Drug to treat malaria could mitigate hereditary hearing loss

Kumar Alagramam. PhD, Case Western Reserve University

The ability to hear depends on proteins to reach the outer membrane of sensory cells in the inner ear. But in certain types of hereditary hearing loss, mutations in the protein prevent it from reaching these membranes. Using a zebrafish model, researchers at Case Western Reserve University School of Medicine have found that an anti-malarial drug called artemisinin may help prevent hearing loss associated with this genetic disorder.

In a recent study, published in the Proceedings of the National Academy of Sciences (PNAS), researchers found the classic anti-malarial drug can help sensory cells of the inner ear recognize and transport an essential protein to specialized membranes using established pathways within the cell.

The sensory cells of the inner ear are marked by hair-like projections on the surface, earning them the nickname “hair cells.” Hair cells convert sound and movement-induced vibrations into electrical signals that are conveyed through nerves and translated in the brain as information used for hearing and balance.

The mutant form of the protein–clarin1–render hair cells unable to recognize and transport them to membranes essential for hearing using typical pathways within the cell. Instead, most mutant clarin1 proteins gets trapped inside hair cells, where they are ineffective and detrimental to cell survival. Faulty clarin1 secretion can occur in people with Usher syndrome, a common genetic cause of hearing and vision loss.

The study found artemisinin restores inner ear sensory cell function—and thus hearing and balance—in zebrafish genetically engineered to have human versions of an essential hearing protein.

Senior author on the study, Kumar N. Alagramam, the Anthony J. Maniglia Chair for Research and Education and associate professor at Case Western Reserve University School of Medicine Department of Otolaryngology at University Hospitals Cleveland Medical Center, has been studying ways to get mutant clarin1 protein to reach cell membranes to improve hearing in people with Usher syndrome.

“We knew mutant protein largely fails to reach the cell membrane, except patients with this mutation are born hearing,” Alagramam said. “This suggested to us that, somehow, at least a fraction of the mutant protein must get to cell membranes in the inner ear.”

Alagramam’s team searched for any unusual secretion pathways mutant clarin1 could take to get to hair cell membranes. “If we can understand how the human clarin1 mutant protein is transported to the membrane, then we can exploit that mechanism therapeutically,” Alagramam said.

For the PNAS study, Alagramam’s team created several new zebrafish models. They swapped the genes encoding zebrafish clarin1 with human versions—either normal clarin1, or clarin1 containing mutations found in humans with a type of Usher syndrome, which can lead to profound hearing loss.

“Using these ‘humanized’ fish models,” Alagramam said, “we were able to study the function of normal clarin1 and, more importantly, the functional consequences of its mutant counterpart. To our knowledge, this is the first time a human protein involved in hearing loss has been examined in this manner.”

Zebrafish offer several advantages to study hearing. Their larvae are transparent, making it easy to monitor inner ear cell shape and function. Their genes are also nearly identical to humans—particularly when it comes to genes that underlie hearing. Replacing zebrafish clarin1 with human clarin1 made an even more precise model.

The researchers found the unconventional cellular secretion pathway they were looking for by using florescent labels to track human clarin1 moving through zebrafish hair cells. The mutated clarin1 gets to the cell membrane using proteins and trafficking mechanisms within the cell, normally reserved for misfolded proteins “stuck” in certain cellular compartments.

“As far as we know, this is the first time a human mutant protein associated with hearing loss has been shown to be ‘escorted’ by the unconventional cellular secretion pathway,” Alagramam said. “This mechanism may shed light on the process underlying hearing loss associated with other mutant membrane proteins.”

The study showed the majority of mutant clarin1 gets trapped inside a network of tubules within the cell analogous to stairs and hallways helping proteins, including clarin1, get from place to place. Alagramam’s team surmised that liberating the mutant protein from this tubular network would be therapeutic and tested two drugs that target it: thapsigargin (an anti-cancer drug) and artemisinin (an anti-malarial drug).

The drugs did enable zebrafish larvae to liberate the trapped proteins and have higher clarin1 levels in the membrane; but artemisinin was the more effective of the two. Not only did the drug help mutant clarin1 to reach the membrane, hearing and balance functions were better preserved in zebrafish treated with the anti-malarial drug than untreated fish.

In zebrafish, survival depends on normal swim behavior, which in turn depends on balance and the ability to detect water movement, both of which are tied to hair cell function. Survival rates in zebrafish expressing the mutant clarin1 jumped from 5% to 45% after artemisinin treatment.

“Our report highlights the potential of artemisinin to mitigate both hearing and vision loss caused by clarin1 mutations,” Alagramam said. “This could be a re-purposable drug, with a safe profile, to treat Usher syndrome patients.”

