COVID-19 AND THE BRADYKININ HYPOTHESIS

Interesting findings, and a reinforcement to keep ones Vitamin D levels up.

A closer look at the Bradykinin hypothesis

Earlier this summer, the Summit supercomputer at Oak Ridge National Lab in Tennessee set about crunching data on more than 40,000 genes from 17,000 genetic samples in an effort to better understand Covid-19. Summit is the second-fastest computer in the world, but the process — which involved analyzing 2.5 billion genetic combinations — still took more than a week.

When Summit was done, researchers analyzed the results. It was, in the words of Dr. Daniel Jacobson, lead researcher and chief scientist for computational systems biology at Oak Ridge, a “eureka moment.” The computer had revealed a new theory about how Covid-19 impacts the body: the bradykinin hypothesis. The hypothesis provides a model that explains many aspects of Covid-19, including some of its most bizarre symptoms. It also suggests 10-plus potential treatments, many of which are already FDA approved. Jacobson’s group published their results in a paper in the journal eLife in early July.

According to the team’s findings, a Covid-19 infection generally begins when the virus enters the body through ACE2 receptors in the nose, (The receptors, which the virus is known to target, are abundant there.) The virus then proceeds through the body, entering cells in other places where ACE2 is also present: the intestines, kidneys, and heart. This likely accounts for at least some of the disease’s cardiac and GI symptoms.

But once Covid-19 has established itself in the body, things start to get really interesting. According to Jacobson’s group, the data Summit analyzed shows that Covid-19 isn’t content to simply infect cells that already express lots of ACE2 receptors. Instead, it actively hijacks the body’s own systems, tricking it into upregulating ACE2 receptors in places where they’re usually expressed at low or medium levels, including the lungs.

In this sense, Covid-19 is like a burglar who slips in your unlocked second-floor window and starts to ransack your house. Once inside, though, they don’t just take your stuff — they also throw open all your doors and windows so their accomplices can rush in and help pillage more efficiently.

The renin–angiotensin system (RAS) controls many aspects of the circulatory system, including the body’s levels of a chemical called bradykinin, which normally helps to regulate blood pressure. According to the team’s analysis, when the virus tweaks the RAS, it causes the body’s mechanisms for regulating bradykinin to go haywire. Bradykinin receptors are resensitized, and the body also stops effectively breaking down bradykinin. (ACE normally degrades bradykinin, but when the virus downregulates it, it can’t do this as effectively.)

The end result, the researchers say, is to release a bradykinin storm — a massive, runaway buildup of bradykinin in the body. According to the bradykinin hypothesis, it’s this storm that is ultimately responsible for many of Covid-19’s deadly effects. Jacobson’s team says in their paper that “the pathology of Covid-19 is likely the result of Bradykinin Storms rather than cytokine storms,” which had been previously identified in Covid-19 patients, but that “the two may be intricately linked.” Other papers had previously identified bradykinin storms as a possible cause of Covid-19’s pathologies.

As bradykinin builds up in the body, it dramatically increases vascular permeability. In short, it makes your blood vessels leaky. This aligns with recent clinical data, which increasingly views Covid-19 primarily as a vascular disease, rather than a respiratory one. But Covid-19 still has a massive effect on the lungs. As blood vessels start to leak due to a bradykinin storm, the researchers say, the lungs can fill with fluid. Immune cells also leak out into the lungs, Jacobson’s team found, causing inflammation.Coronavirus May Be a Blood Vessel Disease, Which Explains EverythingMany of the infection’s bizarre symptoms have one thing in commonelemental.medium.com

And Covid-19 has another especially insidious trick. Through another pathway, the team’s data shows, it increases production of hyaluronic acid (HLA) in the lungs. HLA is often used in soaps and lotions for its ability to absorb more than 1,000 times its weight in fluid. When it combines with fluid leaking into the lungs, the results are disastrous: It forms a hydrogel, which can fill the lungs in some patients. According to Jacobson, once this happens, “it’s like trying to breathe through Jell-O.”

