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Industry hired one of our houses to
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Thank you all for coming and enjoy your

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For research this year very good
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Good morning.

It's a real pleasure to be here today to
be able to talk to you about my research

my lab is interested in the diagnosis and
the treatment for

early stage diabetic retinopathy and
today I'm going to start with a background

about diabetic retinopathy and then focus
on early detection of this disease so

the tests that we're developing
to measure retinal function and

then describe some fluorescent probes
that detect reactive oxygen species and

then I'm going to talk to you about some
early treatment interventions that we

are testing including exercise and
dopamine.

So diabetes is a chronic disease
of high blood glucose levels and

as I'm sure you know there's two main.

Type one where there's little or
no insulin from the pancreas or Type two

which is just poor regulation of insulin
and of course obesity is a risk factor for

that so the prevalence of diabetes
is increasing at alarming rates and

I'd like to does demonstrate that to
you with this map from the C.D.C.

so this on I'm going to take you through
five different years we are mapping

the percentage of individuals who
have diabetes so you can see it

goes from zero to six and then the darkest
color here is over eleven percent so

I think it's most useful if you just
pay attention to the darker colors so

this is two thousand and
four this is two thousand and

five this is two thousand and
six this is two thousand and

seven this is two thousand and
eight this is two thousand and nine.

So I think it's really striking and
alarming at how much of

an increase that we have in
the prevalence of diabetes in the U.S.

and particularly in the south
where we are right now.

So my job is most interested in
a complication of diabetes called diabetic

retinopathy It's a leading cause of
retinal disease and vision loss in the non

elderly about thirty percent of people
with diabetes have diabetic retinopathy

not equates to about four
point two million adults.

And about six hundred fifty five thousand
with vision threatening diabetic

retinopathy now diabetes related
blindness cost about five hundred

million dollars annually and a big portion
of that is the fact that these are working

age adults who no longer can work so
the C.D.C. has some prevention tips for

diabetic retinopathy they include good
control of blood sugar and blood pressure

levels and that's been shown to delay
the onset of diabetic right now.

Bothy and also early detection and
treatment of eye disease and

of course that's what I'm most interested
in and what my lab is focusing on.

So how is diabetic retinopathy
diagnosed right now

well it's clinically recognized
as a vascular disease and

it's diagnosed by these vascular
changes in the fundus and

macular edema so
these are fundus photos of the eye so

this is looking into the eyes
through the pupil and

you can take these pictures of and
see the vessels that are here

the clinicians would notice haemorrhages
on these little spots called cotton wool

spots that would indicate that
there's leakage in the vessels or

any of askers ation new vessel growth and.

I would propose that this is actually mid
to late stage disease that the disease is

actually been going on for
quite some time when these.

Vascular changes are visible and
these are basically irreversible there's

once these changes are happening
we can't reverse them so

these are some other examples of
things that are happening the loss

of parasites on that line the vessels
that causes the leaking this and

the formation of micro aneurisms so.

If this is mid to late stage disease
we really want to be able to detect

the disease much earlier and

there's increasing evidence that in
addition to the vascular changes that

are going on there's also
changes in the retinal neurons.

So my job is asking Is it possible
to detect diabetic retinopathy at

earlier stages and you might aswell What's
the advantage of doing that well you

could have more aggressive insulin control
by the visitation and the patient so

it's a patient knows they are headed
towards vision loss they might be more

motivated to control their insulin.

And their glucose levels.

You could.
Then have treatment with current

neuroprotective agents so a lot of these
no protective agents are going to work

best if they're started earlier and

you can also develop different
kinds of from logical agents.

So I don't want to oversimplify this
disease it's actually very complex and

there's a lot of different processes
that are at work so this is

a figure from the New clues review paper
that she published in two thousand and

seven and you can see that this process is
very complex it starts with hyperglycemia

there's a number of different
pathways that are involved

the near bastardization is often
described by this increase in that Jeff

we have oxidative stress as a major
hub of a lot of these pathways

we have mitochondrial dysfunction
that's happening and cell death and

all of these is leading to retinopathy so
you can imagine that if we can

try to stop any of these pathways
early that that would trigger

would help us in slowing
the progression of the vision loss.

