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New live cell models lay the groundwork for studies into mitochondrial diseases

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The mitochondrion has earned a reputation for its role as the “powerhouse of the cell”. These tiny but powerful organelles play various life-sustaining roles, from supplying energy to our own cells and organs to promoting chemical and biological processes. But when they don’t work properly, a number of rare diseases can develop.

Mitochondrial diseases are a group of debilitating genetic diseases that affect one in 5,000 people worldwide, most of them children. Associated with these diseases are a variety of health problems including, but not limited to, heart disease, developmental and cognitive disabilities, breathing problems, poor growth, and even premature death. There is currently no cure.

But recently published work in the journals Mitochondrion and BMC Molecular and Cell Biology by Aloka Abey Bandara, a research associate professor in the Department of Biomedical Sciences and Pathobiology at Virginia-Maryland College of Veterinary Medicine, and his team offer patients with mitochondrial disease and their parents a glimmer of hope.

Together with a team of Virginia Tech researchers in Blacksburg and Roanoke, Bandara has successfully created living cell models that mimic mitochondrial disease cells. These cells will lay the foundation for drug trials and future studies of mitochondrial disease.

“Our cell models will enable us to see what exactly happens to the cells and their processes when a child develops mitochondrial disease. In addition to these factors, we can further investigate the toxicity and efficacy of new drug candidates, ”said Bandara, who is also a faculty member at the Fralin Life Sciences Institute.

Our bodies produce life-sustaining energy from the food we eat and the air we breathe. Oxygen and nutrients, like glucose, travel through the organs, tissues, and cells of the body until they reach their ultimate destination: the mitochondria. When the nutrients reach the inner membrane of the mitochondria, a unique set of protein complexes called the electron transport chain is set in motion.

Through a series of reactions, the electron transport chain is able to withdraw electrons from the nutrients and push them through the mitochondrial membrane, which forms a proton gradient. When this happens, the body makes adenosine triphosphate, better known as ATP, a molecule that carries energy around cells.

“Sometimes you see disturbances or mutations within the proteins in the electron transport chain,” says Bandara. “As a result, the protein complexes cannot transport electrons, and energy production is then disrupted. Almost all organs of the organism are affected – heart, eyes and muscles – and cannot function properly. “

The electron transport chain consists of five protein complexes or protein groups. Complex I and Complex II are two protein complexes that are mainly responsible for removing electrons from nutrients. If they don’t do their job, the entire electron transport chain fails and the body cannot produce ATP.

Patients with mitochondrial disease may have defects in complex I or complex II. Patients with complex I disorders typically have neurological problems such as seizures and abnormal brain function. People with complex II disorders can develop many other diseases and are more likely to develop more than one type of cancer.

Although researchers are able to pinpoint exactly where the defects are, developing treatments for these mitochondrial diseases has been challenging. Therapies, vitamins, and dietary changes could all help relieve symptoms and slow the progression of the disease; but mitochondrial disease itself has no cure. Therefore, new drugs need to be developed, tested and refined.

Bandara hopes his cell lines will not only support future research, but also the patients and their families who are experiencing mitochondrial disease and all of its effects up close.

“Parents are often helpless because they can’t just go to the pharmacy and get some medicine,” says Bandara. “Hopefully you can see Virginia Tech take great strides to find a cure for these diseases. Perhaps they can feel that they are no longer alone – that universities, government, and academia are battling them.”

In order to test drug candidates, researchers first have to create cell models that act as artificial “diseased” cells. Cellular models are a great tool for drug discovery because mitochondrial diseases can be studied without actually having to extract cells from patients.

To create cells that mimic mitochondrial diseases, Bandara had to use CRISPR / Cas9 technology to “knock out” parts of the genome that generate the coding for Complex I and Complex II.

First, the researchers identified the part of the genome that needed to be deleted. Then they designed a piece of RNA that made that point its “home base”. The RNA then “directed” an enzyme called Cas9 to its home base on the gene. Cas9 is then able to bind to that point and “cut” it.

After this process was completed, Bandara performed genome sequencing to confirm that the part was successfully removed from the genome. Over several months of hard work, Bandara and his team created two mutated cell lines, one without Complex I and the other without Complex II.

Bandara is one of the few researchers on the Virginia Tech campus in Blacksburg using CRISPR / Cas9 technology to treat mitochondrial disease.

After the mutant cell lines were created, Bandara ran them through a disease model in which he tested the functions of the “diseased” cell line against the “parent” cell line, which is made up of healthy cells. Through detailed analysis, Bandara confirmed that the diseased cells used much less oxygen, grew very slowly, and did not produce enough ATP for the cells to function properly – the three hallmarks of cells with mitochondrial disease.

