1:09
at the University of Pennsylvania School of Veterinary Medicine. Eduardo studied animal science at the National University of Columbia.
1:18
So woo hoo, and after working for several years as a nutritionist in the feed industry in Colombia,
1:24
he moved to the US to complete his Master in Doctoral Studies at the University of
1:30
the Cornell University. Sorry. His research focused on how nutrition influenced dairy cow metabolism,
1:37
physiology, milk production and health, particularly regarding fatty acids,
1:42
energy use, immune function, and periparturient ketosis. Daniel Rico, his brother and now here from from Bogota,
1:53
Colombia. Also, he holds Master in Doctoral degrees in
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Animal Science from Penn State, specializing in nutrition, metabolism and milk quality.
2:04
After postdoctoral research at the level University in Canada,
2:10
he has been a researcher in animal nutrition and Physiology at CRSAD since
2:17
2016. Seventeen. Sorry, investigating nutrition impact on animal health, productivity and the environment through
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One Health Concept. So thank you so much for being here. Please for the audience, use the Q& A button for questions.
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This webinar is going to be recorded and will be posted at the dairy website at the UW Madison Extension.
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So you can find all of these videos right there. So thank you so much again for being here.
2:46
We appreciate that you accept this invitation. I'm very happy to have you 2 here because we are from Colombia and I'm very,
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very excited. So the floor is yours and we can start now.
3:00
Thank you so much. Well, thank you, Alison, for having us. It's exciting for us also because it's the first time that we do this sort of
3:07
thing together. As we talked about before and we go way back, Daniel and I, you could say this,
3:13
yes, you could say that. So, yeah, for those who are having realized yet, we are twin brothers and we are both interested in nutrition,
3:20
in animal nutrition in particular, dairy cow nutrition in particular. So there's a lot of overlapping what and you can imagine with similar brains the
3:28
things that we're interested in doing. So as you will see today, there's a little bit of stuff that we
3:34
have in common that we actually are happy to discuss here. And that relates to how nutrition can do something about health and welfare.
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And the common theme that unites us today is inflammation, right? Without any of us being immunologist just trying to dip our toes from the nutrition
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angle. Probably that's kind of like the disclaimer that I will have to start. So yeah, let's, let's let's get it rolling now.
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And I wanted to say, yeah, maybe we can go into questions at any time as you get the questions in the chat, live chat, Alison,
4:07
we can go into that at any time. Yes, of course, I will do that.
4:12
All right. So maybe, Eduardo, this would be a good spot to start explaining why we're talking about inflammation today.
4:19
So it seems like it's a topic that many, many people are talking about for a long time.
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So you have a few examples here that maybe pretty much in the popular culture.
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And we were just discussing this before we started recording that everywhere you look at, and this is an example from the past
4:38
couple of months just going grocery shopping, we talked about how inflammation is something we need to control, right?
4:44
Or in this case anti. That's probably a word that we should evaluate more closely.
4:50
You don't want to stop inflammation. We're going to probably go into that, but the point is that there is something
4:56
about inflammation that we want to avoid, right? And so what do you do with diet in particular? Do you eat more of this, more of that, this particular supplements?
5:05
So there is a bunch of parties interested in this, the ways in which exercise also could help.
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But in the human world, this is a, how to call it, a fledging, burgeoning field that is very, very pretty much in anyone's interest.
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And of course, that's also what you could think about animals for us, there'll be an interest in this area.
5:27
So pretty much in the popular culture. Yeah, yeah. This is something I see also here in Canada.
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There's well also a bunch of podcast, the people on YouTube everywhere on Next
5:38
talking about inflammation and there is a lot of claims. So maybe there's some truth to the importance of this, of course,
5:46
and misunderstanding a little bit if this is a good process or is a bad process because to make enough.
5:53
That was like something that a few years ago we started working on. And maybe the the first confusion for me was, OK, this is good.
6:01
What is why do we have to control it? So I think you have a good analogy for the, the tree forest,
6:08
the the forest fires. Yeah, yeah. Let's go to that. But let's pretend that with saying that inflammation is a necessary protective
6:17
response of the body to things like injury or infection, right. So there is an insult and to that insult we have an army of cells that are ready
6:26
to respond. So here we actually in this slide, we could see two groups of cells on the left side. Red is the ones that are in charge of leaving the charge just to be repetitive.
6:36
Some cells that are taking care of the is the first responders you could think. And then you have some others that are there to put out the fire that was
6:45
started right. So you have an inflammatory response that you can think of as a fire. And I think about this when I, when I think about the Barry Bradford's
6:52
review 10 years ago, we put the fire at the center of this, right? And it's important to keep the health of the animal.
6:59
That's the long story short, right? So these fires in the analogy that I like to place is what people in California,
7:04
places like California think a lot. You do a controlled fire and you contain it so that you can improve or maintain
7:12
the health of the forest. So in the same way you could think of letting inflammation or the fire take
7:19
place, but in a controlled manner, in time, controlling time and controlling intensity.
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Those two things need to be controlled, right? When it goes out of those bounds is when we start having issues.
7:30
So that's the shorthand for the analogy, right? So the analogy, we take it back to the animal then it is,
7:37
let's say the naturally dense forest is having all of these microorganisms that shouldn't be there.
7:42
For example, during an infection, the body is going to deal with it and the
7:48
response can be too much or too long. So chronic inflammation is an issue.
7:53
We talk about that a lot in the on the human side. So for the cow, I guess that's the thing we need to
7:59
resolve that inflammation. There are ways that we can do it. This is where we're going to talk about today to tame it and then resolve it,
8:06
which are two things that are not exactly the same. Yes. And I would say that is a preference to that.
8:12
That also the one of the opportunities we have with nutrition and we'll get that into that part when we talk about the omega-3 fatty acids is that you could do
8:21
something with nutrition to empower the cow to do a, to mount a better resolution of that inflammation, right?
8:27
To put out that fire, which is something that not necessarily pharmaceuticals can do. Pharmaceuticals can act on a particular area which is blocking the inflammatory
8:36
response or reducing it in intensity but not resolving it, which are two different parts of it.
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OK, so yeah, we'll get into that as we go. Yeah, maybe now what we could mention also is
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there is this danger of having uncontrolled inflammation, but what is it exactly for the cow?
8:56
What is the problem that we have with that? You have this list here of things that are happening, tissue damage after the reduction.
