Exercise science and cardiac rehab from the Dr. University of Lithuania. He has been a visitor in the U.S. Army of Affairs for the last 15 years, where he worked in the biological research of the U.S. Army of Research of Physiology at the University of Iowa for David Carter at the Department of Physiology at the Medical College of Wisconsin. Dr. Erick has remained at MCW and is currently an assistant professor in the Department of Pediatrics Division of Critical Care. His research focuses on regulation of cerebral workflow and how the loss of important regularly mechanism results in greater mortality and morbidity following a stroke and traumatic brain injury. Today, he's going to talk about vascular cup. He has to go on with the talk, so sorry, we are short on the time. And I mean, I understand if we don't have this talk on the record, but you know, the students have to go after this and everybody's on a schedule. So I guess we kind of skip this one in terms of being online. Okay, sounds good. So today, Kevin is going to talk about vascular complications leading to end organ damage, role of oxidative stress, and elevated glucose. Kevin, please. Very diverse crowd today. I was told to kind of keep it somewhat educational. So this idea of the barrel reflects within your carotid arteries and even the aorta, you have these sensors, the barrel receptors that respond to stretch, they'll sense changes in blood pressure and they'll act accordingly then to send signals up to your brain, then back to your heart and blood vessels to kind of compensate and then change the pressure, hopefully bringing it back to normal. So when you have a rise in your blood pressure, you'll see a drop in your heart rate and ultimately this brings your blood pressure back and your system is very efficient at doing this. So like if you stand up, normally you'll see that your heart rate rises. It's because your blood pressure drops a little bit. So in a healthy situation, this barrel reflects, helps to maintain your blood pressure nice and stable throughout the day. You don't really see a lot of variability in it. There are several disease conditions, even just aging itself along with different cardiovascular diseases or diabetes, kidney disease. These different conditions could affect this function in this system, so it will impair its response. And if you impair your barrel reflex, it leads to more increases in variability in your blood pressure and those fluctuations in blood pressure then have big complications to damage your blood vessels and other organs. So there are some old studies that looked at what happens when you increase this variability in blood pressure. This graph on the right shows in the white bars in all the conditions is just kind of a controlled animal that has increased blood pressure variability, hypertension, high blood pressure. This is a total damage. This relates to your heart and this one over here is just your kidney or your renal system. What this study was looking at was the gray bar in the middle and then the black bar on the end were two different treatment groups. The one in the middle, they gave a drug that would decrease the blood pressure and this variability and they saw that reduced damage. The other bar, the black bar here on the end, they gave a drug that did decrease the hypertension. So these animals were no longer, they no longer had high blood pressure, but this drug was unable to decrease that variability. So they still had these large fluctuations in their blood pressure. So even being normal-attensive, still having these large fluctuations, they still see this damage occurring. So along with these fluctuations, there's some evidence to suggest that it's really this force going through the vessels, depending on if it's a constant force, the continuous, say, flow or continuous force on the vessels, you don't see much of a change. What happens when you have more of this fluctuating change, if you can induce large increases or decreases in these forces, like the blood pressure going through the vessels, you see this slow rise in these oxidative stress markers. So these oxidative stress indicators, things that you take like vitamin C or vitamin E, all these antioxidants, these are things that would inhibit some of these dangerous markers and prevent some of the increase and then resulting changes in your blood vessels or your other organs. So there's some nice evidence to suggest that variability in flow or pressure leads to this sort of pro-oxidative damaging environment. It's kind of a busy slide, but I wanted to show, this was kind of a cool experiment that we had done to induce variability. So we took some rats and we were able to pace their heart. So we would pace the heart rate at different frequencies and by changing the heart rate, we could change the blood pressure. So if we increase heart rate, you see a decrease in blood pressure. So what we were trying to do was find that actual frequency of the blood pressure variability that would lead to more damage. This works really well acutely. We could do this by pacing the animal and get any sort of blood pressure change that we want. The problem was doing it chronically in these animals. We were having trouble pacing their hearts for long periods of time. Long enough, that would actually allow us to cause some of the heart and organ damage. So there's another model then that we started to use instead of the pacing. We would actually go in and go into that carotid artery around the carotid sinus and we would denervate the barrel reflex. We would take the nerves and do a surgical procedure to just kind of remove all those nerve connections. So when you remove the nerve connections, it can no longer sense the changes in blood pressure. So when you do that, you go from the control condition, nice stable pressure to this very variable pressure because you no longer have that barrel reflex feedback. So this is the model that I'll use and describe for some of the results then. So when you induce this, what is that going to do to your vessels or your heart function? So this is just some other data showing that and so the SAD, this is the denervated rat group. When you do that denervation, you see this increase in these, this is a marker of oxidative stress, this MDA. These ones down here, these are beneficial type of markers. Enos produces a nitric oxide which vasodilates and protects your arteries. DDH2 is another sort of vasodilating sort of enzyme. So when you see decreases in these sort of markers, that's a negative type of effect. So the general idea that we're going with for this study, when you increase the blood pressure variability, you see this change in these mechanical stresses on the vessels. Goes through this cascade, leading to this increase in ROS. That's a reactive oxygen species or the increase in this oxidative stress environment. When you have that increase, you get these downstream dysfunctional vessels, heart and some structural changes that you see, hypertrophy, all these things that could lead to say heart failure. So what we wanted to do was create this model and then see if we could treat it by blocking the oxidative stress with a drug called Tempol. It's kind of an antioxidant. It'll go and it'll get rid of some of these negative oxidative stress markers. So there's been a fair amount of research that looked at this sort of model. A lot of it focused on much larger arteries like ureorta, some of the conduit arteries. So we were interested in looking at some smaller resistance arteries where a lot of the actual function and reactivity is occurring. So these smaller resistance type arteries are ones that really have more control over the flow and the circulation going to your organs. And then the other thing just to see if our treatment to prevent oxidative stress could change and help this condition. So these were the two protocols that we're going to go through. We're going to use some different animal models and different imaging techniques to look at endothelial function within some of these small resistance vessels and then use our drug to treat and see if we could prevent some of the vessel or heart changes. So this was a long protocol. We started out before any of the surgery. We would get some in vivo measures that I'll describe in a couple of slides. Doing some echo data for looking at the aorta. Then we go in and do our protocol to... We would insert some telemeters to measure blood pressure as well as do our denervation to induce the increase in barrel reflex impairment. And then we'd follow these animals over a six-week period and then do some final endpoint measures of heart function. So this is one of our recordings. The top one is the control group. This is just a blood pressure recording. The bottom one is what happens when you denervate the barrel reflex. Hope you could appreciate that. This nice sort of stable blood pressure, it goes away. So this is over an hour recording. You'll see points where you have pretty large drops in blood pressure as well as some spikes in blood pressure. So these animals, it's kind of interesting. So over a 24-hour period, they're still considered normal-tensive. The mean blood pressure still... It's not elevated at all. You have these periods where they kind of look like a normal animal. But then there's other periods just throughout the day where they become potentially ischemic. They have large drop in blood flow. They could have then low perfusion to different organs. So this is some data showing that... Yes, even though we have these large fluctuations, over time they really are normal-tensive. You don't have any sustained periods where they're hypertensive or hypotensive. There's a little bit of an increase at the very first week, but that goes away. That's probably just some of the stress from the surgical procedure. So over the first two, three days, it's a little bit elevated. Then by the end of the week, it comes back. So it's not significantly different between the groups. So this graph shows the... Here's the barrel reflex sensitivity. So this measures how much your blood pressure might change and then how the heart rate changes if it's according or not. So this would just demonstrate that, along with the variability we saw in the blood pressure, this demonstrates that the barrel reflex sensitivity, a lower number would mean less sensitive. So it's not functioning as well. So our denervation surgery worked pretty good and it stayed consistently down, decreased during the whole six-week period. So this one is a measure of the variability in the blood pressure. It's actually quantifying one of the first graphs that we saw. So we can look at the variance within the systolic blood pressure. And you can see that it's quantifies clearly significantly different. And over the course of the