So.

But that said there's probably a point
where there's there it's reversible that

there's too much pathology that's gone
on and we can't reverse it so again this

is a study that was done by renew Colusa
group looking at mitochondrial D.N.A.

levels and this is in diabetic rat so
there's normal rats and

their level of mater contrail D.N.A. and
then she has groups that are either have

poor glycemic control or
good glycaemic control for

a full year so this would be the ones
on good glycemic control and

you see when they do have that then
they have good mitochondrial D.N.A.

levels and if they have poor glycemic
control then it's very much to increased

Now this is the group that I
think is most interesting this.

Group started out with poor
glycemic control for six months and

then the second six months they
had good glycaemic control.

And this I like to emphasize is often what
you find in patients where you'd have

poor glycemic control they don't
know they have diabetes or

maybe they're just not paying
much attention to it and

then they have a period where they begin
to try to control it but you can see that

this group of rats here they don't
they still have mitochondrial D.N.A.

damage right so
the just because they started to have

a good place in the control
didn't prevent that damage.

So when we think about this disease
process we could think about it in stages

where we have the first as an adaptive
stage where we have some oxidative stress

neuronal dysfunction and
perhaps even some mitochondrial D.N.A.

damage that's all going on but

that's adaptive our body can he you know
take care of that but then we move into

a stage of early pathology where you
still have these things going on but they

become reversible they also reversible
even with some vascular dysfunction and

then we go to end stage pathology
where we have this vascular leakage

the need of askers ation in the blindness
and this is irreversible damage and

this is really more of the stages that
we're clinically diagnosing this disease

so ideally we want to look
at early intervention we

want to be able to detect this
disease in one of these two stages and

then intervene so we can either
plateau out this pathology or

in fact even reverse it back
into the adaptive stage.

All right so how we could.

Diabetic retinopathy So
I first need to acquaint you with

a task that we do called an electro retina
ground it's a little bit like an E.K.G.

for the eye we have an electrical
signal that we're going to measure

in response to a flash of light and it
creates a very characteristic way form so.

We measure it using
just a simple electrode

that's laid on the surface of
the cornea and then the animal or

the person is exposed to a flash of light
and in response to that flash of light

we get a full field potential that can be
recorded on the surface of the cornea and

this is what these potentials look
like this would be a dim flash and

then you can see that as the Flash
intensity gets brighter the response gets

larger and it gets faster and it's very
characteristic with two way forms and

a wave and a B. wave and then these little
Satori potentials now the main thing

that I'd like to emphasize to you
today about this is that we can

probe different retinal pathways depending
on what Flash intensity we use so if we're

using doing flashes then we're only going
to be stimulating the rod pathways but

as the intensity gets brighter we're
going to actually stimulate both Rod and

cone pathways.

So this is important because the ear G.

has been found to reveal retinal
dysfunction in diabetic patients and

the first reports of delays were way
back in the one nine hundred sixty S.

and fact this was using very
bright flash stimuli and

looking at these little wavelets called
Also toy potentials so here are some

examples of those in patients
a patient that has no retinopathy and

we're looking at these little wavelets
here and then these are different stages

progressively getting worse
of diabetic retinopathy and

notice that they also try potentials get
much smaller but there's also a delay and

you can tell that the wave by
comparing the peak of that wave and

I've drawn the line down the waves
helps you to visualize that and

you can see that there's a delay
with each and every stage so

this is very characteristic there's many
studies that have pointed this out but.

It hasn't really been adopted for
clinical use.

So we wanted to know what the earliest
functional delays are in diabetic

retinopathy and we wanted to explore
this response a little bit further so

we're using a diabetic model
it's a type one model using

S T Z and long Evans' rats so
struct its own listener as T.-Z.

kills the beta cells in the pancreas which
results in hyperglycemia we consider

the animals hypoglycemic when the glucose
levels are above two hundred and fifty and

we give the animals an insulin
pellet to prevent weight loss and

then getting too sick and
then we're doing this dark adapted.

So this is what I am all
responses look like so

I'm showing you a set of responses
from control animals as well as

diabetic animals across
different time points and.