After confirming that the knockout cell lines were properly simulating the cellular dysfunction of mitochondrial disease, they were able to test a newly developed drug called idebenone. With this treatment, Bandara showed that cell growth and oxygen consumption can be restored to a certain extent.

These cell lines were the product of a fruitful collaboration between experts from the Department of Human Nutrition, Foods and Exercise and the Virginia Tech Carilion School of Medicine.

Mutant cell line construction was led and supported by David Brown, a former associate professor in the Department of Human Nutrition, Foods and Exercise at Virginia Tech College of Agriculture and Life Sciences, now Senior Director of Scientific and Technical Innovation at Stealth BioTherapeutics, in Boston based biotechnology company.

From this work, the team received two preliminary patents for their cells. One of the cell lines has already been patented and licensed to a pharmaceutical company that will develop new therapies for people with mitochondrial diseases.

These cells were made available to interested researchers and pharmaceutical companies by Ximbio, the world’s largest non-profit organization specializing in life science research tools of all kinds, for worldwide use.

“Cell models of mitochondrial complex I and II defects are of great social and economic importance as models for cost- and time-efficient testing of drug candidates for the treatment of mitochondrial dysfunction,” said Justin Perry, a graduate of Virginia Tech, now a Business Development Manager at Ximbio.

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Pfizer says vaccine’s power wanes over time. Are you still protected?

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The effectiveness of the Pfizer-BioNTech Covid-19 vaccine waned over six months, but experts say the data still does not indicate an immediate need for booster vaccines.

The study, which has not yet been peer-reviewed or published in a medical journal, found that the vaccine was 97 percent effective at preventing serious Covid illnesses for at least six months – but effectiveness against any symptomatic illness fell from 96 Percent to 84 percent over the same period, every two months by about 6 percent.

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“I was generally encouraged by the results of the paper,” said lead study author Dr. Stephen Thomas, a coordinating investigator for the Pfizer vaccine study and director of the SUNY Upstate Institute for Global Health & Translational Science in New York.

He said the expectation is always that the protection of the vaccine would wear off. The big question, he said, was whether protection would wane to the extent that the disease was affecting so-called public health; namely, hospitalizations and deaths. So far this does not seem to be the case.

“Although we saw protection wear off after six months, protection from the serious consequences that really put the disease’s public health burden in place,” said Thomas.

Overall, the study found that within six months, the vaccine was 91 percent effective in preventing symptoms of Covid, which ranged from mild to severe symptoms. Pfizer announced these specific results in a press release in April.

Dr. Paul Offit, a vaccine researcher at Philadelphia Children’s Hospital, said he was “pleasantly surprised” that it was as effective as it was in preventing symptoms.

“These data are all very encouraging and exactly what you would expect,” he said.

“You will never be so well protected from an asymptomatic infection or a mildly symptomatic infection, and that’s fine,” he said. “They just want to keep people out of the hospital and keep them from dying. That is the goal.”

The new study examined follow-up data collected as of March 13 from more than 44,000 people who participated in Pfizer’s Phase 3 clinical trial last year. People received either two doses of the vaccine or two doses of placebo three weeks apart. Since the study only looked at data through mid-March, it remains unclear how the shots against the Delta variant, which became the most common strain of the virus in the United States in early July, remains unclear.

The results come as experts continue to consider whether or not booster injections are needed. Pfizer CEO Albert Bourla has long said that a refresher would be needed in the coming months, although federal health officials say there is still no evidence to warrant this.

In a conference call Wednesday morning, Pfizer said a third dose increases antibody levels specific for the Delta variant by five-fold in people ages 18 to 55 and eleven-fold in people ages 65 to 85 have. Although these results suggest better protection against the variant, whether this leads to better protection against disease remains to be explored.

Offit stressed that it was too early to definitively say that booster vaccinations are needed as the vaccine remains very effective in preventing serious illness and hospital admissions.

“If the number of people who are fully vaccinated and still being hospitalized or killed increases to 5, 10, or 20 percent, you can think about a booster, but we’re not there yet,” he said.

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Dr. Bob Wachter, chairman of the medical school at the University of California, San Francisco, agreed with Offit that the new data does not suggest that it is not yet time to rush and get a booster shot.

“It just goes to show that someone who was injected seven or eight months ago is at a slightly higher risk [for a breakthrough infection] than we thought, and it’s a perfectly good justification for self-vaccinated people to wear masks indoors again, “Wachter said, referring to the Centers for Disease Control and Prevention’s decision on Tuesday to put vaccinated people on wearing masks Recommended indoors in areas with high concentrations of community spread.

However, the dominance of the delta variant, combined with the vaccine’s declining effectiveness over time, suggests that boosters will be needed at some point, he said.

“I don’t think it’s a reason to panic and I don’t think it’s a reason to run out and find a booster today because the overall protection against super sickness and dying remains extremely high,” said Wachter. “But I think it’s part of the puzzle that tells us all that boosters will be in our future.”