experiment, it did come down but it still stayed. This is from about 30, still about 60. So it's still about two-fold higher or more throughout the entire experiment. So this is one of the fun experiments we did. This was a non-invasive way to look at vascular function that we were developing in the lab. We would take some rats and while they were conscious, we're basically just using a camera, something similar that an eye doctor would use and we would be taking pictures of their eyes. By doing this, we could actually start to look at some of the arteries within the eye. So this is an artery within the iris muscle. You can see a zoomed in picture here. We can look at the lumen or the wall of the artery as well as apply different eye drops to cause these vessels to dilate or constrict. So we were able to look at their endothelial cell function or their smooth muscle cell function. I was usually the guy working the camera. I would make the students hold the rats because they were conscious. So it's nice to do experiments if you can in a conscious animal as opposed to an anesthetized animal. So some of the data I have later is in anesthetized animals and we could see that some of those effects are, they just kind of mess up your experiment. So anytime you could do anything in a conscious animal or less invasive, it's a lot better of an experiment. So let's show some data that using that technique, these are in hypertensive rats now. So we gave a drug here that would work on the endothelial cells to cause a vasodilation. So you could see a nice rise in the white bars that control normal tensive group. You see a smaller rise in their hypertensive type of rat. And then this other drug would cause a constriction blocking that endothelial cell function. So we're able to use this in vivo technique to show that hypertension. This is about 10 points of measurement from 1 to 10, right? Why are you imagining it's not in one position? To get an average, if you... So what we tried to do is... I'll show a picture, see? This one here, this is because of the structure of the vessels, we can come back week after week and get to the exact same spot. The one thing you do have to watch is because of different vasomotion characteristics, you might have some constriction here and a little bit of dilation down here. So we would always do our before and after drug kind of in the same spot just to try and control for some of those changes. And then it was, yeah, 10 points kind of an average just because you do have spots where it's more or less constricted. So, yeah, trying to be as... trying not to persuade the data to go one way, I guess, trying to get a more overall picture. What is the distance between these points? So there, you know, that's kind of just... I would probably actually take over that whole area for most of the experiments. This was a diagram, I think we put it in that manuscript just to show where we would place the dots around the wall. So we're able to measure the wall thickness as well as the lumen diameter. And you could basically... the program will let you put them anywhere you want. This picture shows 10. We could do more. Sounds. So, yeah, this was... we would go through, do our baseline imaging before any drugs, give this pylocarpene which acted on the endothelial cells cause a nice endothelial cell regulated sort of dilation. The L name, this is a drug that blocks nitric oxide and blocks the effect of endothelial cells. And then there's another drug that we gave. It's a nitric oxide donor. So it just causes a dilation without the endothelial cells even needing to do anything. So it works directly on the other cells in the vessel, the smooth muscle cells. So a lot of times you'll see in diabetes or other diseases that you lose the endothelial cell function, but the smooth muscle cells can still dilate on their own. So most of the experiments you always have to do is kind of these two different measures to look if it's endothelial or smooth muscle cell related. So we're saying we can measure the wall thickness using this technique. So we didn't see any changes in wall thickness or lumen diameter. So suggesting there really wasn't any hypertrophy or structural changes within the eye vessel. We did start to see some, as opposed to the structural changes, we did see some functional changes. So in the SAD group, the group that lost the barrel reflex and had the increase in variability, over the course of the six-week experiment, we saw this loss in this endothelial dependent dilation. So we put the pile of carpene on. The vessel would not respond anymore. So that was a vessel in the eye. We also wanted to move a little bit more towards the brain. So we started to, so since we couldn't image any vessels in the brain, we would wait till the end of that six-week period and then take vessels.  So we were using the middle cerebral artery, which is coming off of the circle of Willis right here. The vessel from the eye would actually be a branch of this ophthalmic artery. So they were actually pretty closely related as far as their structure or size of vessels. So similar type of vessel between the iris vessel and the MCA. And so this would be taking a vessel off of the brain and doing kind of an ex vivo experiment in a little vessel bath in a chamber in our lab. So we would do a similar thing. This is the change in diameter in response to another type of drug that would also act on the endothelial cells. And we see that similar impairment in dilation following the denervation. Okay, but is lumen diameter the only quantitative margin that is important? How long for the density of the vessels? So why only the diameter? That's the most important in terms of... As far as a functional measure, the structural remodeling normally goes to more towards like a hypertrophy or change in that lumen, let the wall to lumen ratio. So thicker wall, smaller lumen of the vessel, maybe less blood being able to flow through. And what is important about six weeks? The six weeks was... It's a lot of work to keep them alive. Well, they were very healthy throughout the whole thing, but to do all these measurements every week. It was based on some of the older literature as well showing structural changes that occur by the fourth week. So a lot of the previous literature would look two, four, six, ten. Probably no one did much more than ten weeks. So we kind of went right in the middle looking for where we assumed there should be structural changes already, but we weren't sure about the functional changes if they would be present or not. And so the SAD group is a denervated group. The blue line shows the temple treatment here. So as we saw before, the temple treatment, it didn't affect the barrel reflex sensitivity. That was still depressed. The variability was still present as well. So these brass that were treated with the temple to remove the oxidative stress, they still had that insult of the variability and the loss of barrel reflex sensitivity. But by giving this oxidant, the antioxidant, we were able to restore this vascular function. So that was one of the smaller vessels. We also did some echo data looking at the aorta coming from the heart. So we were looking at kind of the ability of the vessel to relax and if there were any structural changes in like the size of the aorta. So this was another vessel that also showed a, this is a measure of distensibility, kind of how stiff or how much tone there is on the vessel. So a smaller number, less distensible, it means it's a stiffer vessel. So it's not as flexible. So normally when the blood comes out of the heart, it would stretch the aorta and then it would relax and come back. A stiffer aorta like this one in the denervated group doesn't have that ability to stretch. So you get larger pressures that are affecting the heart as well as going downstream, affecting the vessels. And again, we saw some of the ability of the temple to improve this function as well. Skip that one. We'll go, this is the, so... So this is the structure of the aorta. We did some histology looking at the aorta. So we saw that it was stiffer. We wanted to know if there was any remodeling that was going on. And the SAD group in the middle was showing a slightly thicker wall. It was a thicker wall suggesting hypertrophy, kind of increased. You could see the yellow is this, like the smooth muscle layer of the blood vessel. So some hypertrophy of the vessel then that was reversed with the temple treatment. It's just a quantification of those vessel pictures. This one then is the heart muscle itself. This is a histology looking at the collagen or sort of more hypertrophy and fibrosis of the heart muscle. So again, we saw an effect on the vessel. Now we're seeing some effect on the heart. So the increase in the heart weight, hypertrophy, remodeling of the heart. So all these things are kind of suggesting that this variability is leading to a heart failure type of condition in these animals. So the last thing we wanted to do then was to actually look at the heart function. We're able to put a catheter into the heart. So you could see this is the pressure. Pressure catheter showing the left ventricle function. We could look at the pressure at the end of diastole as well as during systole. And then the slope of this line with the rise from the acolyte to systole gives us a measure of the contractility or the function of the heart. And so this was suggesting that we are seeing some diastolic dysfunction. This is kind of what happens when there's more blood that gets left in the heart. It doesn't get pumped out. So it's kind of what happens during early stages in heart failure. But we weren't really seeing any changes in contractility at this point. So we're seeing some early remodeling of the heart and early loss of heart function. So just to summarize some of those results, we're seeing that six weeks in the increased blood pressure variability, we were losing some functional measures of the vessels as well as there were some structural remodeling within the heart and the vessels. And our temple treatment, it was able to reverse a lot of that. It didn't return everything back to normal. So it was somewhat improved, but there was still some room for improvement. So that was suggesting that oxidative stress does play a role, but there were still some other variables that we would need to look at and see what might be there to help fully return function. Okay, so for the second part then, going to switch a little bit towards the brain and some of the effects of glucose. So we've been studying diabetes because it has a lot of the same, there's a very strong oxidative stress component to diabetes as well as a lot of vascular changes that occur. So a lot of the complications that diabetics have with their heart or kidney or brain, a lot of it comes down