I'm also showing you a response just to
a dim flash over here which is only going

to stimulate the rods as
well as a bright flash

that's going to stimulate both
the rods and the cones so

what I'd like you to notice is that here's
your control response with this little

O P one wave that's marked here
with the line and you can see in

the diabetic animals even as early as
four weeks after having the S.T.C.

injection already have a delay so this is
the same peak of that also Tory potential

and it's significantly delayed it gets
even more delayed at eight weeks and

even more are delayed at twelve
weeks now in contrast in the bright

flash of stimuli we see that there really
isn't a delay in the response until we get

down here to the twelve week time point so
this seems to indicate that the rod

driven in a red no response is actually
much more sensitive to the hyperglycemia.

Instead just that this is a dim flash
stimuli may actually be a good screening

tool so let me just illustrate
this in another way so

this is another group of rats
that we took out much further and

this is the same sort of way forms that
I showed you before showing the delay

in the peaks it with the dim flash but
not the bright but then let me show

you prod it a different way this is
an intensity response function so

here is our implicit time plotted against
the flash intensity from dim to bright and

you can see even at seven weeks
this is our diabetic animals and

here's our controls in the dotted area and

you can see that the diabetic animals
are already beginning to show delays

just in the dim flashes that are only
going to stimulate the rods.

And this becomes significant and

more progressive if we go from fourteen
to twenty to twenty nine weeks and

so this really does seem to be
a progressive effect that we think may

be predictive of the later stage
dysfunction that's happening in

the neurons as well as potentially
the vascular changes that are going on.

All right so this is our one go ahead but
how is this relevant to the clinic

Well when we test patients in the clinic
and we want to look at ASA toy potentials

we don't use Dim flashes we only
use bright flash stimuli in fact

in a clinical year gee we really minimise
the amount of flashes that we're giving

the patient to minimize any discomfort and
so we typically there's only one dim and

one bright flash that's that's
presented and also tried potentials

are only examined with the bright flash so
we did an experiment where we added

additional dim flash stimuli to
see if we could to tap the early

diabetic retinopathy and
these were our treatment groups are so.

Groups we have control healthy and vigils
we have individuals that have diabetes but

have no indication of what not to see
when you look in to the fundus and

then we have patients that actually
have diabetic retinopathy and

you can see here are our
numbers are fairly small.

But even with that we're able to see
a difference in important difference so

here again I'm showing you an intensity
response function implicit time plotted

against Flash intensity and
we have two additional test flashes This

is our test flash that's on the dimmer and
this is a little bit brighter here and

I'd like to draw your attention to
in particular the response to this

test flash so
you can see the controls here and

you can see that the diabetic in
the blue is certainly significantly

different which you'd expect we know
that they have written opposite but

importantly the individuals that hadn't
yet been diagnosed with right not to see.

In using clinical fundus for

Tiger Feet are showing this significant
delay so we think that a D.M.

test flash may actually
be a good screening tool.

Right so that it would be one way that you
could do tact diabetic retinopathy but

how about it using another approach so

another approach could be using hydro
signs these are fluorescent probes that

are can be used to detect
reactive oxygen species so

on these were developed by near him I see
and cause it can do when they were here.

Attack and

there's a number of people about had that
of use these they use them and so culture.

With the potential to use them in vivo and
here on this is an experiment where

they're looking at little polysaccharide
which is a septic shock model and

you can see this animal here.

Is just I say only Plus this is this di
this hydro site seven hundred sign and

this animal is the one that has
the L.P.'s The septic shock and

you can see that there is an increase
in the fluorescents because as this

molecule the spider signed on binds
to the reactive oxygen species

it undergoes a configuration and
it actually fluoresces So

this makes a really valuable
tool to detect oxidative stress

it appears to be non toxic to the animal
models it's highly sensitive it seems to

be stable and it reacts fairly fast.

So the I is a wonderful tool for

something like this because you
can do a lot of different imaging

non-invasively in the eye so
we wanted to see if we could use hydrogen

cyanide to detect retinal
oxidative stress and so

one of the beauties of the hydro signs is
they actually have a number of different

varieties if you will that have different
excitation and emission wavelengths and

so we are most interested in this
one that has excitation at seven

hundred seventy four on animators and
emission at seven hundred eighty nine and

the reason is because it's very similar
to in the Sinai in green which is

a very common filter that's
used in up down the equipment.