9:02
So what are the highlights of this? So there's the things that we see and the things that we don't see when we what,
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what we see in the end is that animals will produce less milk, will have impaired fertility, right, low reproductive and reproductive
9:16
function, which are the outcomes. The cow, tells us that there is something wrong. But what we don't see is what happens before you get there,
9:22
which could be weeks or months. And that's damage to the tissue for because of this inflammation that was not
9:29
controlled. And in the case of the mammary gland, you can think of fibrosis of the mammary gland and tissue that doesn't go back to being, you know, this,
9:36
the milk secreting tissue that should be. And you have a number of things that are happening to the cells themselves that
9:42
are damaging the cells for the longer term. And I'm also going to have an implication on cow longevity or productive life,
9:48
as we say, because the cows are going to ultimately be culled out of the herd early because of these things that we don't see.
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And I'll make emphasis on the things that we don't see because that goes to the topic of markers.
10:00
How do you know what's happening inside of that cow? And other than just looking at the obvious signs of milk yield or appetite,
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right, you don't really know much because it's hard to measure. So this makes me think of something that we will discuss later.
10:14
But we have been working on heat stress for a few years now and we got to it on the side of a cow productivity, milk quality, etcetera,
10:21
but then discovered of course that there is all of this inflammation happening.
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And I think this is a good summary of what's happening during heat stress as well. So there may be some cell function at the mammary level,
10:34
the gut level that there's a loss in that function. So things start going really bad.
10:39
Then the animals reduce their appetite, they eat less. But eating less doesn't really explain everything that is happening during heat
10:46
stress because there's, there's more to it. There's inflammatory response, of course, all of that energy and then that energy
10:53
going into the immune cells and not to milk, to milk synthesis. So that's something to me that was kind of an initial interesting discovery is
11:02
that wow, heat stress is really a variation on a different flavor of inflammation, but it's kind of the same thing.
11:09
Same things are happening during heat stress. So you would do that point, yes, if you could do something about that
11:17
response. so that is not so extreme or that the cows, I would say they weren't empowered. Again. Better prepared to deal with that.
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Then you could do something about how that energy allocation to the immune system, you know, which is kind of like a loss you could
11:32
say for in terms of milk production could be avoided. Bringing us back to the importance of trying to assess inflammation or prevent
11:40
inflammation or do something about inflammation because ultimately it also means not just that the cow gets sick, but that she's going to make less because
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there is less nutrients to go around. Exactly. And then just rounding this idea that many things can cause inflammation.
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We have the example of heat stress. The idea there is that you're going to have leaky gut because the barrier,
12:02
the intestinal barrier is compromised. So you have this bacterial urging compounds such as lipopolysaccharide that
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we have here in the picture, LP's for short, that's going to trigger the, the response.
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There's also mastitis, metritis. So any infection that the animal has to deal with is going to result in that type
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of fire. And then the response of the animal, this is something you could probably they
12:27
go into deeper is we have this primary response with cytokines. And then those, some of the cytokines like interleukin
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IL-6 are going to to trigger the the secondary response, which are the acute phase proteins. So that's another thing about the markers.
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These are markers of inflammation. What is the thing with the markers? This is the thing that again that we don't usually see, right?
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And these things happen very quickly after there is an insult. So for example, the cytokines are produced in a matter of
12:54
hours after there is kind of like a breach, say that they did LP's enter into the blood or that there is an actual
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infection, right. So these things happen quickly in hours. And you could, if you could time it and measure it there you, you will know what's happening, which we don't usually do, of course,
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unless you're doing research. But then there is the longer response that could take days to appear.
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And that's secondary in the sense that the signals get into the liver and the liver is actually going to produce these proteins that we call acute phase
13:20
proteins. And probably you hear more and more of those because they are actually very good markers for some things that are happening chronically in the animal.
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So over the course of days, and they could have been in the many cases in over the course of weeks that the cows dealing with an issue and they
13:35
could be actually helpful. I'm sure that you have and myself have measured some of these in our research.
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It's hard to find good ways to measure them. You know that the tests don't always work. We all suffer with this ailment.
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But things like haptoglobin, C reactive protein, LP's binding protein. They could be good ways to use this as proxies or indicators of something that
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is going wrong. And I understand you have used this actually when you're talking about heat stress, right? Yeah, definitely.
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C reactive protein, LP's binding protein and then the cytokines, all of these are elevated after a few
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days of heat stress. Well, at least it could be earlier, right? But our response is normally day seven, day 14,
14:15
we have really high levels of this and fever. So on top of the heat stress, there is the fever response that is
14:21
related to this cytokinesin and acute phase proteins. That's another thing that we can tackle with nutrition and we're going to talk
14:28
about that. And now let me let me go back to this before I forget because this relates to
14:34
the biomarkers and what we're showing here with ketosis. So one point that we will probably drill on today is that there is a lot of things
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happening in the cow that are modeled, right or muddled, I should say.
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They're happening together and you don't really know who's the culprit. And to some extent that tends to happen a lot with things like ketosis.
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We can argue, which sounds a bit blasphemous to say to some years still, but these things that you see in the list
15:02
are markers, basically indicators that something is happening. And I will emphasize again, invisible to many of us, right,
15:09
because they could be happening now. But you see the consequences 3 weeks, 4 weeks from now. In the case of ketosis,
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some of these markers are actually interesting because this data came from Michigan State and you can add to this if you want, Daniel,
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but the majority of cows that are diagnosed with clinical ketosis appear to display or to have this endotoxemia.
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So, these substances of bacterial origin presumably I, understand come from the gut.
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Did they just filter into the circulation where they shouldn't be? And they are surely causing some issues, right?
15:44
So it brings us to the question, are these cows displaying all of these issues that we call ketosis as a result of the ketones themselves or actually
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because there is infiltration of things that shouldn't be there and they're of course causing damage, reducing energy supply for the cow,
16:00
for milk, etcetera, etcetera. So there's something to be said about things that are happening simultaneously
16:06
and we don't really are able to measure the right thing on time, right. I would also add here that that those ketones are something that we measure
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when the cow is actually very sick and it's what we call the negative energy balance. So what if we could measure these markers earlier which some people are trying to
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do? So with that I have a question. So you say that some of the inflammation tests are not working or they are not
16:31
good enough. So how you can improve them or what is missing that they those inflammation
16:38
tests are not working? All right, I don't know, Daniel, go ahead tackle this one.
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Well, I guess it's a technical issue that sometimes we have to be careful when we use this for example for research,
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we have to make sure that the antibodies that are made for detection of this are actually well developed for the bovine and there's an issue that think an issue
16:59
there. But then there's the other question of using this at the farm level. If we compare them to ketones, things that we can measure really easily
17:07
like ketones, we don't have that yet for the dairy cow on the inflammation side.