to these sort of vascular changes that are shown here on the right side. There's just a list of different structure or functional sort of changes that are known to occur in diabetes. So one of the things our lab is interested in is the effect of what happens during strokes. There's some interesting literature that would suggest that the timing, how long you have diabetes or are exposed to the high glucose, as well as the severity, if it's a moderate or more severe case of hyperglycemia, you might actually have different outcomes based on the stroke. They're showing that some of the chronic or moderate hyperglycemia might actually result in less of an infarct. It's almost protective in some cases. It's going to depend on the model and so it's almost like you have this storage of, storage of glucose that helps you during the ischemic portion but then the reperfusion injury tends to be a lot worse. So regardless of the timing or the severity of the glucose, they still have these vascular related reperfusion type of injuries. So this edema or hemorrhage is a large complication in a lot of the diabetic populations. So this is some of the angiogenesis or new blood vessel growth that isn't seen to occur. So in a control versus the diabetic brain, the diabetic brain tends to have more vessels. There's like more collateral that will start to form. And that's in response to the diet, in response to the glucose and an increase in some of the vascular growth factors. So this is one of the concepts that they think might actually help protect against the ischemia. So you have more vessels. So if you have a block, you could have blood flow coming through one of these collaterals and help to restore the flow there. That's what this one paper here showed. They caused the occlusion of the middle cerebral artery. So a similar sort of drop in flow or occlusion. The very next day, the diabetic rats here had more flow on that occluded side even though they still had the MCA blocked. So it was a permanent occlusion. They would go in, tie off the crowded artery. And without restoring flow, the collaterals in the diabetic brain started to restore the flow on its own. I'll be looking at MRI. Um, these are, it's like a speckle imaging. And is it going to be for animal model? Yeah, these were, uh, it's like, uh, similar to the speckle contrast imaging. This was, there's a company that has, uh, it's a pyramid company. They have their own. It's kind of like a microscope giving you the whole image. So, so when you see that restore and so more flow the very next day, what they did was then take those brains after the 24 hours and they're showing that the increase in flow related to a smaller infarct size within the diabetic rat. Although even with a smaller infarct size, they still have more edema and more permeability. So there was kind of this hemorrhage that was occurring within the brain, more blood flow, uh, some of the fluid leaking out into the tissue. So this was after 24 hours only. If you do have the edema and this permeability, if you would let that animal survive longer, some of these factors now are going to, uh, sort of continue to damage the brain. So most likely if you looked at this rat, uh, the 48 hours or three or four days later, this might be flipped. So it's really more about the, uh, reperfusion injury within the diabetic animal or diabetes. So, so diabetes affects the vessels in the brain. It's also going to affect different cellular components within the neurovascular unit.  You also have some cells within the brain, uh, different glial cells, uh, neurons, other cells related to that are found around blood vessels, this parasite. So not only will the vessel structure function be affected in diabetes, but the high glucose will have an effect on all these other cells that are there and that help to mediate or control blood flow as well. So the one cell that we look at in our lab is this astrocyte. It's kind of right here in the middle of everything. It's one of the schematics you see a lot. You have neurons and the astrocyte is kind of poised in the center there. So it could sense the activity or the communication between the neurons. So when neuroactivity increases, the astrocyte here will get activated. It goes through a whole bunch of different signaling cascades in the middle and on the other side, then it would release different factors to, uh, control or change blood flow. So it would release some of the things we look at or like this one, the eats. These are different things that I'll call this, uh, cause a vasodilation or so when you have an increase in neural activity, you get more of the vasodilator and you get more blood flow. So there's some literature then showing that this DCF is just a measure of that oxidative stress. So high glucose has been shown to increase oxidative stress similar to the model we used the first time and it also is shown to cause a decrease in these vasodilators. So it's impacting the astrocyte. The astrocyte, its ability to control blood flow as well in a negative way. The other kind of opposite of that. So people are now finding out that the astrocyte can also release another factor. Known as 20 heat, which is kind of the polar opposite. It's actually a vasoconstrictor. It's more of a negative type of factor. So even though high glucose decreased the other one, we're now seeing that high glucose probably increases this vasoconstrictor or negative sort of protein. So it's not exactly sure what causes this switch from the antioxidant to the pro-oxidant into the oxidative stress, but there's a bunch of different cytokines as well as these oxidative markers that are increased suggesting a different inflammatory type of processes that are occurring in response to the high glucose environment. So we're doing a cell experiment to kind of look at some of the signaling. We take our astrocytes and we were growing them in a lower glucose media and then we would switch them, either switch them to the high glucose to represent a diabetic condition or keep them in the low glucose media. And then we would do some measures looking at the ability of the cell viability or its health as well as some calcium signaling and then changes in some of the receptors that would be receiving the messages from the neurons. So if it goes in parallel with the tissue? We have not. This other paper, this was some of that here. A lot of it is like some of the fluorescence signaling looking at either hydrogen peroxide or superoxide. So they do show when you have cells in a higher glucose, it does go up. Some of it was kind of time-dependent, like in these graphs with the cytokines. There's some other data showing that the longer they're in, it just kind of does keep accumulating. These are our astrocytes. One of the interesting things we found out, so a lot of research is done on what is considered a neonatal astrocyte. So you take those cells out of like a one, two or three-day-old animal. It's just because it's a lot easier to get them out. People don't usually use cells from adult animals because the brains are so much more developed it's harder to kind of break up those connections and get the cells back out. But what we're seeing is there's a big difference in the effects of the neonatal versus the adult cells. So if you're going to do something like studying Alzheimer's or some of these more chronic disease conditions, it's probably better to use cells from that sort of correct point in development. This is one of the other differences we see. So glutamate is a neurotransmitter that is commonly seen to cause changes in astrocytes. So this is a calcium signal. So most people consider, if you have a rise in calcium in the astrocyte, that's kind of this activation. It tells you the cell is working. So we're looking at the response to glutamate, which is often used to stimulate the astrocytes, and you don't really see any change in the adult cell, but you do see kind of this is a classic response in the neonatal cell. So it's again one of these developmental differences that could really sort of impact your experiments. Again, so this is the effect of glucose. So even though we didn't see, this is a receptor for glutamate, but we didn't see a change in that receptor. We still, or there was no change in the signal, we still can detect the receptor and we can detect that glucose has a large effect within the astrocyte, but maybe only on the adult astrocyte. So this was one other marker we used. So we can't get a nice rise in calcium or activate adult astrocytes, not with glutamate, but other factors such as ATP. So different metabolic factors. So we can't show nice activation of these cells. And this is one that we saw was, had a pretty good effect from the glucose. So when we would switch the cells to a higher glucose, we saw this rise in calcium. So anytime you have an increase in calcium within the cell, that could be this condition of calcium overload, which affects the mitochondria and affects the health of the cell. So that's usually a negative type of situation. So you get this rise in the baseline calcium and then when you try to stimulate the cell, we're seeing less of an activation as well. So this is kind of, then the last part of the talk, try and get through this kind of quicker. So we were looking at the neurovascular unit, some of the smaller blood vessels, some of the cells. Glucose also has an effect then on some of your larger arteries that control the blood flow. So going into some of what is known as the cerebral auto-regulation or blood flow auto-regulation. So cerebral auto-regulation, there's a whole bunch of mechanisms that control it. We still don't know everything. I like this figure legend down here. It's a simplified diagram. And it's not very simple, but this is my simplified diagram over here. So within a certain range of blood pressure, your blood flow should be pretty stable. If you go outside of that range too low of a pressure or too high of a pressure, and then you're going to have these large fluctuations in the blood flow that's going to your brain. So this is a model that we use to study blood flow regulation. So we have some catheters that we have. These are actually in one of the arteries. We just kind of tunnel them under the skin and bring them out to the back so we can access them during our experiment. We have a, this is a Doppler device. This gives us this line down here. So it's kind of a way to quantify the perfusion to the brain. So we developed this sort of technique with the catheters and the Doppler device. So now we can do our experiments in a conscious rat. He's kind of tethered. He's got these things coming off of him. But he's in a cage. He could walk around. He could be active. He could do all these different things. And we have the catheters. We could infuse drugs or measure the