This may explain why ventilators have proven less effective in treating advanced Covid-19 than doctors originally expected, based on experiences with other viruses. “It reaches a point where regardless of how much oxygen you pump in, it doesn’t matter, because the alveoli in the lungs are filled with this hydrogel,” Jacobson says. “The lungs become like a water balloon.” Patients can suffocate even while receiving full breathing support.

The bradykinin hypothesis also extends to many of Covid-19’s effects on the heart. About one in five hospitalized Covid-19 patients have damage to their hearts, even if they never had cardiac issues before. Some of this is likely due to the virus infecting the heart directly through its ACE2 receptors. But the RAS also controls aspects of cardiac contractions and blood pressure. According to the researchers, bradykinin storms could create arrhythmias and low blood pressure, which are often seen in Covid-19 patients.

The bradykinin hypothesis also accounts for Covid-19’s neurological effects, which are some of the most surprising and concerning elements of the disease. These symptoms (which include dizziness, seizures, delirium, and stroke) are present in as many as half of hospitalized Covid-19 patients.According to Jacobson and his team, MRI studies in France revealed that many Covid-19 patients have evidence of leaky blood vessels in their brains.

Bradykinin — especially at high doses — can also lead to a breakdown of the blood-brain barrier. Under normal circumstances, this barrier acts as a filter between your brain and the rest of your circulatory system. It lets in the nutrients and small molecules that the brain needs to function, while keeping out toxins and pathogens and keeping the brain’s internal environment tightly regulated.

If bradykinin storms cause the blood-brain barrier to break down, this could allow harmful cells and compounds into the brain, leading to inflammation, potential brain damage, and many of the neurological symptoms Covid-19 patients experience. Jacobson told me, “It is a reasonable hypothesis that many of the neurological symptoms in Covid-19 could be due to an excess of bradykinin. It has been reported that bradykinin would indeed be likely to increase the permeability of the blood-brain barrier. In addition, similar neurological symptoms have been observed in other diseases that result from an excess of bradykinin.”

Increased bradykinin levels could also account for other common Covid-19 symptoms. ACE inhibitors — a class of drugs used to treat high blood pressure — have a similar effect on the RAS system as Covid-19, increasing bradykinin levels. In fact, Jacobson and his team note in their paper that “the virus… acts pharmacologically as an ACE inhibitor” — almost directly mirroring the actions of these drugs.Medium Coronavirus BlogA real-time resource for Covid-19 news, advice, and commentary.coronavirus.medium.com

By acting like a natural ACE inhibitor, Covid-19 may be causing the same effects that hypertensive patients sometimes get when they take blood pressure–lowering drugs. ACE inhibitors are known to cause a dry cough and fatigue, two textbook symptoms of Covid-19. And they can potentially increase blood potassium levels, which has also been observed in Covid-19 patients. The similarities between ACE inhibitor side effects and Covid-19 symptoms strengthen the bradykinin hypothesis, the researchers say.

ACE inhibitors are also known to cause a loss of taste and smell. Jacobson stresses, though, that this symptom is more likely due to the virus “affecting the cells surrounding olfactory nerve cells” than the direct effects of bradykinin.

Though still an emerging theory, the bradykinin hypothesis explains several other of Covid-19’s seemingly bizarre symptoms. Jacobson and his team speculate that leaky vasculature caused by bradykinin storms could be responsible for “Covid toes,” a condition involving swollen, bruised toes that some Covid-19 patients experience. Bradykinin can also mess with the thyroid gland, which could produce the thyroid symptoms recently observed in some patients.

The bradykinin hypothesis could also explain some of the broader demographic patterns of the disease’s spread. The researchers note that some aspects of the RAS system are sex-linked, with proteins for several receptors (such as one called TMSB4X) located on the X chromosome. This means that “women… would have twice the levels of this protein than men,” a result borne out by the researchers’ data. In their paper, Jacobson’s team concludes that this “could explain the lower incidence of Covid-19 induced mortality in women.” A genetic quirk of the RAS could be giving women extra protection against the disease.