17:12
So I think you're aware of some work that is being done on that. Yeah. So the latest I've seen, and this came recently in the Journal of
17:19
Dairy Science, there is some work at Cornell at the vet school, which is, I understand done by Sabine Mann,
17:24
Doctor Mann in collaboration with some other people. And they're trying to develop this immune tests so that we could use hopefully at
17:32
the farm someday. And of course, she will be the best person place to to talk about this and explain this. But as far as I understand from our short conversation recently,
17:39
it is a big challenge. So it's not only challenging for us to measure these things in the lab, but it's challenging to actually make them work in an easy cow side test at the
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farm. The advantage that I see in the future, if we get to overcome that hurdle is that
17:55
we would be able to do better diagnosing animals that don't have, you know,
18:00
these issues late, but early, right? So you detect them really much a pretty much pre onset before things go south
18:07
when you could do something. So that's kind of like the the challenge that we have right now when it comes to measuring these things.
18:14
All right. So hopefully that answers the question. So this is the point that we wanted to make to about biomarkers,
18:21
right indicators and ketosis, because we're going to talk about a little a little bit about ketosis after this.
18:28
Maybe now there's it's a good time to go into why that increased immune response
18:34
is kind of a drain in the fuel economy, let's call it like that. So we should have these slides that we discussed the other day.
18:42
So if we just take the example of glucose, that glucose that is being used by the immune response to, to face this challenge,
18:48
it's going to go there. There's good data from Lance Baungart that we also have in, in the slides that the immune, the immune cells are going to use a lot
18:57
of that glucose. When there's a challenge, an LPS challenge for instance, is that's something that is really important because it's not going to go to
19:05
the mammary gland to make lactose and to make milk. It's not going to go to muscle, to the ovaries,
19:11
to other places because there's a priority, there in facing that challenge. So it's something also that is going to affect metabolism.
19:18
We know that the immune cells can talk to the pancreas and tell the pancreas, please release more insulin when there's more insulin that's going to allow the
19:27
immune cells to use that glucose. And it's going to do the opposite for the mammary gland because mammary gland
19:33
doesn't really respond in the uptake of glucose to insulin. So this is how so this is what people talk about when they talk about different
19:40
in differences in partitioning of nutrients, right, Correct. Where is the energy or the nutrients, I should say more generally going?
19:48
Are you going to close? Are you going to close the tab to the mammary gland so that they can go to the
19:53
immune system to their defense army to to feed the army, I guess. And so if that's happening, you're going to reduce the flow to the
19:59
mammary gland and of course you're going to have less milk. That's kind of like the short explanation. I guess that's a good way to say it.
20:05
Like the the water tap, it's going there, but it's not going there or it's closed. So we're going to see effects of metabolism in productivity, etcetera.
20:13
So I guess that's the only to say there's, there's a lot of interesting information story because of this angle as well.
20:20
It's not just the damage that the cytokines or chronic inflammation could do, but the use of fuels.
20:26
And the productivity of the cows and how, how they, we, we look at their well-being and all of these things.
20:32
Yeah, we have this data here that maybe we can go into if we're thinking about that glucose that is not going to make milk.
20:38
So where is it going? So we have some data here to show that. Yeah. This is from a couple of groups, Lance Baumgart from Iowa State and then
20:47
Professor Trevisi at the Catholic University in Italy.
20:52
I've been working on this area for a while now. I would say, and what Baumgart's data showed us is,
20:58
is pretty interesting in that when you activate the immune system. So imagine there is a challenge like an infection in a 12 hour period.
21:06
They show that they could be around 2 lbs of glucose being consumed in that period
21:11
of time, which in the course of a full day is around 65 lbs of milk that are lost, right?
21:17
Because that energy for 65 lbs of milk could not go to, to be to the mammary gland to actually synthesize the milk.
21:24
The other example is the, the peak milk and milk yield in lactation, right? So when cows reach the peak, that's around 10% lower in cows with
21:33
increased inflammation. This is the, the Italian, Italian data. So inflammation, even if you don't see any other obvious
21:40
signs, it's silently reducing the performance because those energy, those nutrients are being, you know,
21:46
diverted to to feed the army again. So that's kind of like a very easy example of why this is relevant.
21:52
How much milk is being lost? How much money for farmers is being lost ultimately. And on top of that, there is a reproduction issue.
22:00
And I think you also have this data set that illustrates really what's happening
22:05
with fertility. So, yeah, defining inflammation is kind of difficult if you use just one thing.
22:10
But these markers, I think that you could make the case that are very good indicators that there is inflammation happening,
22:16
especially chronic or over the long period of time. In this case, Hp stands for haptoglobin, which is one of those things made in the
22:24
liver in response to a challenge or an insult. And when this cows in the orange have an elevation in that haptoglobin above this
22:32
threshold, they show two things, reduced fertility, which obviously you can see from that pregnancy fertility curve over there cows
22:41
not pregnant. So there is more cows not pregnant when there is high haptoglobin and there is
22:47
also the consequence on production which is around 1000 lbs less over the course
22:52
of 305 day lactation. So significant, pretty, pretty major and not necessarily
22:58
something you would obviously see unless you're tracking this type of markers.
23:04
Now that we have discussed the issues with inflammation and the immune response being one of the places where the energy or the glucose can go, maybe, you know,
23:13
we could talk about this confusion that we may have around what causes disease in cows. And that's something that a lot of people are talking about to have been talking
23:20
about for a few years now. And again, you have some work that I really like this review that you guys prepared.
23:28
And I guess this is a good point to to say to to illustrate that ketones are part of the equation. Of course, this is something we should be paying
23:35
attention to. So that, let's say, blasphemous statement that ketones are
23:40
not important is not necessarily true. And I guess there's just an integration to be made with the immune activation,
23:47
inflammation, insulin resistance, all of this. So what what was the highlight of of your review here?
23:53
I think after that, let's discussed observational and control research because that's something that you also talked about in your review.
23:59
I think something that we don't often talk about. And we should really talk about that to understand why this can be a complex
24:06
issue. Yeah, no, not all types of science are equal. And what we interpreted it could be in the human world and in animal science
24:13
world. The type of research that we use to back our statements is important because it
24:18
tells you something about how, how much confidence you can put in those statements.