blood pressure while we're doing our experiments. So this is one of the main reasons we wanted to go towards this conscious preparation. You see, this is your blood pressure. If we give a drug to rise and increase blood pressure, your auto-regulation should keep flow the same. You get this nice barrel reflex. Heart rate goes down. The flow stays the same. If you have an anesthetized animal, though, the whole thing gets messed up. In that auto-regulation capacity, the normal function kind of goes away. So you have to be able to control the animal so you go back to this sort of normal response. So that last one showed a giving a drug to increase pressure. We also have ways that we can decrease the blood pressure in a nice controlled manner. So we could look at that lower side of the graph to the left of the smiley, green-faced guy. So as we lower blood pressure, you should also maintain your perfusion until you get to a certain point. Just somewhere around this 40 millimeters of mercury here, you get to a point where the blood pressure's so low that eventually the blood perfusion to the brain has to go down. It will decrease. So this is in an animal under room air. And then what we wanted to do was have the carbon dioxide go increase to the animal. What that causes then is this rise in blood flow and a kind of a loss to this auto-regulation function. So then this is our diabetic rat. So we have these nice tools to study auto-regulation. Now we're looking at what happens in a diabetic situation. We have our controlled rat. We decrease the blood pressure. The blood flows maintain pretty well unless the animal's now been exposed to high glucose. This was only even after one week of high glucose exposure. So even after just one week of diabetes, this rat lost all of its auto-regulatory capacity. And then the other component of this, if you restore the blood pressure, you see on the right here the blue line, the control rat, you should be able to control that reperfusion period. This is what we were saying is the worst part for the diabetic rat or the diabetic condition. It's that sort of this larger increase in perfusion. So this is where a lot of the vascular and organ injury comes from. So that goes back to this reperfusion period. So leading to more edema or more hemorrhage within the diabetic condition. This was just a quick showing of some of the different stroke models we can do. But I think I'll stop there because we're about out of time. So this is going to be the next step now is to actually take that diabetic rat. We know it has no auto-regulation capacity. So now we're going to go through and we're going to give that diabetic rat a stroke and kind of see if what we see with the auto-regulation, if that leads to more of this infarct, this damage, and then how can we attack sort of this reperfusion period here to prevent that either in a diabetic or a non-diabetic animal. Great. Thank you so much for that. Pass this microphone around. It's for the equity. Okay. I have one question. You mentioned that there's a separate mechanism like endothelium dilation and smooth muscle dilation. I thought if smooth muscles don't let any dilation, then the cell doesn't dilate, right? I didn't know that endothelium can also dilate the vessel. So it's sending the endothelial cell will send, say, the nitric oxide or the dilating message to the smooth muscle. It will tell it to dilate. So that's kind of that normal response. Even just that shear rate of the blood flow causes nitric oxide release and sort of that dilation of the vessel.  So now you have that shear flowing through. There is no nitric oxide release. So you don't get a dilation unless you come at the smooth muscle cell with something else. And that was what our other drug did, the SNP, that is basically nitric oxide. So we're stepping over the endothelial cell and we're just giving nitric oxide to it, to the vessel, and causing a dilation. So it's possible to have the situation where smooth muscles just relax but the vessel doesn't dilate because of the endothelial. Right. There could be less dilation. In the diabetic condition you see this increase in tone. There is more vascular tone. It's like there's more, say, calcium buildup maybe. That's causing this constriction all the time. That could be due to endothelial dysfunction. It could also be due to this depolarization that's directed at the smooth muscle. Any other questions from you guys? I have a question. So what I understood or concluded is that you said the infarct size in the scabial perfusion model is smaller in diabetes due to endogenesis. Is that right? And some of that is, it's like that other experiment that showed that was, it was more of a, there was some re-perfusion, but it wasn't, say, like they got rid of the occlusion. It's like they didn't treat them, remove the occlusion. It was still ligated. It was still ischemic. There was some flow from the collateral. So part of the smaller infarct size could be that collateral flow from other areas. So it's going around the occlusion. Otherwise, it could be some of what we're seeing now with our astrocytes is, so the brain doesn't normally store energy. The astrocyte may actually store some glycogen. So it might have a small component where it could have some energy substrate around. And in the diabetic condition, there could be an increase in this glycogen content. So that could be part of it, as well as this collateral flow. But it's actually the re-perfusion that causes more damage. I think so, yeah. Especially in the diabetic condition, because you have this sort of change in the blood-brain barrier. You have change in a lot of the vascular properties that would protect, like you see this large sort of re, like when we cause... This is our normal baseline flow. This is a two-hour period where we've actually gone in and blocked the flow to the MCA. And then at this point, I could remove that suture and restore the flow. And you see this huge sort of re-perfusion period. And this is even higher in our diabetic rats. And this is a stoke model, right? Right. Any other questions for Kevin? I guess Romina and I have still a lot of questions. We can do it offline. I think I'll leave if you have to. All right, so let's tank our speaker again.


Our first conversation is helping us think about the challenges that the Navy will face in 2030 and beyond. And to help us envision that topic and that idea, we are joined, have the pleasure of being joined by Admiral John Richardson who is serving as the 31st Chief of the Naval Operations and he's been doing that since 2015. Admiral Richardson graduated from the US Naval Academy in 1982 with a Bachelor's of Science in Physics. He holds master's degrees in Electrical Engineering from MIT and Woods Hole Oceanographic Institution and National Security Strategy from the National War College. He has served as both Commodore and Commander several times as well as Chief of Staff to the US Naval Forces Europe and US Naval Forces Africa. His staff assignments have included duty in the attack submarine division of the Chief of Naval Operations staff, Naval aid to the President and Director of Strategy and Policy at US Joint Forces Command. The conversation will be moderated by our very own CEO extraordinaire Anne-Marie Slaughter whom you've met already but a little about Anne-Marie's background is that prior to becoming CEO of New America she served as a Director of Policy and Planning for the US Department of State and was the first woman to hold that position and before then she was Dean of Princeton's Woodrow Wilson School of Public and International Affairs from 2002 to 2009 and before then Professor of International Foreign and Comparative Law at Harvard Law School. So our very distinguished leaders for this morning please join me in thanking them for the conversation. So good morning again. We have we have lots of things to cover. I know I'm not sure who set that up. The Army managed to get its imagining the future in on the video before the Navy got here but I can't compete with the Ghost Brigade. Although Ghost Fleet is singer's wonderful novel if any of you have not read it you absolutely should. So I've been reading some of your testimony and some of your speeches and I can't help noticing that you you have a the Navy gets a big boost from our first president. George Washington said I'm not sure if I can quote it exactly but he essentially seems to have said without a Navy we can't do anything with the Navy we can do everything that is honorable and glorious. Just a pretty good way to start anything and I thought we're gonna we're talking about the future of war we're talking about the future of the Navy and I've got a lot of specific questions but one of the things I'm most interested in is when George Washington was talking he was talking about the Navy as ships right there were ships and there were sailors and they sailed the different places and of course they had naval combat and they still do that but when you talk about ships and actually when you talk about ships and planes and all the different parts of the Navy you talk about them as platforms so I'm gonna start by asking you just to reflect on that big change that you now think of a ship or a plane as a platform. Well maybe if I could just back up a little bit and talk about why we start with that quote and the quote talks about hey without a Navy we can do nothing decisive and with it everything honorable and glorious and so your question really goes to the idea of what makes a Navy decisive and we spend a lot of time thinking about that right that's really what our our strategy goes towards and and then whether we call them platforms or ships or whatever we go towards putting together the right mix of those things to deliver a Navy to the nation that is decisive but the other reason that we start with that more and more is that we are taking every opportunity that we can to go back to what I would say as first principles and I think it's very much a theme that we have in common that this honorable and glorious part is as important as the decisive part and you know George Washington our first president has a lot of street cred in the founding father group and if we think about what the Navy can do for the nation certainly we contribute to the military dimension of national power and we'll talk a lot about that but in addition we also a quick scan of our history shows that the Navy is deeply involved in the diplomatic element of national power and so if we think about the role of the Navy in diplomacy very very important it up to this day a Navy ship visits a foreign port the US ambassador to that country will host a reception on US sovereign territory that Navy ship and then just like George Washington did and particularly Thomas Jefferson one of the very first missions