The bradykinin hypothesis provides a model that “contributes to a better understanding of Covid-19” and “adds novelty to the existing literature,” according to scientists Frank van de Veerdonk, Jos WM van der Meer, and Roger Little, who peer-reviewed the team’s paper. It predicts nearly all the disease’s symptoms, even ones (like bruises on the toes) that at first appear random, and further suggests new treatments for the disease.

As Jacobson and team point out, several drugs target aspects of the RAS and are already FDA approved to treat other conditions. They could arguably be applied to treating Covid-19 as well. Several, like danazol, stanozolol, and ecallantide, reduce bradykinin production and could potentially stop a deadly bradykinin storm. Others, like icatibant, reduce bradykinin signaling and could blunt its effects once it’s already in the body.

Interestingly, Jacobson’s team also suggests vitamin D as a potentially useful Covid-19 drug. The vitamin is involved in the RAS system and could prove helpful by reducing levels of another compound, known as REN. Again, this could stop potentially deadly bradykinin storms from forming. The researchers note that vitamin D has already been shown to help those with Covid-19. The vitamin is readily available over the counter, and around 20% of the population is deficient. If indeed the vitamin proves effective at reducing the severity of bradykinin storms, it could be an easy, relatively safe way to reduce the severity of the virus.

Other compounds could treat symptoms associated with bradykinin storms. Hymecromone, for example, could reduce hyaluronic acid levels, potentially stopping deadly hydrogels from forming in the lungs. And timbetasin could mimic the mechanism that the researchers believe protects women from more severe Covid-19 infections. All of these potential treatments are speculative, of course, and would need to be studied in a rigorous, controlled environment before their effectiveness could be determined and they could be used more broadly.

Covid-19 stands out for both the scale of its global impact and the apparent randomness of its many symptomsPhysicians have struggled to understand the disease and come up with a unified theory for how it works. Though as of yet unproven, the bradykinin hypothesis provides such a theory. And like all good hypotheses, it also provides specific, testable predictions — in this case, actual drugs that could provide relief to real patients.

The researchers are quick to point out that “the testing of any of these pharmaceutical interventions should be done in well-designed clinical trials.” As to the next step in the process, Jacobson is clear: “We have to get this message out.” His team’s finding won’t cure Covid-19. But if the treatments it points to pan out in the clinic, interventions guided by the bradykinin hypothesis could greatly reduce patients’ suffering — and potentially save lives.

3d rendering of multiple coronavirus.
Photo: zhangshuang/Getty Images

Thomas Smith

https://elemental.medium.com/a-supercomputer-analyzed-covid-19-and-an-interesting-new-theory-has-emerged-31cb8eba9d63

Life in the Time of Coronavirus

…And how to stay sane!!!

MENTAL HEALTH WELLNESS TIPS FOR QUARANTINE

1. Stick to a routine. Go to sleep and wake up at a reasonable time, write a schedule that is varied and includes time for work as well as self-care.

2. Dress for the social life you want, not the social life you have. Get showered and dressed in comfortable clothes, wash your face, brush your teeth. Take the time to do a bath or a facial. Put on some bright colors. It is amazing how our dress can impact our mood.

3. Get out at least once a day, for at least thirty minutes. If you are concerned of contact, try first thing in the morning, or later in the evening, and try less traveled streets and avenues. If you are high risk or living with those who are high risk, open the windows and blast the fan. It is amazing how much fresh air can do for spirits.

4. Find some time to move each day, again daily for at least thirty minutes. If you don’t feel comfortable going outside, there are many YouTube videos that offer free movement classes, and if all else fails, turn on the music and have a dance party!

5. Reach out to others, you guessed it, at least once daily for thirty minutes. Try to do FaceTime, Skype, phone calls, texting—connect with other people to seek and provide support. Don’t forget to do this for your children as well. Set up virtual playdates with friends daily via FaceTime, Facebook Messenger Kids, Zoom, etc—your kids miss their friends, too!

