Lecture 45

Graham.com, welcome to another Med cram covid-19 updates now for the first time the US tops the charts at 80 5653 infections that are confirmed staggering 24,000 total deaths daily new cases in the United States are continuing to rise and if we look at total cases in the United States the state of New York tops that list by a large amount.

It is the epicenter of the new cases at this point and because of that supplies are running scarce. There’s an article here in the New York Times talking about the scarcity of mechanical ventilators New York starts sharing ventilators. And this was approved by the governor to keep coronavirus patient’s breathing hospitals Pioneer a little tested method. You can see there a portable ventilator that ambulances used to transport patients who are on ventilators. They

Here that this is not the first time that this has happened before they did this in Las Vegas when there was a mass shooting in previous updates here on make creme. We showed you dr. Babcock the ER physician demonstrating that in a video on YouTube also in the news and updated about six hours ago was a story on Fox by Prisma Health that says that their new Innovative ventilator

After can actually treat up to four patients on a ventilator at a time. It was another ER physician named Sarah Ferris and her husband who is a software engineer developed this device called Vesper as it turns out this is a 3D printed device and they are making it available so that it can be printed in your local hospital. In addition to this the US Food and Drug Administration has granted emergency use authorization.

This type of ventilator and down here. You can see a link other hospitals that want to begin using Vsepr can receive the free source code and printing specifications for the device today by registering on prism has Health Website and you can see it there. Okay, so not so fast because there is a joint statement that was put out by the American Association for Respiratory Care in conjunction with a number of other societies, which are pretty heavy hitting like the society for Critical Care Medicine.

Issued a joint statement basically saying no, we don’t think that this is a good idea the reasons they include here are quite numerous including the fact that volumes could go to the most compliant lung segments that it would be impossible to manage the positive end expiratory pressure among other things and you can read some of the others and they give references as well in this joint statement.

So it’s going to be interesting to see what happens because as the New York Times pointed out the other option is death the aarc however is saying that it could jeopardize both patients on the ventilator. I think regardless of which way you take it. It’ll be clear that they’ll be people taking care of people on ventilators that aren’t used to taking care of people on ventilators.

If you or if you know somebody that’s going to be taking care of somebody on the ventilator. We wanted to offer this course as a refresher on mechanical ventilation.

Okay, I wanted to continue our discussion with improving immunity. We talked before about the beneficial effects of an elevated body temperature with respect to killing infections in the virus and we are going to move on to other things, but I wanted to restate Andre underline the importance of rest and sleep in terms of the activation of the immune system, especially at a time like now where people are very concerned.

Concerned they may not be getting enough sleep. It’s important for us to not underestimate the benefits of sleep. Now. We’re just going to review a little bit. But if you want to know more in detail go back to update 17 on the coronavirus that we’ve done but real briefly. This was a study that looked at the effects of sleep deprivation on response to immunization.

the participants were sleep deprived and given a vaccine to the influenza virus and those that were not sleep deprived had a much better immune response in terms of antibodies to the vaccine and the conclusions that the authors Drew were these results indicate that the response to the influenza vaccination is likely to be impaired in individuals who suffer from chronic partial sleep restriction because adults who show poor responses to vaccines and

Other antigenic challenges also experience higher rates of clinical illness our findings support the concept that adequate amounts of sleep are needed to maintain resistance to an infectious challenge such as covid-19.

This is the other study that we looked at in update 17 and it looked at the Sleep habits how long they slept and what was the efficiency of their sleep in terms of 14-day Baseline and then they went ahead and dropped rhinovirus filled drops into the nasopharynx of these subjects and they waited to see how many of them would develop the common cold symptoms and what they found was quite astounding they found that those

With an average sleep duration of less than seven hours. We’re not 10% more or 50% more or even a hundred percent more likely to develop the cold but actually almost three times more likely to develop a cold and when they look for confounders these things could not be explained in terms of differences in pre-challenge virus specific antibody demographics season of the are body mass socioeconomic status.

Psychological variables or health practices and so here we have at least four rhinovirus evidence that poor sleep efficiency and shorter sleep duration in the weeks preceding and exposure were associated with a lower resistant to the viral illness.

But there’s even more research that just came out last year and this is the focus of sleep that I want to look at today.

So the first thing you have to understand is that there is a cell which is infected with a virus. And in this case. It was a CMV infected cell.

CMV stands for cytomegalovirus. It’s a common virus that can cause a chronic infection here. We have the nucleus and because this cell is infected with cytomegalovirus. It makes its normal proteins on the cell surface so that the cells of the immune system would recognize it but it also puts a little portion of that cytomegalovirus protein out on the surface to let the immune cells know that

A infected cell and so these regular proteins that are made in the cell are known as an MHC 1 that’s not that important to understand but that’s the name of the protein. This here is a portion of the virus that lets the immune system know that it is in fact an infected cell. There are other proteins that are also on the cell and these proteins help immune cells dock with them so that they can make the appropriate.

Opiate determination of whether or not this cell should be destroyed or should survive and this protein is known as I cam. I see a am

So far so good. Now let’s bring in our immune cell. It’s our cytotoxic T-cell. It’s responsible for going around and making sure that cells are not infected and taking care of cells that are infected and this would be the cells that would be going around and getting rid of coronavirus infected cells. So they don’t produce more virus to infect more cells. And in fact, if this can be done early in the course, you would have a limited disease and it wouldn’t lead to many many cells being infected.