the Navy undertook was to go overseas to the Strait of Gibraltar to protect our trade against the Barbary pirates at the time and we still do a lot of that that's why we are deployed around the world to make sure that the Navy continues to meet its responsibilities to contribute to the economic dimension of national power and then all in the service of the value proposition that the United States presents to the world and so this idea of life liberty and the pursuit of happiness so important for us to center up on that and so we begin a lot of our discussions both internally in the Navy and externally reminding ourselves of those founding principles so that when somebody meets a US Navy sailor that might be the first actual you know manifestation of the United States that they meet so it's important that all of our folks understand that we certainly are part of the military dimension of power but also diplomatic also economic all in the service of these values so that's really why we start with that now to your to your question I think that as we start to appreciate the anything that can contribute you know certainly platforms the only thing that George Washington was thinking about was ships right sailing ships and then as you just sort of track the progress of technology through well we've introduced more things that can deliver naval power over time and so it's just become more complicated you have to stop thinking about these things as almost as individual things but also how they can contribute in a combined way and so you start to generalize them to these this idea of platforms some thing that can deliver naval power so whether that's a submarine or a satellite or a plane this integrated and network distributed but networked vehicle for delivering naval power right so that it operates together with everything else and and then we can't forget the human dimension of naval power as well which so with that's overview and I do think I remember reading the strategy that you all put out in like 2007 where really these these integrated military economic diplomatic and really value-based missions but right now in some ways we are we're going back to the future right the prep the national security strategy the national defense strategy talk about a return to great power conflict return in many ways to 19th century views of the world and I was struck those of you who are dinner last night no I'm a Game of Thrones fan the end I hope spoiler alert but sorry I mean if you didn't see it last night you had to be prepared the end of the war against the Night King and back to great power conflict we're back to conflict among the nation so when we talk about that now we talk about China and Russia and I wanted to ask you how you think about China and Russia and how how how alike they're both powers that are adversarial to us in some ways not in all ways but they're also very different and so how you think about that specific part of great power conflict well there's certainly a great deal of difference between those two powers and particularly over time you know I think that China growing very fast becoming more and more global and with with tremendous ambitions Russia trying to regain a near abroad security and using a little bit different approach to to maintain their security more asymmetric I would say and so they require a little bit different approaches but in general I think the approach is the same one is that there are certainly areas where we have a lot of differences and in the discussions that I have at least with my peers in China it's really about how do we mitigate manage risk as we resolve these differences the it's going to be important to the future of the whole world how China and the United States resolve their differences in a way that hopefully avoids conflict to to the point that the president of Arizona state made in his opening remarks and then with respect to Russia you know how do we just sort of sort of try and anticipate these moves that Russia is making but as you as we are starting to think about it really exists along a spectrum of competition right and we want to be trying to move things to the sort of lower kinetic end of that spectrum with every every move that we make there's a lot that goes into that one that we have to sort of be able to control the high end of spectrum so that we can deescalate on on our terms and and then you know just really do the hard analysis to sort of deconstruct each one based on its own merits you know I'm interested when you when you talk about mitigating risk and I think about I know you have regular dialogue with your Chinese counterpart and we've learned those lessons of the last great power conflict that there's great power conflict you can't avoid but of course World War one much more where people or are rising power as with China now where with the security dilemma the risk of mistake of misinterpretation is as great as anything else and so you can't stop the sort of head on we want this territory no you can't have it but you can stop the I'm not sure what you mean and I'm gonna make decisions I think you're exactly right and so we spend a lot of time we're obviously focused on things that happen at sea and near the sea and so what are those operational arrangements that are going to do everything we can to minimize the risk of miscalculation so we have this code for unplanned encounters at sea which is a communications protocol so that when us ships and foreign ships and this is spreading to more and more navies as they adopt it okay let's let's talk to one another let's arrange you know a passing that's going to be predictable and safe and not confrontational so that we minimize the risk of any kind of a miscalculation because it'll go the most tactical miscalculation will go strategic very very fast right and then to the point of responsive communications if something like that should happen one by virtue of our time together we can understand each other's thinking so we can and then we can get each other on the phone real quick and say okay this just happened let's not let this thing escalate you know beyond where it's helpful for either one of us de-escalate and to keep it in perspective exactly yeah what's that so let's turn to technology and but this is inevitable in all our lives in particularly when we think about the future of conflict and the future of security I was I was very interested looking at your your testimony presenting the most recent budget and senator in hope I think basically said to you you're taking the Harry S. Truman out why are you doing that and you said look we you know we need to to use those funds for new technologies and I want to invite you to talk about some of the specific technologies that that the Navy's investing in them and that you think about yeah no well you know Dr. Sanders up here he just wrote a piece that I read this morning about this thing and so one thing that characterizes success and failure I think is our ability to just move right though the most mortal sin we can have right now is to stay stable or stagnant right and so we're trying to move and that's exactly the decision dynamic with respect to hey what's more relevant for the future is it going to be the Harry S. Truman and its air wing where there's a lot of innovation taking place or is it going to be something else and those technologies are really right around the corner you know I know that it was a scientific science fiction award that we started with and if you think about the time horizon of science fiction for you know for readers it's it's steadily moved in whereas science fiction writers were used to write about a hundred years in the future 150 years in the future now it's like 25 30 years in the future thanks it's an indication that things are moving fast so you know the Navy's also trying to move fast in these directions things like unmanned and autonomy artificial intelligence things like directed energy which I think are going to really be very decisive directed energy at energies that make a difference I would say that you're gonna have to explain to me a little more directed energy think lasers high-power microwave you know electromagnetic energy in a in a focused way they can deliver either sort of kinetic right or non-kinetic effects I would say that additive manufacturing and the ability to create things from printers you know from raw material very decisive particularly for the Navy because we're always making these hard decisions you know what parts do I have to carry right and you know we only have very limited space well if I can make whatever part I need then it's it's a much different logistics thing for us so so you know these are the types of technologies that I think are going to have very decisive impact on the future and then you know the information systems that need to support it the artificial intelligence and machine learning and then you know how do we team all of that technology with people which I think are really the that's the competitive edge of the future the technology field if we can maintain pace is going to be relatively even so then it comes down to how we team with that technology as people to be more innovative creative etc so I want to come to your people how you're training them what you're offering them but when you talk about these different technologies one of courses they will all be connected so even if you think about a 3d printer and all the things it has to be connected to so that's part of how we're going to fight but it's also part of your economic mission so we think about the Internet of Things and everything being connected that you know those connections go through under underwater cables so you're when you now think about protecting our economy it used to be protecting ships from the Barbary Pirates it's now protecting cables how do you think about that and you know cables just being one part of sort of a national infrastructure that's all very very vulnerable because it's all being run by some network which is getting increasingly interconnected and therefore if you want to talk about a an attack surface is kind of the term of art lots of ways to get into that and so you know so how do you manage all that both the physical infrastructure and you know I will tell you that it's not just undersea cables but it's you know the technology has given us the ability to get to resources in deeper and deeper water so there's a lot of energy resources a lot of infrastructure at the sea it's one of the most dynamic parts of being in the maritime domain right now and then how do you protect all that sort of a seabed approach to our thinking is one way that we're getting after it and so now you know to get down to that well think about a network of unmanned vehicles remotely operated vehicles they can go down