6. Stay hydrated and eat well. This one may seem obvious, but stress and eating often don’t mix well, and we find ourselves over-indulging, forgetting to eat, and avoiding food. Drink plenty of water, eat some good and nutritious foods, and challenge yourself to learn how to cook something new!

7. Develop a self-care toolkit. This can look different for everyone. A lot of successful self-care strategies involve a sensory component (seven senses: touch, taste, sight, hearing, smell, vestibular (movement) and proprioceptive (comforting pressure). An idea for each: a soft blanket or stuffed animal, a hot chocolate, photos of vacations, comforting music, lavender or eucalyptus oil, a small swing or rocking chair, a weighted blanket. A journal, an inspirational book, or a mandala coloring book is wonderful, bubbles to blow or blowing watercolor on paper through a straw are visually appealing as well as work on controlled breath. Mint gum, Listerine strips, ginger ale, frozen Starburst, ice packs, and cold are also good for anxiety regulation. For children, it is great to help them create a self-regulation comfort box (often a shoe-box or bin they can decorate) that they can use on the ready for first-aid when overwhelmed.

8. Spend extra time playing with children. Children will rarely communicate how they are feeling, but will often make a bid for attention and communication through play. Don’t be surprised to see therapeutic themes of illness, doctor visits, and isolation play through. Understand that play is cathartic and helpful for children—it is how they process their world and problem solve, and there’s a lot they are seeing and experiencing in the now.

9. Give everyone the benefit of the doubt, and a wide berth. A lot of cooped up time can bring out the worst in everyone. Each person will have moments when they will not be at their best. It is important to move with grace through blowups, to not show up to every argument you are invited to, and to not hold grudges and continue disagreements. Everyone is doing the best they can to make it through this.

10. Everyone find their own retreat space. Space is at a premium, particularly with city living. It is important that people think through their own separate space for work and for relaxation. For children, help them identify a place where they can go to retreat when stressed. You can make this place cozy by using blankets, pillows, cushions, scarves, beanbags, tents, and “forts”. It is good to know that even when we are on top of each other, we have our own special place to go to be alone.

11. Expect behavioral issues in children, and respond gently. We are all struggling with disruption in routine, none more than children, who rely on routines constructed by others to make them feel safe and to know what comes next. Expect increased anxiety, worries and fears, nightmares, difficulty separating or sleeping, testing limits, and meltdowns. Do not introduce major behavioral plans or consequences at this time—hold stable and focus on emotional connection.

12. Focus on safety and attachment. We are going to be living for a bit with the unprecedented demand of meeting all work deadlines, homeschooling children, running a sterile household, and making a whole lot of entertainment in confinement. We can get wrapped up in meeting expectations in all domains, but we must remember that these are scary and unpredictable times for children. Focus on strengthening the connection through time spent following their lead, through physical touch, through play, through therapeutic books, and via verbal reassurances that you will be there for them in this time.

13. Lower expectations and practice radical self-acceptance. This idea is connected with #12. We are doing too many things in this moment, under fear and stress. This does not make a formula for excellence. Instead, give yourself what psychologists call “radical self acceptance”: accepting everything about yourself, your current situation, and your life without question, blame, or pushback. You cannot fail at this—there is no roadmap, no precedent for this, and we are all truly doing the best we can in an impossible situation.

14. Limit social media and COVID conversation, especially around children. One can find tons of information on COVID-19 to consume, and it changes minute to minute. The information is often sensationalized, negatively skewed, and alarmist. Find a few trusted sources that you can check in with consistently, limit it to a few times a day, and set a time limit for yourself on how much you consume (again 30 minutes tops, 2-3 times daily). Keep news and alarming conversations out of earshot from children—they see and hear everything, and can become very frightened by what they hear.