Thomas, the study’s author, said more research is needed.

“I believe [the study] says it is possible that if the protective effect of the vaccine continues to wear off over time, we may need booster doses, ”said Thomas. “But that’s still an unanswered question for me.”

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How to stop eye twitching, and why it happens

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Usually the eye twitching is mild and goes away on its own after a few seconds or a few minutes. It is usually not a sign of an underlying disease. However, there are a few things people can try to stop it.

Mild eyelid twitching or eyelid myokymia is common. It has associations with stress, fatigue, and caffeine consumption. Reducing the factors that contribute to eyelid twitching can help reduce the frequency of its occurrence.

This article takes a closer look at eye twitching, what causes it and how to stop it.

A slight twitch occurs when the orbicularis oculi muscle, responsible for closing the eyelids, contracts spontaneously, causing small and uncontrollable twitching movements. The medical term for this condition is eyelid myokymia.

Eyelid myokymia can affect the upper or lower eyelid, but most commonly it affects the lower eyelid. Usually the twitches are light and brief and go away on their own after a few seconds or minutes. In some cases, they can last for hours. Less often they can become chronic.

Learn more about eyelid twitching here.

Other less common types of eyelid twitching include:

Essential blepharospasm

Essential blepharospasm causes the eyelids to close spontaneously. This may be like a blink or a wink, but the eyelids may close for a longer period of time in some cases. Blepharospasm can last a few seconds to a few hours, and some people may not be able to see during this time.

Doctors believe a problem with the nerves around the eyes is causing essential blepharospasm, but aren’t sure why it develops. Sometimes another condition such as Parkinson’s disease can be the cause.

Hemifacial spasm

Hemifacial spasm is a rare condition that causes the muscles on one side of the face to contract. Sometimes this starts near the eye and causes eyelid cramps before other areas of the face are affected.

Hemifacial spasm can occur alone, because something is pressing on the nerves that control the muscles of the face, or as a result of another condition.

Eyelid myokymia often goes away on its own. However, if a person wants to stop or reduce this symptom, they can try the following:

  1. With a warm compress: People can use a warm compress and apply it over the eyelid area. This can help relax the muscles around the eye and stop the cramps.
  2. Reduce stress: Eyelid myokymia is linked to stress, so it may help reduce the exposure to stress. People can do this by delegating tasks to others, taking time each day to relax, trying stress relieving hobbies, and practicing stress management techniques like breathing exercises or mindfulness.
  3. Avoid caffeine: Tea, coffee, some sodas, and chocolate can all contain caffeine, which can trigger or worsen eyelid twitching. Try to gradually reduce or eliminate caffeine intake.
  4. Getting enough sleep: Taking a nap can help resolve the eyelid twitching. It’s also good to get enough sleep each day by setting a regular schedule for falling asleep and waking up. If a person is having trouble falling asleep, a doctor, sleep specialist, or other health care provider can provide advice.
  5. Fight dry eyes: Dry, irritated, or gritty eyes can make your eyelids twitch. People can use moisturizing eye drops to relieve dryness.

More severe or persistent eyelid cramps, such as blepharospasm and hemifacial spasms, may require medical treatment.

Scientists aren’t entirely sure what causes eyelid myokymia. It is a common condition that can occur in healthy people for no apparent reason. It seems to be related to lifestyle factors such as:

The side effects of some medications, including topiramate, flunarizine, and clozapine, can also cause eyelid twitching. However, this is unusual.

A 2017 study from Taiwan on chronic eyelid twitching found that around half of the participants had differences in nerve function. This could be due to a nerve conduction defect that explains why some people develop persistent twitching.

Chronic eye twitching also seems to be more common in women, although experts don’t know why.

The authors of the study suspect that this could be due to the fact that women, especially in China, are exposed to higher levels of stress than men due to social or cultural pressure. Overall, however, more research is needed.

Doctors don’t know what causes blepharospasm, but it can sometimes be related to underlying conditions, such as:

The underlying conditions that can cause hemifacial spasm are similar and include:

  • traumatic injury
  • Brain lesions
  • Bell’s palsy
  • Mastoid or ear infections
  • Tumors
  • other structural abnormalities in the posterior region of the cranial cavity

Many of the known triggers for mild eye twitching are lifestyle related, so changing their daily routine may help people avoid this symptom. This can mean:

  • go to sleep earlier
  • Sleep and wake up at similar times each day, including weekends
  • Practice sleep hygiene
  • Switch to decaffeinated drinks
  • Reducing activities or habits that cause stress, such as B. Revision
  • Seek support from a therapist for anxiety or high levels of stress
  • Avoiding tobacco smoking or alcohol consumption

If eye twitching is common, it can be helpful to record when it occurs and note any other contributing factors. This can help someone see a pattern.