and hopefully be effective at securing all of that infrastructure so I mean yeah that economic mission is so much bigger than protecting ships even though we're protecting ships it's still a pretty big mission so from undersea to outer space because you also talk about cyberspace and space right the two domains we talked about mixed right make mixed reality right there how do you think about protecting our assets in space and to what extent do you think about that but I you know the layman would say well surely that's the air force but I know it's not we've got tremendous equities in space if you think about trying to maintain awareness and stay connected over you know over the vast distances particularly in the Pacific in the Atlantic you know space very very important sense so we're teaming very closely with all the other services the army has a tremendous investment and equities in space as well and then the idea of this interconnectedness well starts with the space architecture but it really goes all the way down to each individual system as well and so thinking about the communication standards that are going to be required to really truly connect this thing so that you know as the internet of things comes real and it gets more and more ubiquitous you know we don't want to be left behind as the only kind of network of stuff that's not to networked right so we've got to think about all that so I promised I'd I'd ask you to talk about people and again I mean it's the size of your workforce the range of things they have to do I was fascinated you have something called sailor 2025 right and this idea also of offering your workforce flexible career options I mean it's ahead of a think tag can action platform I think about that all the time I've got 60% millennials they their careers are changing in all sorts of different ways and so we think about how to offer that but you've got a much much bigger task so I wanted to ask you when you look forward at the future of the Navy and also the need to have a very diverse workforce because in many of the things that you're thinking about if you don't have a reflective workforce you're not going to be able to do the AI the right way you're not gonna be able to really think about use the technology in the full way that we need to talk to us about sailor 2025 and how you think about the future of your workforce I'll tell you sailor 2025 is really a suite of things that we're doing to really move our human resources into the 21st century and so we had and a lot of it starts with very sort of mundane things like a we've got to refresh the information technology right so there's been a number of events in the past two or three years that have honored Admiral Grace Hopper right great pioneer in computer science and I think some of our personnel databases were actually written by Admiral Grace Hopper I mean they're that old they don't talk to one another and we were sort of the you know the masters of small date right and so we've got all that moving up into the cloud now and with modern software which allows us now to get down to the individual sailor and understand what that sailor's priorities are right their professional priorities what they want to do their personal priorities and you know everything about that person and then we've got a proposition that we can make consistent with meeting the needs of the Navy if let's say sailor just wants to run from one operational assignment to the next and just move move move I got a lot of jobs like that so I can help that person if on the other hand maybe a sailor and their family want to stabilize because they have children going through school hey listen dependent upon where you want to live I can make you have some pretty good offers in that way if you want to get educated yourself we've got options there and so you know what is the compensation package that we can meet up and then how can we just eliminate all of the bureaucratic inefficiencies to make this literally all done on your smart phone and so that's what we want to do is deliver all of that flexibility transparency control of a sailor's career to their smart phone so that's just the human resources then you know there's the training part and so as we think about technology another thing in the past 20 25 years we've learned a tremendous about amount about how people learn right and so we're bringing all of that knowledge technology assists but also just the techniques through which information is presented all of that bringing you know brought to bear and then again you know we're networking our training venues as well so you put on you know the the goggles you're you're sitting in Norfolk you're in the simulated cockpit of an F-18 another sailor sitting in San Diego or Fallon Nevada and they're all networked together all fighting the same you know thing because the training systems are networked together you go to sea right now on a ship and you are presented a very complicated problem with the rest of your strike group and fleet half of that problem is real so you look out on the horizon and there's the ship when half of that problem is completely simulated and so there's live and virtual mix in terms of training opportunities gives us a chance to really ramp up the complexity of the scenarios and and make us much better you know I'll tell you also kind of going back to where we started knock on wood the Navy's met its recruiting goals for the past 12 and a half years every month and it's been you know a challenging thing and you sort of have to ask yourself why is that right I mean I can't compete on salary we have the most talented Navy by every measure of performance that we've ever had and I think it goes back to that value proposition Dr. Slaughter that hey we they join the Navy to do something noble and we need to make sure that when they join and they become part of that organization that our walk is consistent with our talk and that our behavior is consistent with their values honorable and glorious honorable and glorious wonderful so I think we have a few minutes for for questions I'm it's hard for me to see who's got the microphone and I'm just gonna say whoever is controlling the clock somebody needs to give me a hand sign when we're done because the clock is not telling me what I need to know so floor is open yes keep your hand raised there we go thank you Admiral for your service and for joining us here today Candace Rondo I'm a fellow with New America and a professor at ASU congratulations thank you feel very lucky my question for you is actually I recently took some a trip to Ukraine where we've seen a lot of challenges on the Sea of Azov and also on the Black Sea I'm wondering what lessons you and the Navy have taken away from this last period of confrontation in that part of the world I know that the USS Ross is patrolling now I've had the Donald Cook there as well what should we expect and what lessons would we take away and also what does this mean for interoperability for for NATO going forward as well as for the Ukrainian Navy yeah well that's a heavy question there's not enough time but I think some of the big lessons from that episode and many other like it are that one I think it's easy but a mistake to think of this in terms of kind of a bilateral approach hey what are we gonna do as the United States to be more resilient to things like that and as and this happens I think both in the Atlantic Mediterranean context the NATO context also in the Pacific as well where it's really a regional approach that we have to take and so one aspect of this is to make all of our allies and partners in that region I think more resilient and resistant to those types of actions going forward and so how do we all team together to respond as as an alliance or a team rather than just make this sort of a bilateral thing I think that's a that's a vulnerability we really want to try and avoid both in as I said in the Atlantic and the Pacific and then it goes to this idea of response time as well and so we've got to be able to respond or even better to anticipate these types of behaviors in fact in the ideal we would want our competitors responding to our first move rather than always being in the response mode ourselves and so you know if you think about that full spectrum of competition we would want to hey be making plenty of first moves of our own so that we can force the the competitor to respond and then you know the the decision cycle we've got to be able to when it when we do that to respond we've got to be able to do so on a timescale that's relevant right so that we can't let one actor go in you know potentially establish a new normal and then move on to the next thing before we've had a response to the first move so we've got to both think about this as making the region more resilient to these types of things so that one would give a great deal of thought before trying something like that and then when they happen be a little bit more responsive I think the building resilience point is again I mean whether you're thinking about climate or you're but but it's such as a core part of how we think about the future of our security is really a key point here in the front sir George Nicholson with the global special operations forces Foundation a little over a year ago at the Atlantic Council general Miller said our biggest threat in the future for the Marine Corps is our dependence upon GPS and Satcom and he talked about being in Afghanistan the year before I mean the month before asking one of his Marines where was something on the map makes he said they looked at me like I was a dinosaur and said we don't use maps I think about two or three weeks later you made the comment that you had the same problem in the in the Navy and I think that you said that you asked the question about can we use sections we're told we stopped using sections year ago how do you see this problem being resolved yeah well the problem I think comes under a group of problems that we call I think it's positioning navigation and timing right at PNT and because we you know the other thing is we just got to make an acronym for it so the the challenge of positioning navigation and timing is going to I think it's we're making good progress there right this is an area where technology is helping us there's a lot of these positioning systems up in in space and and in geo types of approaches to this I think that all of our systems should be able to use all of them right and so that it makes it more robust if we're going to use kind of those electronic navigations types of systems and then you know we have returned to celestial navigation and some of those things which technology here we can do better than a sextant right now in terms of getting a star fix and so it's the combination of all of those things that