15. Notice the good in the world, the helpers. There is a lot of scary, negative, and overwhelming information to take in regarding this pandemic. There are also a ton of stories of people sacrificing, donating, and supporting one another in miraculous ways. It is important to counter-balance the heavy information with the hopeful information.

16. Help others. Find ways, big and small, to give back to others. Support restaurants, offer to grocery shop, check in with elderly neighbors, write psychological wellness tips for others—helping others gives us a sense of agency when things seem out of control.

17. Find something you can control, and control the heck out of it. In moments of big uncertainty and overwhelm, control your little corner of the world. Organize your bookshelf, purge your closet, put together that furniture, group your toys. It helps to anchor and ground us when the bigger things are chaotic.

18. Find a long-term project to dive into. Now is the time to learn how to play the keyboard, put together a huge jigsaw puzzle, start a 15 hour game of Risk, paint a picture, read the Harry Potter series, binge watch an 8-season show, crochet a blanket, solve a Rubix cube, or develop a new town in Animal Crossing. Find something that will keep you busy, distracted, and engaged to take breaks from what is going on in the outside world.

19. Engage in repetitive movements and left-right movements. Research has shown that repetitive movement (knitting, coloring, painting, clay sculpting, jump roping etc) especially left-right movement (running, drumming, skating, hopping) can be effective at self-soothing and maintaining self-regulation in moments of distress.

20. Find an expressive art and go for it. Our emotional brain is very receptive to the creative arts, and it is a direct portal for release of feeling. Find something that is creative (sculpting, drawing, dancing, music, singing, playing) and give it your all. See how relieved you can feel. It is a very effective way of helping kids to emote and communicate as well!

21. Find lightness and humor in each day. There is a lot to be worried about, and with good reason. Counterbalance this heaviness with something funny each day: cat videos on YouTube, a stand-up show on Netflix, a funny movie—we all need a little comedic relief in our day, every day.

22. Reach out for help—your team is there for you. If you have a therapist or psychiatrist, they are available to you, even at a distance. Keep up your medications and your therapy sessions the best you can. If you are having difficulty coping, seek out help for the first time. There are mental health people on the ready to help you through this crisis. Your children’s teachers and related service providers will do anything within their power to help, especially for those parents tasked with the difficult task of being a whole treatment team to their child with special challenges. Seek support groups of fellow home-schoolers, parents, and neighbors to feel connected. There is help and support out there, any time of the day—although we are physically distant, we can always connect virtually.

23. “Chunk” your quarantine, take it moment by moment. We have no road map for this. We don’t know what this will look like in 1 day, 1 week, or 1 month from now. Often, when I work with patients who have anxiety around overwhelming issues, I suggest that they engage in a strategy called “chunking”—focusing on whatever bite-sized piece of a challenge that feels manageable. Whether that be 5 minutes, a day, or a week at a time—find what feels doable for you, and set a time stamp for how far ahead in the future you will let yourself worry. Take each chunk one at a time, and move through stress in pieces.

24. Remind yourself daily that this is temporary. It seems in the midst of this quarantine that it will never end. It is terrifying to think of the road stretching ahead of us. Please take time to remind yourself that although this is very scary and difficult, and will go on for an undetermined amount of time, it is a season of life and it will pass. We will return to feeing free, safe, busy, and connected in the days ahead.

25. Find the lesson. This whole crisis can seem sad, senseless, and at times, avoidable. When psychologists work with trauma, a key feature to helping someone work through said trauma is to help them find their agency, the potential positive outcomes they can effect, the meaning and construction that can come out of destruction. What can each of us learn here, in big and small ways, from this crisis? What needs to change in ourselves, our homes, our communities, our nation, and our world?

  This is shared from a community site thanks to Eileen Feliciano, PsyD.

Massage eases low back pain in randomized controlled trial

http://www.sciencedaily.com/releases/2011/07/110704174603.htm

Summary:
Massage therapy helps ease chronic back pain and improve function, according to results of a randomized controlled trial. The first study to compare structural and relaxation (Swedish) massage, the trial found that both types of massage worked well, with few side effects. Massage helped people with back pain to function even after six months. They were more able to work, take care of themselves, and be active.