Alagramam added that the unconventional secretion mechanism and the activation of that mechanism using artemisinin or similar drugs may also be relevant to other genetic disorders that involve mutant membrane proteins aggregating in the cell’s tubular network, including sensory and non-sensory disorders.

Gopal SR, et al. “Unconventional secretory pathway activation restores hair cell mechanotransduction in an USH3A model.” PNAS.

Drug to treat malaria could mitigate hereditary hearing loss

Children wise to fear hand dryers, and 13-year-old proves it with published paper

Calgary student Nora Keegan has been studying decibel levels in hand dryers since she was 9 years old.

Children who say hand dryers “hurt my ears” are correct.

A new research paper by that very title has just been published in Paediatrics & Child Health, Canada’s premier peer-reviewed pediatric journal. And the researcher, 13-year-old Nora Keegan, has been studying the issue since she was nine years old.

“In Grade 4, I noticed that my ears kind of hurt after the hand dryer,” Keegan told the Calgary Eyeopener. “And then later, at the start of Grade 5, I also noticed that my ears were hurting after I used the hand dryer. So then I decided to test it to see if they were dangerous to hearing, and it turns out they are.”

Keegan used a decibel meter, and measured the noise at different heights and different distances from the wall.

“I thought it would be good to have a lot of children’s heights and also women’s height and men’s height, and then I measured 18 inches from the wall, which is the industry standard. And I also measured 12 inches from the wall since I thought the children might stand closer because their hands and arms are shorter.”

She discovered something even more alarming.

“And then one time I was testing on the decibel meter and my hand accidentally passed into the airstream flow, and the decibels shot up a lot,” she said. “So then I decided to make that another part of my testing method. So I also measured with hands in the air flow and without hands in the air.”

Keegan discovered that the sound was even louder with the hands in the airflow.

“And it was also really loud at children’s heights and manufacturers don’t measure for children’s height as much either.”

Eventually, Keegan determined that there are two models in particular that are harmful for children’s ears: the Dyson and XCelerator, which both operate at about 110 decibels. Health Canada has regulated that no toys operate at more than 100 decibels.

“So this is very loud, around the level of a rock concert,” Keegan said. “And this is also louder than Health Canada’s regulation for children’s toys, as they know that at this level it poses a danger to children’s hearing.”

Children have smaller ear canals and more sensitive follicles. And they tend to stand closer to the dryers because their bodies are smaller and their arms are shorter.

These are all things Keegan started documenting in a series of research projects.

“So it started out as a school science fair in Grade 5. And then I really enjoyed it, and I thought I could do more with it,” she said. “So then I continued working on it in Grade 6, and then Grade 7, I started writing the paper, and it just got published now in Paediatrics & Child Health.”

Keegan is a Grade 8 student at Branton Junior High School in Calgary. The full title of her paper is, “Children who say hand dryers ‘hurt my ears’ are correct: A real-world study examining the loudness of automated hand dryers in public places.”

But the young scientist, who says she hopes to have a career as a marine biologist, isn’t stopping with this personal success. She wants to do something about the problem.

By experimenting with different materials, she’s made a model that reduces the noise by 11 decibels.

Keegan’s synthetic air filter, which looks like a fuzzy handbag, absorbs the sound waves.

“The air comes down further so even though your hands still reach the airflow, then your ears are a greater distance from where the air comes out.”

Keegan conducted an informal test of the air filter at her school.

“I couldn’t really find a way to test it, but I installed it in my school’s washroom and I found that it didn’t (heat up). People seemed to enjoy it and it didn’t seem to have a problem.”

Keegan said she hasn’t tried to do anything official with the air filter — yet.

“I think I might go and talk to the manufacturers and also I might go and talk to Health Canada because even though this is a study, it’s still only one study. So it’d be better if they tested more hand dryers and found more about that loudness of hand dryers.”

Keegan assessed 44 different hand dryers, from places that kids would be using them all over Calgary — arenas, restaurants, schools, libraries and shopping malls.


Woman suffers acute reverse-slope hearing loss (RSHL) and becomes unable to hear male voices

By Fiza Pirani,

A woman in Xiamen, China, unexpectedly developed an ear condition that left her unable to hear male voices, the Daily Mail recently reported citing local AsiaWire reports.

The woman, who has only been identified by her last name (Chen), said she realized something was wrong when she woke up and couldn’t hear her boyfriend’s voice. Before going to bed, she said she heard ringing in her ears and vomited.

When she made it to Qianpu Hospital, doctors diagnosed Chen with reverse-slope hearing loss (RSHL), a rare condition in which lower frequencies become difficult to hear. It’s named for the shape it produces in visualizations — “the graph starts in the lower-left-hand corner and slopes upward steeply,” according to Georgia audiology clinic, Audiology HEARS, P.C.