24:23
So you made a good point with the ketones. I'll try to make it short. Of course, you're invited to, to read the review that we made on this,
24:32
what we call a changing paradigm. So the idea that we have about ketosis is being modified, I will say,
24:38
is not being put down necessarily or put to rest. It's just that we, we think, we posted here that there is more to it
24:46
than just the ketones. And the ketones are actually something very easy to measure. So when you, when you can measure ketones, everything is going to, I mean,
24:53
it doesn't surprise me that you're going to call anything that is related to problems when you measure them, you're going to call ketosis or it
25:01
becomes a bad word, right? So in many people's minds, still a bad word. I will I will briefly, briefly say in the human world,
25:08
this used to be a bad word decades ago and it transitioned briefly to the really cool thing that it reduces chronic inflammation that helps you lose weight.
25:18
You know that became like this amazing thing ketogenic diets. And yet in the cow world, we're still thinking on this very unique
25:26
tunnel vision way sometimes that it has to be bad. So that preference to say there is much more as you can see in this diagram
25:33
happening in a cow that is making milk than just the ketones, right? There is a number of things that could be causing issues,
25:39
cause could be causing insulin resistance. We could argue about that if that's an issue or not. Oxidative stress, cellular dysfunction, things that ultimately make the cause be
25:49
less fertile or make less milk. Inflammation, you could see it. Also there is one of those things that we don't measure usually and tend to happen
25:57
at the same time. So imagine that you have inflammation with all the negative effects that it has and the same time you have ketones, but you can measure only ketones.
26:05
So you say, OK, ketones is an energy molecule, let's fix that. Let's fix the energy issue. Is it enough to give propylene glycol or to give dextrose drench or something?
26:15
500 grams, Is that enough in the sea of on the ocean of the drain that you have on, on glucose itself, as we show before,
26:24
that equals 65 lbs of milk per day. It's very hard to make a dent on that when you are focused on fixing the ketone
26:30
issue. So that's kind of like the short, long story short of why we should care about more other factors that we cannot usually measure other than just the
26:38
ketones. OK, so you guys are talking a lot about like cows, you know, like the peripartal cows.
26:47
What do you think about the calves? You know, they also have some inflammations and some issues and some disease.
26:54
So what about them? Well, this is a concept that would apply to any
26:59
type of animals in general, when you have an insult that this is my crack at the question about do you can complement later.
27:06
But if there happens to be any inflammatory challenge, immune challenge,
27:11
the animals, especially around the weaning period Are going to experience every life in general,
27:17
depending on the conditions where they are, etcetera. The environment can also put a lot of stress on the animals.
27:22
So they're going to experience inflammation and one of the things we're going to see later. That is true for the daily cows, but also for the calves is that we're not
27:31
really sure about the requirements for these periods of challenge. And the, I would have to be more familiar with the
27:38
the Catholic Church here, But I guess the principle applies to any period of challenge in at any moment in
27:45
anonymous life. So if, if there's going to be immune activation, is that going to be controlled?
27:50
Is that going to be optimally like disposed of when it's when it's really done it's job?
27:56
So the resolution part, all of this that we can talk about with Omega threes, is that something that would be important
28:04
to the calf? Yes, definitely, yes. Now the work that has been done, I need to be more familiar with.
28:11
So I guess that's fine. That's fine. That's a good crack at it. I mean, obviously we don't really work so much specifically on calves, but I will say something.
28:18
We do work on early life stress in general and we have some work also together doing some, some work on models that reduce
28:25
inflammation during critical life periods. So we started with the piglet model and then we want to graduate into calves.
28:32
But the idea is overall the same that when you are presenting the animal with a very challenging situation, which is, for example,
28:40
going from mother's milk into the, you know, the concentrate feed or, and forages at weaning
28:47
There is this apparently unavoidable slump, you know, fall in, in growth rates and the animals are not doing great.
28:53
And we talk about weaning stress. Now we could discuss to what extent that could actually be the fight is winning
28:59
stress, but there should be things like inflammation happening. So that would be the common thread that I see into this.
29:05
Those, those types of stresses could to some extent, apparently based on what we have seen in other species, alleviated with nutritional strategies.
29:12
There may be others that are not so easy to tackle. So if we're talking about a viral infection in a calf or we're talking
29:19
about a bacterial infection, that's a whole other kind of worms, right? That is not necessarily so easy to tackle.
29:25
But but I would say that there is something to say about preparing the animal or arming the animal with everything you can to defend itself
29:34
against the regular insults, given that there is good management, right? Because it doesn't work if there's no good management.
29:41
So that would be probably the way that we could kind of answer the question.
29:47
All right. So this, this whole thing was just to illustrate that there is a number of things happening and that we're going to
29:52
probably migrate to the one thing that we could measure. So one of the solutions is measure more things, right?
29:58
So we would start with saying inflammation, which is the case we're trying to, argue today is important.
30:06
It's an important part of this equation. And we should be able to do more about measuring and detecting it, hopefully early enough that we could prevent downstream, downstream issues,
30:15
right. So let me just just cut you there for a second. In the interest of time, maybe we should move before we go into
30:21
the nutrition part because that's what we do in nutrition. Let's just round up this idea that there is a type of research that can lead us to
30:30
have some answers and that we have to be mindful when we think of the types of
30:35
research. And this is something that is part of your, your review. So I don't want to leave that forget about that when we talk about this.
30:44
And for some reason that slide is not showing, but the point that I want to make here, not sure you have the the shark.
30:50
We wanted to talk about sharks today. Yes, that's good. Well, when we compare observational research
30:57
versus controlled studies, controlled clinical trials, we have the issue that we cannot control for everything in the observational data.
31:04
So we just look at the world how it is and we try to draw conclusions from that,
31:09
let's say from an observational study that can give us a lot of clues about things that are happening.
31:16
We don't really get all the time cause effect. Sometimes we could, sometimes we we don't know really, right.
31:23
So we get relationships, right. The example here with the with the shark is, is kind of an example in,
31:29
in my opinion, because we get when, when we get to the summer months, there's going to be an increase in ice cream sales, of course,
31:36
and also in shark attacks. But we already know intuitively looking at these data sets that even though the
31:41
correlation is super strong, is not really true. Like you're not really more at risk if you eat ice cream if you think about
31:50
shark attacks. So is it is intuitive, we know, but it could also apply to anything else
31:56
that we just measure, for example, ketones going up when the animal is sick and it could prevent us from understanding what the real cause is.
32:04
So maybe as you said, we're measuring ketones that must be the culprit because the animal's sick.
32:10
But those ketones could be also elevated in an animal that is not sick at all and is producing a lot for different reasons.
32:15
So how good is a market like that when it's present in healthy and not healthy
32:20
animals, right? Yeah, we're going to get to that in terms of issue. But before that, I would say that this is one of the
32:26
reasons for which I don't need ice cream when I go to the beach in the summer. I just want to be less, less tasty for the sharks.