will make us be more resilient your question though sort of elicits a kind of a broader matter which is we've talked a lot about the network today and that network of course is going to be the first point of attack I think if when conflict starts to move to the higher end of that spectrum and ours is not going to be 100% resilient all that we can expect ours to degrade but our hope is that and our goal is that while ours degrades it won't degrade as much as theirs and at the lowest point of connectivity or performance will be better than our adversaries and then we'll heal faster and so it's really you know thinking about that information space whether it's navigation whether it's communication that's contested battle space right now and thinking about some of those fundamental ideas of contested space those principles will do us well in this space as well they're over there hello admiral Pete Montsuor I'm a professor of military history at the Ohio State University what are your concerns that the Navy hasn't engaged in a major blue water conflict since the Battle of Leyte Gulf in 1944 and I'm thinking the parallel here would be the Royal Navy between Trafalgar in Yutland doesn't see a lot of blue water comp conflict and then at Yutland it doesn't do very well because its culture had ossified how do you prevent that from happening in the United States Navy I'll tell you it's a it's a real challenge and there's that great book rules of the game that talks exactly about that problem for the Royal Navy and has tremendous lessons for us in terms of the culture of command and a freedom of action the ability to innovate you know it's just up at New Port last night and talk to the course that we teach to future joint force maritime component commanders we talked exactly about this right and then we went to dinner with a bunch of the prospective commanding officers that are going to go out and command ships and we talked exactly about this and so it's a matter of how are you training right I mean that's the best that we can do Pete is just sort of make our training as challenging and prototypic as we possibly can including the decision structures and the challenges that are going to poke right at that problem that you just talked about and then you know what is the response and what is the ability of each of our commanders at every level to sort of think on their own innovatively creatively use their initiative exercise the full scope of the authorities that we have given because I think what happens in these long periods without exercising those muscles that we just you know just like an athlete we sort of get out of shape and so we're trying to push out an exercise but I'm mindful you know you mentioned late day golf at the beginning of World War two even after Pearl Harbor even after Guadalcanal you know we were still learning on the fly at you know at great cost right in combat and so you know I'm mindful that every opportunity we can to make that training more representative of the complexity of the challenge we face will get us closer and then we've got to sort of build in that resilience and toughness and I guess humility to understand that we're not going to get it all perfect and we're still going to have to fight through that transition yes Chris Wolf BBC I'm sure you're not going to be any Admiral Jellicos or but the we've talked a little bit about great power competition but a lot of smart people have been talking about John Bolton for example pushing towards a confrontation with Iran so I was wondering you know what your advice might be when that issue comes up. I think well the United States is a global power right and one of the lessons that we have learned we have to internalize is that every time we try and focus on one thing too much without maintaining a balanced perspective that well there's vulnerabilities associated that people will you know steal a march on us in our blind spots and then I think particularly with the Middle East and other areas the importance of allies and partners is even more made more manifest and so building those meaningful networks where we're sharing you know not only kind of military capability but every time we get together with our allies and partners in any kind of an international contest it's really like hey what are we going to how much more information can we share right so that we can get out in front of this start to be in the anticipatory phase of things rather than the reactionary phase of things and then so I think that that's a you know a big part of the solution and then as we think about sort of you know those adversaries identified in the national defense strategy we've got to watch out for any kind of alliances between them so you know China Iran Russia Iran those sorts of things those types of alliances only complicate our problem as well with somebody in the back there no Peter thank you good morning I'm rolling you started off I'm Tom Squattery with talk media news you began your comments about communication on the high seas between navies and over the weekend two US ships again went through the Taiwan Strait this year there have been an increased number of freedom of navigation operations in the South China Sea of course you know with the incident last fall where it appeared a Chinese vessel was going to ram a US vessel can you talk a little bit about the South China Sea in regards to the communication aspects that you mentioned at the beginning remarks and how to avoid an accidental ramming or something like that thank you yeah I mean I think I was pretty complete when I talked about it it's really just an operational construct that in the vast vast majority of encounters that we see in the South China Sea and everywhere else that you mentioned we both parties behave all parties really because it's bigger than just the two of us behave consistently with those with those arrangements and so in fact that's one of the things that we stress quite a bit when I last visited China was this responsibility that we have to make sure that we train our commanding officers who have so much responsibility on their shoulders to make sure that hey if we're not if we don't consider ourselves enemies well let's not treat ourselves like enemies let's pass peacefully in the South China Sea or wherever and let's not make it hard to abide by these constructs and pass peacefully so let's not try and drive erratically in front of one another let's try and not throw obstacles in front of each other etc and it's the responsibility of those commanding officers to make sure that they make a very measured approach in this and then it's the responsibility of higher echelon commanders to teach that and hold the commanding officers responsible and so you know I think that that's about all that said there the South China Sea a very important body of water for a lot of reasons you know the United States as well about a third of the world's trade flows through that body of water and so it's extremely important that as we advocate for continued freedom of navigation through their and other international waters like the Taiwan Straits that were mindful that we've got a tremendous economic interest in that as a maritime nation have to say for all our talk about mixed reality and virtual reality you go to Singapore you look at your hotel room you see all those ships lined up right about to go to the streets and it's it just reminds you how physical it is and and how much we do rely on these these very narrow passageways no yeah you and you can map them out through the world there's the Malacca Straits where you were talking about there's Hormuz there's Babel Men Dem there's Gibraltar there's Suez Panama you know you can just sort of take a look at them and you know geography is still destiny you can't simulate that away Peter Peter singer with New America thanks again for joining us I'm gonna ask you a question maybe less likely to get you in trouble than Bolton and Iran policy it actually goes back to the prior question about Naval Warfare a hundred years ago so one of the challenges of that period that you face now is that there were a set of technologies a set of platforms some of which had been dominant were still believed to be dominant you know that was the last great dreadnought battle and yet wasn't moving forward you had other technologies that were not yet realized to be as powerful as they would be aircraft carrier submarine and then you had a third category of ones akin to the like the blimp aircraft carrier that seemed like it was the future and yet it was like a false alley so as you're planning the Navy of 2030 how are you navigating these questions of which kind of investments to make how are you testing them how are you visioning this now that's a great question and so it's very central to our approach right now and so I'll just tell you story and I apologize if I'm repeating myself but there's this number 10,000 that's out there and it gets a lot of play right so if you think about 10,000 of us out in a would-be island just last week at where we have a lot of our electronic attack squatters this is a new area right that's proving more and more valuable and they had this quote on the wall of their building that talked about hey it's a Thomas Edison quote right I didn't make 10,000 mistakes I just learned 10,000 ways not to make a light bulb so there's 10,000 in that context in terms of experimentation you know if you read Malcolm Gladwell he talks about the 10,000 hours right that it takes to become an expert I feel like oftentimes I'm a trapped in a world of 10,000 briefs right where it takes 10,000 briefs to kind of get the consensus in the group of fellow travelers to come together with the unity of effort that's the way it's not going to work right and so I would as we think about all of these technologies and in the context of the Navy as a learning engine a global learning engine I would say that as always we want to move forward on an evidence based approach and so the more that we can get out and test these concepts in every possible way some we test by analyzing them a little bit more some we test by wargaming them you know up in Newport or wherever some we test by going out and doing a fleet experiment we actually get on the water and check it out but we've got to make sure that when the nation security is involved that we're not making a leap of faith right so some people use this battleship to aircraft carrier example as a as a pivotal moment for the Navy and I suppose it was but hey there was 20 years of experimentation with naval aviation that prepared us for that time right and so it wasn't like we just sort of invented it on the fly we had a lot of evidence and and tactical development and technological development and so as we move forward we've got to make sure that we continue those experiments those prototypes that refining and we have to be mindful that hey this exponential pace of change is getting more and more rapid so also our pace of experimentation needs to get more and more rapid so that we don't fall behind so you know I'd much rather be in the 10,000 experiments realm than the 10,000 brief realm well that is a perfect note on which to end okay and we thank you it's a perfect kickoff to a day of discussion about the future of security well thank you very much thanks for having it's great to be together