However, if the eye twitching is bothersome and doesn’t seem to be related to daily habits, a doctor may be able to offer other treatments to contain or prevent it.

This could include botox injections, which temporarily paralyze the affected muscles to prevent the twitching.

In rare cases, doctors may recommend an eyelid angle myectomy to correct blepharospasm or hemifacial spasm. This procedure removes the muscles that are causing the cramps. Identifying any underlying medical conditions that are causing the convulsions will allow a doctor to manage or control this symptom.

Most of the time, eye twitching is mild and goes away on its own. However, people should see an ophthalmologist if they experience:

  • Twitching that has lasted for more than a few weeks
  • severe twitching that affects vision
  • spontaneous closing of the eyelids
  • Twitching in other parts of the face
  • often dry eyes
  • other new symptoms that could indicate an underlying condition

Many people experience slight, temporary twitches in their eyes. It is usually not a sign of serious health and often does not require treatment.

People may find that twitching occurs less often if they can reduce stress, anxiety, trouble sleeping, or caffeine consumption.

The more bothersome forms of eye twitching include essential blepharospasm and hemifacial spasm. These can affect a person’s eyesight and make activities such as working or driving difficult to perform.

If a person has severe eye twitching, it is important to speak to a doctor.

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The fashion industry’s ‘plus-size’ label shames women to fit an unhealthy standard

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This first-person article is the experience of Laura Sang, a doctor in Montreal. For more information on CBC’s first-person stories, please visit the FAQ. Content Warning: This article covers eating disorders and Suicidal ideation.

Over a year after the pandemic, I finally had enough courage to venture out and buy new clothes. I know that most of us have experienced “COVID 15” to some extent, and I was no exception.

No amount of regular exercise has been able to counteract the stress, long working hours and the occasional lack of access to healthy food despite the curfew of several months in Quebec. I couldn’t deny that I had gained a few pounds and most of my pants were uncomfortably tight. It was time to upgrade.

I went to my local thrift store and found that my pants size had changed. Once again. When browsing the shelves of last year’s “out of season” pants, the same waist / hip size was marked as extra large instead of large on branded pants. When I tried on piece by piece, nothing worked until I tried on the pants in the “plus size” range.

For the first time in my life, I was forced to shop in a separate area, even though I was only 10 pounds above the upper limit of a healthy body mass index for my height. I was now referred to as a “plus-size” woman and could no longer shop in many of the trendy mainstream stores because their items were not in my size.

I was shocked, angry, and instantly embarrassed.

Thinking back on my pediatric rotations over the past several years, I have spoken to dozens of adolescent girls and boys with eating disorders. They cried in front of me and said they were too fat, their thighs too big, and they were “not doing well enough to lose weight.”

Despite the fact that their ribs were protruding, their blood pressure was unstable, and menstrual / pubescent development was stopped, many of these teenagers struggled with suicidal thoughts because they couldn’t meet their “standards” for thinness.

Eating disorder rates among adolescents were already high and have increased significantly during the pandemic. Unfortunately, unless hospitalization is required, the wait times to get help are daunting. While not all of them have, many teenagers have been able to tell me about one cause of their eating disorders: from the inability to fit into an outfit to a comment from a gym teacher like “You’re great too” for pull-ups make.”

Stop making zero the standard

As a doctor, I cannot deny that being overweight or obese is a risk factor for a number of diseases. Regular physical activity, a healthy diet, and good habits are essential to feeling good and living a happy and healthy life. However, we need to stop misunderstanding what a healthy body looks like and stop shaming people for not conforming to that unattainable and unhealthy standard of size zero.

This is especially true for women. I remember asking a member of staff about a particular dress in my size ten years ago, only to say, “Sorry, we don’t have this in your size.” I have friends who are having trouble finding clothes to fit because sizes don’t go below XS. By only making these beautiful dresses available to people of a certain size, companies are subtly telling us that anyone outside of this range is less valuable and doesn’t deserve to feel beautiful.

Stop making size zero the standard for health and beauty because it isn’t. All women are beautiful, whether they wear XXS or 15X and beyond. All women can be physically active (to their own limits, watch out for injuries). All women and people deserve to be comfortable and beautiful in the clothes they wear. That means offering the same clothing to women of all sizes and not shaming anyone for the number on their clothing label.

At some point I found a few items of clothing in the “plus size” section that were comfortable and fit me well. As soon as I got home, I cut off the labels and threw them in the trash. My body suffered like no other from the effects of health care work during a global pandemic, and I don’t need pants to feel bad about it.

The views expressed here are merely my own, based on anecdotal experience. Please contact your local emergency hotline or health department if you are struggling with suicidal ideation or eating disorders.

CBC Quebec welcomes your first-person essay pitches. Please send an email to povquebec@cbc.ca for details.

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