32:33
Yeah, good point. So that brings us to the observational research. So we want to try to close this with a bow tie here.
32:40
Observational research is telling you A is related to B, and controlled research is telling you A causes B unequivocally, right.
32:47
So we try to, most of the time as much as we can do randomized controlled studies or RCTs for controlled research.
32:53
When you change one little factor, only that factor and you, kind of like block the rest from influencing your outcomes.
33:01
So you want to know if, for example, if ketones are good or bad or NEFA are good or bad, you change that thing in research.
33:07
That's the beauty of research, you can control. But in observational research, you only can see, for example,
33:12
these cows have ketosis and at the same time they have increased inflammation and increase exudative stress. Chicken or the egg, which one was it?
33:19
You cannot really know, right? So that could be good to guide us in to do studies that we're trying to do.
33:24
For example, I'll show you the example of ketosis. Now, when you actually say if that relationship holds, but that's an important thing to consider.
33:31
You have this funnel, in this case of this soup, I guess, of factors all interacting together when an animal gets sick and you measure one
33:40
of them and you do research on that one that you, you're observing and then you make a disease named on, on that, right.
33:48
So if we could measure NEFA, we would be talking about not ketosis or, or something more like nephaosis.
33:56
That's a good point, right? But it sounds facetious, but it's probably a fair point to say
34:01
that it depends on what we can measure. So I will try to drill that point as much as I can. Inflammation could be happening at the same time that NEFA is high and ketones
34:08
are high. And the cows experience is what we define fatty liver. Which one was it? Are all of them conspiring?
34:14
Which one is more important? Hard, hard to know. So what do we do? We go to do randomized research.
34:19
So I'll show you now the the example of the ketones just to illustrate that point. So there's a few trails that you have run on this yes, type of research.
34:28
So we're trying to change the ketone particularly as a factor that we isolate and say if we add the ketone to the body of the cow,
34:36
is that going to do something good or bad or neutral? And we have done a nutritional induction.
34:42
So we create a ketogenic diet, that's one thing. Or we actually put the ketones directly into the vein. Yeah,
34:48
more like this of the cow, which is what you see in the figure. So overall, this is just one example from all of that
34:54
research. When we get to subclinical levels of ketosis, what we consider subclinical that is supposed to have negative effects on the
35:01
animals. We don't see any of that in, in terms of health acutely at least over the course of anything between 24 hours to five days.
35:09
We have done evaluations that would be this blue line, correct? That would be that blue line. This is just an example intravenously and we didn't see any changes in the appetite
35:18
of the cows during the time, during this time or milk production or anything of relevance, right. The actual markers that matter is the cow eating well and milking well.
35:25
We didn't see that change except when and I put that in the title here during immune activation.
35:30
So it brings us again back to the topic of immune activation and immune system and inflammation. So when you actually challenge that cow within something that makes that immune
35:41
system freak out. In this case, we call it the LPS challenge. We give them the carcass of a bacteria and we make the immune system think that
35:48
there is a pathogen, right? But there is really no a live pathogen there. It's just kind of the carcass.
35:54
But that's enough to activate the immune system. And in that situation, when you actually need to do some have some inflammatory response, you cannot stop it with the ketones or
36:02
reduce it with the ketones. So we may think that ketones may be conditionally important in terms of the
36:07
peripartum in situations where you actually need to deal with some kind of insult, but not always most of the time.
36:14
And this could explain why a cow that is milking a lot could actually have very high ketones, right?
36:20
So no, no signs of being not healthy, which is again, paraphrasing Lance Baumgart, if the cow is milking well and eating
36:27
well, is she sick, right? So this would probably support that that statement.
36:33
One question about your model, because as you mentioned, there are different ways to to do this controlled research.
36:38
You could just give calcium butyrate and increase ketones like that like we did here. You have the intravenous infusions, which I think is a is a really good model.
36:46
But isn't it true that is you're missing the NEFA like a really sick cow is
36:51
mobilizing a lot of high position and relaxation. She has high BHB.
36:57
The 2 are associated, of course, and it's it's not part of your model here, is there? Is there a reason for that?
37:03
Like what do you think will happen if you add the NEFA? Yeah, when you. That's kind of like the issue. There is great work done back in the 90s, Doctor Drakely from Illinois,
37:12
the model that he used to induce ketosis, actually increase NEFA and BHB at the
37:17
same time. So that's good in terms of reflecting what a cow with ketosis is experiencing
37:23
because there's many things happening, as I said, but it's not necessarily the best way to pin down on the effects of ketones
37:29
themselves. So we want to answer first the question, what do ketones alone do by themselves? And then we're adding, this is current research we're doing.
37:37
We're adding on top of that a pile of other factors. So ketosis plus immune challenge, ketosis plus NEFA ketosis plus other
37:44
things. So that that's a question that we answer progressively, but we need to isolate factors. So that's probably, I don't know if that answers your
37:50
question, but we, we don't want to do everything at the same time because then you cannot disentangle that. Well, I guess one, one thing that comes to mind is that you
37:58
can try different models and see where, where the data point in which direction and then conclude if there is a role of ketones or not.
38:07
There is not one single experiment that is perfect for, for showing everything that is happening in a complex period of time,
38:13
such as the true. And we that's the reason for which we tried this in the mid lactation, but also in the early lactation.
38:20
We try this with a nutritional model and also try with a intravenous infusion. So different ways to try to see what answer we get is a convergence of data,
38:28
not necessarily single isolated studies. It's tricky. This is not necessarily easy to do, but I think it's important at least to
38:34
see if we should be moving in a different direction or slightly correct course. Yeah, of course.
38:40
I think you're doing very cool research. So I guess I'm biased, but it's Interesting data to see.
38:46
What is that? That's called a twin brother bias. Yes, it's a particular type of logical fallacy.
38:54
So let's continue with the nutrition part. I guess we have something like maybe 10 minutes more going to the nutrition part.
39:01
So what is your. Yeah. OK, big picture, we're going to switch gears here a little bit.
39:07
Part of what we wanted to do was to set the stage to say inflammation is something we should care about.
39:12
And of course, you hear not only from us but from many people. But then what we as nutritionists care about,
39:18
which is how can you help animals in terms of health and welfare ultimately to
39:23
do better in terms of controlling that inflammation. So if you if we made a case that inflammation should be controlled,
39:30
how do we control it? So here in this in this slide, you could see many ways in which you could try to do something about inflammation.
39:36
A lot of that has to do with management. So probably I would just point out to forage and graze management is one of
39:42
those things that you should do to to actually provide the bare minimum from the nutritional side.