Good day everybody. Dr. Sajja Sanyal, professor of department chair. This is going to be a demonstration of the wrist and the palm especially the neuro-muscular structures and some muscles. This is supine cadaver. This is the left side. I am standing on the left side and the camera person is also the left side. So we have dissected out this portion of the palm. So let's first identify the structures. We can see this tendon here. This is the flexor carbide radialis. In this particular cadaver, we don't have the palm wrist longest. We see this tendon here. This is the flexor digitorum superficialis. Under that, we can see this is the flexor digitorum profundus. This is the flexor polisus longus. This is the flexor carbide ulnaris. This is the radial artery. This is the median nerve. And further, immediately, we can see this is ulnar artery and this is the ulnar nerve. Ulnar artery is lateral to the ulnar nerve. Both of these are located under the cover of the flexor carbide ulnaris and we have separated them out. Just like the radial artery is located under cover of the radialis and we have separated them out. So let's take a look at some important landmarks and some important distributions. This place where my finger is located, this is called the carpal tunnel. The carpal tunnel is bounded by a tough ligament structure and we have already cut it here. This is the flexor reticulum and if you look very closely and we zoom the camera, we can see that this is the cut edge of the flexor reticulum on the radial side. Likewise, we can see that this is the cut edge of the flexor reticulum on the ulnar side. This is the cut edge on the other side. So therefore, this was the bridge of the carpal tunnel and we have cut it. So one cut it is here, other cut it is here. And we have opened up the carpal tunnel. Passing through the carpal tunnel, we have the following structures. We have the median nerve, which we saw just now. Then we have the four tendons of the flexor reticulum superficialis and the four tendons of the flexor reticulum profundus. And we have the flexor policies along this. So therefore, nine tendons with the sign of your sheets pass through the carpal tunnel and the median nerve is located in a very tight compartment where it can get compressed. And that is known as the carpal tunnel syndrome. Now I am going to put my finger deep inside and I have put my finger in a space in the palm. This space is referred to as the mid-palm space. This space is deep to the central compartment of the palm. And this is the potential space where, if there is an infection, pus can collect here. And from here, the infection can travel through the carpal tunnel as traced by my finger. And it can come under the flexor digital profundus, between the profundus and this muscle. This is the perimeter quadratus muscle. And this space is referred to as the space of parona. And the pus can then track and stop here where my finger is stopped at the profundus. So this is the space of parona. This is the carpal tunnel. This is the central compartment of the palm. That brings me to these bundle of muscles that we see here in the palm. This is the tenar muscles. They were covered by a fascia called the tenar fascia. And this is hypothera muscles, which is covered by a fascia called the hypothera fascia. So therefore, these two are located in the tenar compartment and the hypothera compartment. In the middle is an aponeurotic sheet, little bit of which is retained here. And that is known as the palmar aponeurosis. The proximal part of the palmar aponeurosis is attached to the flexor necrolum. And the distal portion has got four slips, which views with the fibrous flexor sheets of the digits. And we have removed that. And under that passes these four and four tendons of the flexor digital superficialis and the profundus. The tenar muscles are the outermost is the abductor policies previous. Then we have the opponents policies and deep is the flexor policies previous. And the counterpart on the hypothera side is the abductor digitimini. The opponents digitimini and the flexor digitimini previous. This is supplied by the median nerve. This is supplied by the ulnar nerve. Now let's take a look at the course of the median nerve. The median nerve after it has passed through the carpal tunnel, it enters the palm. And we can see it is giving the following branches. It gives a branch here. This is called the recurrent branch of the median nerve, which supplies the tenar muscles. Here the recurrent branch is quite superficial. And if a person falls on his outstretched hand and if he gets a superficial cut of the palm here, it can injure the superficial branch of the median nerve, the recurrent branch, and can produce paralysis of the tenar muscles. This is a picture of tenar paralysis showing what is known as the ape thumb deformity of the semen hand. Thereafter we can see that the median nerve is giving these branches. These are the cutaneous branches, digital branches to the thumb, index finger, the middle finger, and to the radial side of the middle finger. That is one structure that we see here. We have already described the flexor digitimini profundus and the superficialus. Let's take a look at the flexor carpal ulnaris. We can see that it is stopping here. This bone is the pissiform bone. And from there there is a tendon which runs and gets attached. To the hook of hamate and that is known as the pisohamate ligament. We notice that ulnar artery and ulnar nerve, they run superficial to the flexor retiniculum. And for that I will again show you the flexor retiniculum more clearly. So we notice that ulnar artery here and ulnar nerve, they are located superficial to the flexor retiniculum and I have lifted up the cut edge of the flexor retiniculum on the medial side. So therefore these two structures do not get compressed in carpal tunnel syndrome unlike the median nerve. And we see that the ulnar artery, it forms a superficial pommel arch. And from the superficial pommel arch we have the common and the proper digital arteries. Let's take a look at the ulnar nerve itself. We can see that the ulnar nerve is giving a branch which goes posteriorly and supplies the hand on the ulnar one-fourth on the dorsum of the hand. And then the main ulnar nerve goes superficial to the flexor retiniculum. Here it is located in a small tunnel called the chion tunnel which is bounded by the pisipomb bone, the hook of hemate, the bolar carpal ligament which we can see here and the pisohamate ligament. And after that it comes into the palm and we can see the course of the ulnar nerve in the palm. And here again we can see when I lift up the ulnar nerve we can see it is giving branches to the ulnar nerve. On our side of the ring finger and the little finger. So this is the distribution of the ulnar nerve here. The ulnar nerve can be endured here in three different ways. One is known as the Gion Canal syndrome and I mentioned the boundaries of the Gion Canal just now. The other is fracture of the hook of hemate. And the third condition is what is known as handlebar neuropathy. When a person is riding motorcycle for long duration it presses on the ulnar nerve. In all these situations ulnar nerve will be endured. Ulnar nerve supplies the hypothermia muscles which are shown here, which is actually the opponent's digestive enemy, abductor digestive enemy and the flexor digestive enemy brevis. Additionally the ulnar nerve supplies all the introsiae muscles. The dorsal, four dorsal, three mammary introsiae and it also supplies the lumbrical muscles, ulnar to lumbrical muscles. If the ulnar nerve is endured it will produce claw hand. When the person is asked to straighten the hand it becomes like this. This is called a radial claw hand. This is a picture of a radial claw hand which typically occurs in proximal ulnar nerve injuries. In contrast this is a picture of an ulnar claw hand which typically occurs in distal ulnar nerve regions. So this is the manifestation of ulnar nerve injury. The rule of thumb is the median nerve supplies more of the skin. It supplies lateral three folds of the palmar skin and the digital skin. And it supplies less of the muscle. It supplies only the ulnar eminence and it also supplies only the lateral two lumbricals. Ulnar nerve supplies more of the muscles. It supplies muscles of the hypothermia eminence. All the seven introsiae, the medial two lumbricals and it supplies less of the skin. It supplies only the medial one fold of the palmar skin. So these are the structures which I wanted to show you. Extending from the palm to the wrist and distally and with a respective neurovascular distribution and the clinical correlations. Thank you very much for watching. Dr. Sanjay Sanyal signing out. Mr. Ken Rolk, Amber Badge, the camera person. If you have any questions or comments please put them in the comment section below. Have a nice day.


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Now a quick overview for the lingo, if you're not familiar, resident is basically somebody who's finished medical school and is going through their three or seven year training to be that kind of doctor. So I spent three years to do internal medicine residency and now I'm doing sub-specialty even further to just be a cardiologist, so three year fellowship. But usually between your residency and your fellowship you get board certified in your broad field. So I got board certified in internal medicine. I can work as an independent medicine doctor which I actually have done as a year as a hospitalist. If you guys are interested, I'll go ahead and link that video up here or as well in the description. But as you can imagine, because a fellow has more certifications they have more opportunities to work both independently as well as oversee other trainees. So when I was a resident working in the ICU's often sometimes there wouldn't always be a supervising attending in-house in case we had an emergency but there would be a moonlighting fellow that'd be usually in cardiology, a pulmonary who had their medicine license. It could just oversee us making decisions. So we had no indication to bother them because we kind of knew what we were doing overnight. The fellow made a decent amount of cash which we'll go to in a second and really not do anything.