphones playing Marconi Union's "Weightless," -- an eight-minute song, created in collaboration with sound therapists, with carefully arranged harmonies, rhythms, and bass lines designed specifically to calm listeners down. Researchers evaluated levels of anxiety before and after the use of each method, and found similar changes in the levels of anxiety in both groups.

However, the team noted that patients who received midazolam reported higher levels of satisfaction with their overall experience and fewer issues with communication. Researchers attribute these findings to a number of factors, including the fact they used noise canceling headphones, didn't standardize the volume of music, and didn't allow patients to select the music.

From Science Daily