39:47
And that's leaving aside things that include, for example, stresses like heat stress that you should correct to some good extent with proper
39:56
heat abatement, right. But let's focus on the nutrition. So other than forage and graze green management, there could be other things.
40:03
I put ketones there because they're actually inflammatory and that's a probably we're going to keep that from our discussion there is.
40:10
Botanical compounds, right? So things in plants that could actually have some anti-inflammatory effects. There is people working on this from a couple of different companies.
40:17
Interesting area. But I guess Daniel and I, for the purpose of this presentation or this discussion, we're working on 2 main areas, Vitamin D3,
40:24
which is Daniel's work and omega-3 fatty acids, which is work that we have in common and in some cases collaboration.
40:32
So I'd probably like to start with Vitamin D3 and ask you the question, why did you get interested? Just briefly, I guess, interested in vitamin D3 in particular.
40:40
We already figured this out, right? We should know what vitamin D3 requirements are. Why are we doing this and how could it be helpful?
40:47
Well, the initial interest came from actually human research and experiments using mice as a model for understanding what happens
40:57
during inflammatory bowel disease. So intestinal inflammation, there's a lot of that and it was in the
41:05
interest of applying those concepts to a leaky gut under heat stress. So it looked like from this mice data that when you have higher concentrations
41:15
of vitamin D in the diet and you combine it even with calcium, you can potentiate in a way the response reducing inflammation and improving
41:24
health outcomes of these animals. So that concept should apply to the cow. There was not a lot of research at that time on vitamin D specifically on the
41:33
immune response. So we got interested in that for the heat stress. And I guess the the larger point if we're going to talk about nutrients is that we
41:42
could have an optimal concentration of nutrients in the diet. We we say that there's adequate levels now for the animal depending on the stage
41:52
of life, the production level of the animal etcetera. So we find those optimals and we have the things like the nathem or previously NRC
42:01
that tell us at this level you're not going to encounter any problems. Animals are healthy.
42:06
That is based on a few variables that you can measure at the time. Maybe it is production depending on the nutrient.
42:13
So if animals are producing well, like there's no issue. This is the the concentration and you should avoid deficiencies.
42:20
You should avoid excess formulate diet for the typical animal. And that's all well and good that the way the way it works is, is kind of like that.
42:29
If we took the example of vitamin D for a second, we think about it in,
42:34
in terms of how good it is for helping calcium metabolism. Like for example, we want to prevent hypocalcemia in a
42:43
lactation. That's a really good way to do it. Bone formation, etcetera.
42:48
The immune side is also part of it, but it's not often discussed or as far as I remember it was kind of new to me the the importance that I can have.
42:56
So we started doing that research keeping in mind that people already formulate diets to have higher concentrations of vitamin D relative to requirements or
43:05
recommendations. And in the case of of vitamin D is around 2 to 3X to two to three times more above
43:13
the requirements. And people do it, feed nutritionists, they know why they're doing it.
43:18
They could, they could be in relation during storage and there's variation in the intake of animals. So you want to guarantee that everyone is around that optimal even if they eat a
43:27
little bit less and you don't want to have that excess again. But it's not really optimized as far as I know for this nutrient or many other
43:37
nutrients that we are interested in for periods when the animal is stressed or
43:42
diseased. So say the requirement for stress, the requirement for disease states,
43:47
not any requirements for when everything is OK were acceptable, right? So maybe heat stress, the requirements could come up.
43:54
And this is something that we discussed previously, animals eat less. So let's say a 30% reduction under moderate hip stress,
44:01
animals are going to ingest less vitamin D and less of other nutrients that may
44:06
influence the immune response. So for that particularly important challenge, do they have enough?
44:12
Maybe we have to boost it, the concentrations in the diet and that you don't, sorry, you don't boost it by 30%.
44:18
That is accounting for the intake loss. You do it more, even more. So we have an experiment where we have gone to well, 4X in this one.
44:26
For example, in the heat stress experiment, we went up to 3.6 above the requirements.
44:33
And just briefly, we see that animals have lower rate of temperatures, lower respiratory rate. So there's an improvement in the conditions of the animals under heat
44:41
stress. So that would be the yellow group here. And what I'm showing in the graph is association of that temperature with the
44:50
within TNF-alpha I mean over time TNF alpha, which is an inflammatory cytokine on this
44:55
pathway that we can see here that responds to LPS It's also decreased the same as it happened for the rectal temperatures and
45:03
the respiratory rates on day 7 and day 14, there is a big reduction in the concentrations of the cytokine.
45:11
So that could explain the results that we have for the hyperthermia alleviation and
45:17
the respiratory rates. These animals are actually doing better. In this case, we didn't really see a response on
45:23
productivity, but we have data that show I think that the animal is doing better.
45:29
So we're helping cows with relatively small modification of the diet, maybe targeting a particular time of period
45:37
during the year to give this type of supplement. It would be the way to go.
45:43
And then we followed up on this on a different model. So let's not focus only on heat stress.
45:49
There's other scenarios where the animal can have endotoxemia so that LPS going into circulation.
45:55
So here we have a dose response experiment and the preliminary data that we have so far tells us that cows are the highest levels of vitamin D.
46:04
So for exterior recommendation have lower rectal temperatures during an LPS challenge, in this case, intermammally LPS challenge,
46:12
which is kind of creating a mock mastitis. You could do it in the uterus, different places where you could put the
46:19
challenge and it will tell you a slightly different story. But in the end, this how the immune response is being
46:26
modulated by your diet, in this case by vitamin D. We also see that these animals have lower reductions in intake and lower reductions
46:34
in productivity. We're yet to see what happens with the expression of these immune cells, somatic cell counts and all of these.
46:39
This is very fresh, fresh data that we have. But overall, what the story seems to be telling us is
46:45
cows do better when you boost their vitamin D3 in the diet, which some people do intuitively, I guess.
46:51
But there is confirmation here that in particular periods of stress, in this case heat stress or immune challenge, you could do something about it, correct?
46:58
I guess that's the take home for this. OK, I will. I will just point out now to the similarities that we have in terms of the
47:04
other parts of our research before we end up the Omega 3's because there is overlap when it comes to this, which is again the activation of the
47:11
immune system. So let's go to that. As we finalize maybe focus here on this path with the NF-kB pathway.
47:17
This is something that's going to come up also for the Omega 3's that you can see here is being blocked in a sense.
47:25
So cytokine production and some lipid intermediates that result from this cycloxygenase pathway are going to be different.