Massage therapy helps ease chronic low back pain and improve function, according to a randomized controlled trial that the Annals of Internal Medicine will publish in its July 5 issue. The first study to compare structural and relaxation (Swedish) massage, the trial found that both types of massage worked well, with few side effects.

“We found that massage helps people with back pain to function even after six months,” said trial leader Daniel C. Cherkin, PhD, a senior investigator at Group Health Research Institute. Better function means they are more able to work, take care of themselves, and be active.

“This is important because chronic back pain is among the most common reasons people see doctors and alternative practitioners, including massage therapists,” Dr. Cherkin added. “It’s also a common cause of disability, absenteeism, and ‘presenteeism,’ when people are at work but can’t perform well.”

The trial enrolled 400 Group Health Cooperative patients who had had low back pain for at least three months. Their pain was “nonspecific,” meaning with no identified cause. They were randomly assigned to one of three treatments: structural massage, relaxation massage, or usual care. Usual care was what they would have received anyway, most often medications. The hour-long massage treatments were given weekly for 10 weeks.

At 10 weeks, more than one in three patients who received either type of massage — but only one in 25 patients who got usual care — said their back pain was much better or gone. Also at 10 weeks, a questionnaire showed nearly twice as many massage patients (around two thirds) as usual-care patients (more than one third) were functioning significantly better than at the trial’s outset. Patients in the massage groups spent fewer days in bed, were more active, and used less anti-inflammatory medication than did those with usual care.

“As expected with most treatments, the benefits of massage declined over time,” Dr. Cherkin said. “But at six months after the trial started, both types of massage were still associated with improved function.” After one year, the benefits of massage were no longer significant.

The bottom line: “We found the benefits of massage are about as strong as those reported for other effective treatments: medications, acupuncture, exercise, and yoga,” Dr. Cherkin said. “And massage is at least as safe as other treatment options. So people who have persistent back pain may want to consider massage as an option.”

Prior studies of massage for back pain had tested only structural forms of massage, not relaxation massage. But relaxation (also called Swedish) massage is the most widely available and is taught in massage schools. It aims to promote a feeling of relaxation throughout the body. By contrast, structural massage involves identifying and focusing on specific pain-related “soft tissues” (like muscles and ligaments). It requires extra training and may be more expensive — but more likely to be covered by health insurance plans — than relaxation massage.

“The massage therapists assumed structural massage would prove more effective than relaxation massage,” said Dr. Cherkin’s colleague Karen J. Sherman, PhD, MPH, a senior investigator at Group Health Research Institute. “They were surprised when patients in the relaxation group got so much relief from their back pain.”

Next steps include figuring out whether the structural and relaxation massages were equally effective for the same — or for different — reasons:

  • Structural or relaxation massage, or both, might have specific effects, such as stimulating tissue or calming the central nervous system.
  • Either or both might work through “nonspecific effects” that may promote a person’s ability to play an active role in their own healing. Possible nonspecific effects include: being touched; spending time in a relaxing environment; receiving care from a therapist who seems caring; getting advice on caring for yourself, such as exercises to do on your own; or becoming more aware of your own body, so you’re better able to avoid triggers for your back pain.
  • Some combination of specific and nonspecific effects might be at play.

Drs. Cherkin and Sherman’s co-authors are Assistant Investigator Andrea J. Cook, PhD, of Group Health Research Institute and the University of Washington; Biostatisticians Robert Wellman, MS, and Eric A. Johnson, MS, Project Manager Janet Erro, RN, MN, and Analyst/Programmer Kristin Delaney, MPH, of Group Health Research Institute; Janet Kahn, PhD, of the University of Vermont School of Medicine in Burlington; and Richard A. Deyo, MD, MPH, of Oregon Health and Science University in Portland, OR.

The National Center for Complementary and Alternative Medicine (NCCAM), part of the National Institutes of Health, funded this study.