Chen “was able to hear me when I spoke to her,” treating provider Dr. Lin Xiaoqing, a woman, told the Daily Mail. “But when a young male patient walked in, she couldn’t hear him at all.”

Xiaoqing told local media she believes fatigue and stress played a role in Chen’s condition and expects her patient will make a full recovery.

When humans hear sounds, the tiny hairs inside the ear vibrate. But genetic conditions, injuries or types of drug use may make the hairs “brittle and prone to breakage,” affecting one’s ability to hear higher-pitched sounds, Dr. Michelle Kraskin, an audiologist at New York-Presbyterian Hospital who was not involved in Chen’s case, told Live Science. But hearing loss of low-pitched sounds like Chen experienced is less common because the ear’s cochlea, responsible for the lower frequencies, is usually highly protected.

In fact, RSHL only affects an estimated 3,000 people in the United States and Canada. For every 12,000 people with some type of hearing loss, Audiology HEARS states on its website, only one individual has RSHL.

It’s most often caused by genetics, and many people with the condition might not even know they have it. Those with Wolfram syndrome, Mondini dysplasia and inheritance through a dominant gene are at increased risk, according to the clinic.

Other causes of RSHL may include diseases like sudden hearing loss, viral infections or Ménière’s disease, all of which affect the hair cells. Autoimmune disorders that affect the inner ear, also rare, are another potential source. These conditions could also lead to dizziness, nausea and vomiting.

Any procedures or conditions that cause a change in pressure of inner ear fluid (or the endolymph) may also cause RSHL. These conditions include spinal or general anesthesia, intracranial hypertension or a perilymphatic fistula.

Some symptoms of RSHL may include difficulty comprehending speech over phones, which largely deliver low and middle frequencies; an inability to hear low-frequency sounds like a running refrigerator or thunder and, as Chen displayed, a difficulty hearing male voices compared to higher-frequency speech of women and children.

It’s best to catch the condition within 48 hours for the best chance of recovery, Kraskin said. Once diagnosed, treatment may involve high doses of steroids.

Though RSHL may go away without any treatment at all, the condition can potentially worsen and become problematic in terms of safety.

“If you can’t hear a car coming, you can’t avoid it. If someone some distance from you is trying to warn you away from something, you might not hear it, because volume is a product of the lower frequencies,” according to Audiology HEARS.

Because general industry standards cater to high-frequency hearing loss, which is much more common, treating worsening RSHL can be quite difficult. Audiologists are encouraged to listen to the patient’s concerns and customize hearing aids and should take the time to determine “channel by channel, frequency by frequency” what patients finds “comfortable, audible, and helpful.”

Approximately 25 percent of people in the United States between ages 55 and 64 have some degree of hearing loss, according to the Mayo Clinic. It becomes increasingly common as you age. In fact, hearing loss affects 1 in 2 people older than age 65. Anyone who experiences sudden hearing loss, particularly in one ear, should seek medical attention immediately.


A Simple Treatment May Minimize Hearing Loss Triggered by Loud Noises

It’s well known that exposure to extremely loud noises — whether it’s an explosion, a firecracker or even a concert — can lead to permanent hearing loss.
But knowing how to treat noise-induced hearing loss, which affects about 15 percent of Americans, has largely remained a mystery. That may eventually change, thanks to new research from the Keck School of Medicine of USC, which sheds light on how noise-induced hearing loss happens and shows how a simple injection of a salt- or sugar-based solution into the middle ear may preserve hearing. The results of the study were published today in PNAS.

Deafening sound
To develop a treatment for noise-induced hearing loss, the researchers first had to understand its mechanisms. They built a tool using novel miniature optics to image inside the cochlea, the hearing portion of the inner ear, and exposed mice to a loud noise similar to that of a roadside bomb.

They discovered that two things happen after exposure to a loud noise: sensory hair cells, which are the cells that detect sound and convert it to neural signals, die, and the inner ear fills with excess fluid, leading to the death of neurons.

“That buildup of fluid pressure in the inner ear is something you might notice if you go to a loud concert,” says the study’s corresponding author John Oghalai, MD, chair and professor of the USC Tina and Rick Caruso Department of Otolaryngology – Head and Neck Surgery and holder of the Leon J. Tiber and David S. Alpert Chair in Medicine. “When you leave the concert, your ears might feel full and you might have ringing in your ears. We were able to see that this buildup of fluid correlates with neuron loss.”

Both neurons and sensory hair cells play critical roles in hearing.