47:31
So that's the interest in the Omega 3's So when we talk about the omega-3 just briefly,
47:38
we're talking about things that the cow already has in their diet. For example, pasture, fresh pasture is a good source of
47:43
linolenic alpha, linolenic acid, but also some of the things that are actually the longer chain omega-3's or VLC's that you should hear from fish oil,
47:51
from algae, right. So those things in many animals, agreeing the cow seem to be good at reducing inflammation on two different sites,
47:58
the initiation of the response and the resolution of the response. So that's kind of like why we are interested in this and we both have some
48:06
data on this. So probably just finalize briefly discussing what we have found. I think that's, that's a good point.
48:12
The 2 are doing complementary actions. Sometimes they do the same, for example, for this pathway.
48:17
But I guess that's why we have some interest in doing follow up experiments where we have additive, the additive effects of both.
48:24
That's one thing that we want to really get into to get some funding for doing that. So maybe just briefly show that during heat stress,
48:32
we tried giving cows Omega 6 or omega-3 fatty acids. This was all amazing infusions.
48:38
So we got recovery of production by 2 kilograms around 4.4 lbs, something like that by giving just the Omega 3's versus the Omega 6,
48:48
both corn oil, basically the fish oil versus corn oil. When you give fish oil, you have four more pounds, right?
48:55
Tuna oil versus tuna oil. So Omega 6 versus omega-3 and particularly long chains, EPA and DHA.
49:02
So we get that alleviation of the rectal temperature increase to some point. It was around 1 Celsius degrees degree, which is a lot like 2 Fahrenheit, I think.
49:11
We, said that, yeah, it's like going from a fear of 104 to 102, correct.
49:17
So that's an important decrease. And on top of that, we see that is associated with inflammation.
49:22
So this is another indicator of inflammation that we mentioned earlier. So like polysaccharide, my new protein is decreased in these
49:29
animals compared to the animals receiving the Omega 6, Omega 6 in red, Omega 3 in yellow.
49:35
So that came with the increased productivity and changes in metabolism that we don't need to go into right now.
49:43
But insulin sensitivity was also improved. Yeah, we couldn't discuss that if there's any
49:49
questions, but it seems positive. I guess that's the main take home there. We just to finalize with my, my part of this is that we did similar
49:57
studies in which is not heat stress, but we basically do the inflammatory challenge with the lipopolysaccharide again and we can we can skip over this
50:05
just to finalize. So we compared algae versus fish oil versus a very prominent popular fatty
50:12
acid, which is oleic acid shown here is OA. And so these are potentially all beneficial for health in many animal
50:19
species. But what we saw here is a couple of important things. Algae, which is a good source of DHA is a very,
50:27
very good source of of DHA. As I said, increase milk yield, reduce rectal temperatures when the cows
50:33
were experiencing this heat of the inflammatory challenge and interestingly reduce the somatic cells. So in terms of milk quality also seems to be doing something because the
50:42
neutrophils, which are cells that are infiltrating into the milk actually are reduced in numbers. So it's telling us a story about this immune system freaking out a bit less and
50:50
that resulting actually in positive effects for the cow and for the quality of the milk that the cow is making.
50:57
And all of of that again accompanied by reductions in inflammation, which is borne out by other research in which we see that omega-3's
51:04
supplementation, particularly very long chain omega-3's. You can click on that, Daniel, for it's an animation I think reduces a
51:11
number of things related to inflammation. So it is, it seems to be going in that direction in which the diet, in this case Omega 3's can do something
51:19
to improve that. And that's true for algae or fish oil, but also flax seeds depending on the
51:25
style you look at. So very promising. I think stuff happening in this area now.
51:31
Agreed. I guess, Alison, we're done with this section with
51:36
everything, with everything. I guess I'm, I'm well, yeah, we don't have much time and we have very
51:43
good questions. So again, thank you so much for all these interesting presentation and all these important information for everybody.
51:53
So I'm going to start with the questions that we have here. So the first one is how can systematic inflammation influence feed intake?
52:02
And then go back, go back, please. Thank you. OK. How can systematic inflammation influence feed intake and exacerbate negative
52:11
energy balance in dairy animals? All right. So I guess the long, the short answer to that,
52:20
I should say is inflammatory signaling in the brain reduces appetite.
52:27
So that's a very predictable response. If there is inflammation, there's going to be a reduction in
52:32
appetite. If you get that appetite reduction in a moment in which the animal is already struggling to get enough energy, which is again the onset of lactation,
52:40
you're going to have a more dramatic situation for the animal. So you're going to make it spiral down more likely.
52:46
So yeah, probably that answers the question. It's just it's not a good combination. If you have an inflammatory challenge, that's going to reduce appetite for sure.
52:53
And we know that cows that show early reductions in appetite and we had that
52:58
slide somewhere, but every reductions in appetite tend to have a higher propensity for developing things like ketosis later on, right?
53:08
So that's again going back to the marker that you can measure 3 weeks before partition already inflammation showing there.
53:14
So you have to glow in and then the cow getting sick later, right? But that started somewhere far away when you could not see it.
53:19
So that's very important. It's going to make things worse in terms of appetite. OK, we have another one.
53:25
So the $1,000,000 question, what comes first, inflammation,
53:31
fat tissue mobilization or drop in DNDMI. And the other one is, and perhaps a better question,
53:39
how soon should we start assessing this physiological challenge?
53:44
21 days before calving, at dry off. I would argue that we should look at even before the dry off.
53:52
OK, Yeah, maybe let me start with a few things that that come to mind when when we think about this.
53:59
We have discussed this plenty with Eduardo because there's one major thing,
54:05
one major thing, there's the drop in intake around calving and the mobilization of hypostitia that is even greater in cows that are over
54:14
conditioned. And this is thing, these are things that have been on for a long time.
54:19
There's a series of markers before partrition that you could look at a different time, 7 days, 14,21 days, thinking of a maybe the end of lactation
54:28
as well, the previous lactation. That is a point that I, I would say it is also important to know
54:34
to characterize. But there's one thing that I really think makes a strong case for inflammation
54:40
coming first the, the chicken or the egg question is that there's also some data, for example, from Michigan State, from Brazil's group.
54:48
That's why I said, remember it was some observational data, but it showed that animals that had lower concentrations of vitamin D in plasma
54:55
before parturition. And I have to remember yet if it is 3 or 4 weeks before calving,
55:01
those animals were more likely to be sick in, in the postpartum period in early lactation.
55:07
And that was an independent marker, independent of other things. So a very good marker of the propensity to be sick later related again to the
55:15
immune system, to the immune system as probably we discussed enough today.