In many T cells to have to try to fight and causing that cytokine storm. Well, there’s a couple of proteins on these T cells. So this is a T-cell and it’s a cytotoxic T-cell not toxic to you but cytotoxic to the cell that’s infected. These are actually your friends. So there is a receptor on the T cell that sees that little particle of the virus and understands that this cell needs to be destroyed and that is called the

T Cell receptor or the TCR the TCR also activates right next to it and I’ll show this here in green that it’s activating the beta integral in this interaction between beta integrins and the I cams allow for a very strong docking that allows these cells to bind very very strongly to these infected cells and that allows these T cells to secrete cytokines that

Shut down and kill the cell before it produces more viruses. So it’s very important that the beta integrins and the I cams are able to bind together. Normally the beta integrins are not activated and they will not bind these I cams otherwise your immune system would start to destroy your own body. So they’re shut down but there are certain situations where they need to be turned on and if they are not turned on your immune system is not going to work very well.

Well, in this case it is the TCR which activates these beta integrins and allows this to occur. The purpose of this article was to see whether or not things can affect this turning on of the beta integrins and sure enough. They discovered that there is a receptor called the G alpha s receptor and this receptor is coupled to what is known as a g-protein.

And it’s coupled to an enzyme known as adenylate cyclase. There’s a lot of moving parts to this receptor, but I’m going to simplify it and show you that essentially it takes ATP which is abundant in the cell and it converts it into something called cyclic A and P and as it turns out cyclic A and P shuts down the ability of the TCR to activate the beta integrase. So the

In is what is actually stimulating this G alpha s receptor. There’s a number of things that can activate this. One of them is epinephrine typically dopamine histamine serotonin. And the thing about all of these things that can actually stimulate this receptor here. They’re all quite elevated when you are awake and so you can see it’s possible that epinephrine dopamine histamine serotonin could stimulate this receptor.

Which would eventually convert ATP into cyclic A and P which would then inhibit TCR is ability to have the beta integral in buying with I cam and to have this T-cell destroy with cytokines this infected cell. So is it possible that sleep could stop epinephrine dopamine histamine and serotonin from binding this receptor and allow the beta integral and the I cam to bind tightly so that the immune response would be more robust.

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And so now the title becomes a little bit more understandable gaas coupled receptor signaling and sleep regulate integrand activation of human antigen specific T-cells, and this was published last year in the Journal of experimental medicine.

They infected these with the Epstein-Barr virus as well. And so we’ve got data for both of those.

So here we can see the data for CMV specific cd8 cytotoxic T cells they looked at isoproterenol which does hit that receptor epinephrine, which does hit the receptor and norepinephrine as well and here on the x axis as we increase the concentration. You can see that that effect is that The Binding of icam one as a percentage of the control starts to drop off precipitously and you can see that here with prostaglandins as well.

Adenosine in the EBV or the Epstein-Barr virus cell cultures that were infected as the increased concentration of the same substances that we talked about. You can see that the icons Dew Drop. So it’s one thing to say that these specific substances make it drop but the question is whether or not sleep is actually beneficial in making sure that the cells can bind to their targets and take them out and that’s what they attempted to show here in human patients.

What we see here again is the same thing on the y-axis we’re looking at I can binding but we have two types of patients in this scenario. We have the ones that are filled in with black circles. And these were the ones that were sleeping at night and awake during the day as opposed to these Open Circles which are white in the middle where they’re awake during the night and also awake during the day and so you can see the effects here in the CMV infected cells on the left and the EBV infected cells on the right.

In the night time which is shaded here and over here as well at least at two o’clock in the morning and here at six o’clock in the morning. There was a statistically significant increase in icam binding in these patients that were sleeping at two o’clock in the morning as opposed to being awake at 2 o’clock in the morning, and I just wanted to point out for those of you who are doing shift work that so long as you are working at night and going home and sleeping with your

Your lights off and no light coming in through the windows. And you do this every single day throughout the weekend. You can also get the same benefit from getting sleep. Even though it’s when the Sun is up and then they decided to look at that over the different types of differentiation of these cytotoxic T cells. They looked at ones that were early in their life intermediate in the cell life and late in the cell life and what they found was this effects seem to be the strongest in the early phase.

Of the cell’s life despite the fact that it didn’t have a lot of these G receptors that we talked about that might suggest that it’s the early cells that are being Amplified against the infection at hand that is more influenced by the effect of sleep versus Wake.

So the conclusions of the authors are this we show here that several G alpha s coupled receptor ligands potentially inhibit TCR mediated integrand activation on antigen-specific cd8 T-cells. These are the ones that are doing The Killing here, whereas sleep up regulates integration activation by suppressing G alpha s coupled receptor signaling given the importance of integrand activation for the formation of immunological synapses are

Suggest a critical role of conditions like sleep that are characterized by low level G alpha s coupled receptor ligands in boosting the T-cell responses and I’ll tell you it’s those T Cell responses that are very important in your immune system getting rid of coronavirus infected cells.

So you can imagine the current scenario and it doesn’t take a lot of drawing on here to modify this picture for the current covid-19 situation sleep is important and you don’t have to go to the store to buy it and you don’t have to wait for pharmacists to dispense it. It’s something that we can do put down your iPad’s put down your phones and go to sleep and wake up with a better immune system.

For those of you who have difficulty sleeping if you have insomnia, we have a free course on how to deal with. Insomnia. Thanks for joining us.

 

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