“The death of sensory hair cells leads to hearing loss. But even if some sensory hair cells remain and still work, if they’re not connected to a neuron, then the brain won’t hear the sound,” Oghalai says.

The researchers found that sensory hair cell death occurred immediately after exposure to loud noise and was irreversible. Neuron damage, however, had a delayed onset, opening a window of opportunity for treatment.

A simple solution

The buildup of fluid in the inner ear occurred over a period of a few hours after loud noise exposure and contained high concentrations of potassium. To reverse the effects of the potassium and reduce the fluid buildup, salt- and sugar-based solutions were injected into the middle ear, just through the eardrum, three hours after noise exposure. The researchers found that treatment with these solutions prevented 45–64 percent of neuron loss, suggesting that the treatment may offer a way to preserve hearing function.

The treatment could have several potential applications, Oghalai explains.

“I can envision soldiers carrying a small bottle of this solution with them and using it to prevent hearing damage after exposure to blast pressure from a roadside bomb,” he says. “It might also have potential as a treatment for other diseases of the inner ear that are associated with fluid buildup, such as Meniere’s disease.”

Oghalai and his team plan to conduct further research on the exact sequence of steps between fluid buildup in the inner ear and neuron death, followed by clinical trials of their potential treatment for noise-induced hearing loss.

A Simple Treatment May Minimize Hearing Loss Triggered by Loud Noises

Why roosters don’t go deaf from their crowing

by Noel Kirkpatrick

There’s a reason a rooster’s crow rouses the farm from a night’s slumber: It can be a very, very loud noise. It’s so loud, in fact, that you have to wonder how roosters don’t lose their hearing.

Which is exactly what researchers from the University of Antwerp and the University of Ghent in Belgium were wondering when they undertook this study in the journal Zoology.


The secret? Roosters can’t really hear themselves cock-a-doodle-doo.

A crow for your ears only

Our ears are delicate. A sound louder than 120 decibels — which is roughly the sound of a chainsaw — can cause permanent hearing loss. The air pressure waves from the noise can, over prolonged exposure, harm or even kill the cells that convert sound waves into the noises our brains can process. At 130 decibels, all it takes is half a second to cause a bit of hearing damage.

Given that roosters can crow at least as loud as 100 decibels, or the decibel level of a jackhammer, you’d expect them to experience some modicum of deafness over the course of their lifetimes. Instead, they continue to hear just fine — and to greet the new day with a blaring hoot.

To figure out just how loud the roosters got, and how they were able to keep their hearing, researchers strapped microphones to the heads of three roosters, with the receiving end pointed at their ears. This was done to measure the sound levels that the roosters themselves would hear when they crowed. The crows were also measured from a distance away. And one other measurement was taken: the researchers performed micro-CT scans on roosters and hens so they could pick apart the geometry of how sounds bounce around in their respective ear canals.

The decibels levels were all over 100 decibels, meaning loud enough to potentially cause damage. One rooster even hit 140 decibels, or the sound level on an aircraft carrier deck, and easily loud enough to cause some damage.

It turns out that roosters keep themselves safe from their own crows with an anatomy adaptation. When they open their beaks to the fullest, a quarter of the ear canal closes and soft tissue covers 50 percent of the eardrum. Basically, they have built-in earplugs that protect them from their own noises. Hens are also protected. Like roosters, the hens’ ear canals also close up, but not as much as their male counterparts’ do.

This built-in protective ability makes sense from an evolutionary perspective. Crowing also serves as a warning to other roosters that this particular group of hens is spoken for — so superlatives rule. The loudest rooster would end up being seen as the most fit to mate with the hens.


New research shows that infants need to be able to freely move their tongues in order to distinguish sounds.

A team of researchers led by Dr Alison Bruderer, a postdoctoral fellow at the University of British Columbia, has discovered a direct link between tongue movements of infants and their ability to distinguish speech sounds.

“Until now, research in speech perception development and language acquisition has primarily used the auditory experience as the driving factor. Researchers should actually be looking at babies’ oral-motor movements as well,” said Dr Bruderer, who is the lead author on a study published in the Proceedings of the National Academy of Sciences on October 12, 2015.

In the study, teething toys were placed in the mouths of six-month-old English-learning infants while they listened to speech sounds – two different Hindi ‘d’ sounds that infants at this age can readily distinguish.

When the teethers restricted movements of the tip of the tongue, the infants were unable to distinguish between the two sounds.

But when their tongues were free to move, the babies were able to make the distinction.

“Before infants are able to speak, their articulatory configurations affect the way they perceive speech, suggesting that the speech production system shapes speech perception from early in life,” the scientists said.

“These findings implicate oral-motor movements as more significant to speech perception development and language acquisition than current theories would assume and point to the need for more research.”