55:21
So I think the inflammation part seems to be key and the Andreas Contreras from MSU
55:26
data that I wanted to show as well, it says in my opinion that most cows that are really sick have an inflammatory issue.
55:35
It's not all of them, but the inflammation seems to be like the root of this. So now otherwise, I don't know if you, I will just add a couple brief point.
55:42
They all may be happening normally. All cows are normally going to redevelop ketosis to some extent that like all
55:49
mammals, any animal that makes milk develops negative energy balance and ketosis. So I would just point out that that's a normal response and it would happen and
55:57
maybe the drop in intake around calving that happens or parturition in other species, that's all to be expected.
56:02
What we could do is to try to measure early in advance so that we know which animals on top of these normal responses, physiological responses is going to get a
56:11
more dramatic negative response on a negative trajectory early. So the question was 2 weeks, 3 weeks, 6 weeks, at dry off.
56:19
Right now we don't really have a good answer, but we should be measuring trajectories for sure. So I would be an advocate to measure as early as possible because every time that
56:27
we expand that frontier, frontier to, you know, early, as early as possible, we find that these markers keep on changing early.
56:34
So I think that we, we need to answer that better. And I will put money on saying, well $10 maybe not one million that the
56:41
the further we go back and before parturition the better it will be at
56:46
least to know where we are. Yeah, OK. We have two more.
56:52
So, OK, you talk about fibrosis and reduction of in milk production in this part of the mastitis process we when we have first
57:03
infection, then inflammation and then fibrosis. Can you talk about the fibrosis please?
57:11
Also are there nutritional recommendations for cow with mastitis or to prevent mastitis?
57:20
Well, I, I will have to admit not knowing details to that level of depth that were required to explain the fibrosis or done an an
57:28
exacerbated chronic prolonged immune response is going to resolve resulting in
57:33
tissue damage. So we're talking about cells dying and that place being occupied by others,
57:38
which is a collagen like tissue that is part of what we call the fibrosis there. So that's as much as I can explain without reading,
57:46
being able to go much deeper. So that's something you could avoid to some extent, not by avoiding the infection.
57:52
If the if the environment is terrible, you cannot really avoid animals getting sick. You need to do good management.
57:57
But if you're there, what we're trying to make the case for is preventing through arming the animal with better defenses is going to be key.
58:06
So that goes to the nutrition part. So hopefully that's good enough. Quickly add to this, and I know it's not part of the question,
58:13
but it makes me think we're trying to also improve the quality of life of animals. So well-being is one concern of welfare.
58:20
So when they have something like mastitis and it develops well all the way to fibrosis, there's many stages. Of course, one of the things that we know is that
58:26
there is edema, there is inflammation, there is pain. And with some of these therapies, we can reduce pain.
58:32
For example, if we give the Omega threes, we're going to end up with a series of prostaglandins, for example, prostaglandin E3 that is
58:40
anti-inflammatory and it reduces the pain and feeling of the animal compared to prostaglandin E2.
58:46
So there's things beyond that that process that makes cows produce less.
58:52
And it's also the welfare part. I think we can do a lot with that in in this type of scenario where we help cause
58:59
with nutrition. OK, OK. Well, thank you so much. And just for outside research, what are the practical applications for
59:08
managing inflammation? What do you guys think? So strategies that we could use tomorrow at the farm.
59:16
I guess that's kind of let me start. Let me start with one point before you get there. The first thing that we didn't really mention a lot,
59:24
we would remove this light because of time, is management doing the basics, well with many farms do already, It could be as simple as not feeding an
59:32
animal they've same feed for two days, you know, or three days in a row during the summer months, you know,
59:38
like simple stuff like that, which sometimes happens. It could be social interactions with proper group management.
59:45
There's a number of things that we know already and we don't need this research to tell us that you could do better for the animals.
59:51
And that all seems to result in reduced inflammation. So inflammation is going to be normal, but you don't make it go as wild if you
59:57
if you actually handle the basics. Well, now we're talking about something beyond the basics, which is saying, OK, give more Omega threes and and we can
1:00:06
discuss because this is a costly thing, or give more vitamin D3, probably a more cost effective thing to do.
1:00:11
But there is a number of things outside of the normal about the normal has to be the the regular management has to be on point.
1:00:19
That probably would be the first thing that we should fix the base of that pyramid before getting to the more expensive stuff.
1:00:25
That's my take home I guess. Agreed. OK, well let's go to the next slide.
1:00:31
Thank you so much. Join us next month for the Badger Dairy Insight.
1:00:36
On August 19th at 11 AM, our topic will be adopting and evaluating mechanical ventilation in dairy barns, a calculator guide.
1:00:45
Find more information at the Wisconsin at the UW. UW Madison Extension website you can go to the next one is scan the QR codes.
1:00:58
We have here three different QR codes. You can go the first one for the dairy website.
1:01:03
You can find ton of different information research. The next one is the Badger Dairy Insight that you can sign in for the next
1:01:11
following sessions. And the third one is for the Dairy E-newsletter. So you have it monthly.
1:01:17
All this information about what is happening in the dairy industry and the dairy academia in the last one.
1:01:24
Well for addition information and unbiased please the university have
1:01:30
extension dairy program online. So you can go to the dairy, go to the next one, go to the dairy.
1:01:38
extension.wisc. edu or find us on Facebook at Extension
1:01:43
agriculture. Thank you so much, everybody to be here. Thank you, Daniel. Thank you, Eduardo.
1:01:48
Really appreciate your time and thank you everybody for stay here for three more minutes.
1:01:54
I hope you guys enjoyed these big conversation. I know we just missed some things, but that was very, very important.
1:02:02
Thank you so much everybody. Thank you. Yeah, and you guys are the best, the best brothers, twins ever.
1:02:09
Thank you. And OK, thank you so much. And have a great day, everybody. And have a beautiful evening.
1:02:16
Thank you. Bye. Bye.
1:02:25
OK. And that's it. Thank you so much. Good. All's done. Thanks.
1:02:30
We we tend to talk a lot. We try to measure ourselves. But anyway, it's OK.
1:02:35
It's OK. I I think, I think, Yeah, I think it was good. Daniel. Daniel needs to talk a little bit more.
1:02:42
I guess he was a little quiet. No, I was trying to be the host to Eduardo.
1:02:48
Oh, OK. OK. I can see that now.
1:02:54
OK. Well, thank you so much. And we can talk later. Yes.
1:03:00
Awesome. Thank you for having us again. It was a cool exercise, so I appreciate. Yeah. No. Thank you so much. Have a great day.
1:03:06
You too. Bye. Bye. Bye.