And so we could actually visualize
this style without adding any

additional filter to what's already
existing in the clinic and we found that

we can use a scanning laser up down
the scope to to visualize the dye so

we went ahead and did a validation
experiment to see if this would work and

to do that we're using a right
induce retinal degeneration model so

if you expose the animals to very
bright light so this is a series.

L.E.D.S. that we put on top of a cage and
you can see a whole set of

these cages here with the lids on them
what happens is that this will actually

cause the photoreceptors to degenerate
over time and here you can see that this

is our intensity response function looking
at amplitude this time from that your G.

and you can see that the bright light
exposed animals have much smaller

amplitudes indicating they have
loss of function and if we look

at the number of photoreceptor nuclei we
also can see that the photoreceptors have

degenerated after bright
light exposure so.

Using this model we went ahead and
we exposed some mice

to different durations of toxic
light either zero one two four or

six hours we then injected the animals
with the hydro science and.

We visualized the funded using
the as a low with A I C G filter and

that's what you're seeing
here in the black images so

this little ring here is the fluorescents
that's formed when the hydro Sinai and

binds to the reactive oxygen species and
you can see it six hours this nice.

Fluorescents this.

Series of panels here is
simply reversing the color and

that allows us to see the area that's
actually for us in a little bit better and

then we've plotted that here to quantify
it so here's our mean florescence that

corresponds to these figures you can see
that we have a nice linear relationship or

if we look at the area of hyper for
us and here.

So.

We also were able to do a sections
of the right now and this hopefully

you can see the red label in here so
this is actually the hydro sign on.

And we can see that it is in the inner
segments of the photo receptors which is

exactly where we would expect
it to be in this model so

this looks really promising for
a marker for

oxidative stress oxidative stress for
retinal disease and

we're very anxious to now start
moving this into our diabetic model.

Right sir let me take you through a couple
of our treatments that we're testing.

To try to intervene very early
in diabetic retinopathy So

the first one is exercise so
as you know exercise is protective and

rehabilitative it promotes no
non-survival and acts on regeneration and

stimulates neurogenesis you may have
heard there's a lot of excitement

that it improves cognitive function
in patients that have Alzheimer's or

Parkinson's or LS And
even in healthy age in young individuals

it can enhance cognitive function such
as memory so these are all very exciting

studies and we have.

Been hearing about these I'm wondering if
in fact exercise could also be no more

protective in the eye and so we've done a
number of experiments to test just that so

this is just a brief overview to show
you that treadmill exercise them protect

the retina their function and structure
after right induce retinal generation so

we took mice and we ran them on
a treadmill for two weeks and

then we exposed them to the same toxic
light that I just told you about and

when we do that you can see this is the
function here of the two groups exposed

to D.M. the control groups here is on
right right in active so they have

a significant decrease in function but
when the animals of are on the treadmill

they have a significantly larger amplitude
response and that's just if a sigh.

It's here showing you the bright treadmill
group versus the bright inactive group so

they have almost twice as much
function as the bright inactive and

we see the same sort of trends when we
look at photo receptor numbers so here's

a photo receptor numbers structurally
they're much more preserved when they're

running than the groups that are not and
this is the quantification of that.

In addition we've done some experiments
where we looked at far interior we

are running in an inherited generation
model so here I'm showing you a measure

of visual function called spatial
frequencies threshold that we measure with

optical tracking that I'll tell you about
a second with little bit more detail but

the take home message here is that in
comparison to our rat type animals

that have very steady thresholds
across time this mouse

called the R D ten mouse has a progressive
degeneration and you can see it here and

these are the inactive animals but when
we give them wheels to run on they have

significant preservation of their
foot receptor and significant.

Visual function preservation.

All right so we wanted to see if treadmill
exercise was also protective in a rat

model of diabetic retinopathy and so again
we're using this as a type one model and

we're confirming hyperglycemia we
know it's above two hundred fifty and

there were exercising the rats on
the treadmill for thirty minutes a day

just for five days a week at fifteen
meters per minute so I want to emphasize

that this is not really that stressful for
the rat This is not very fast and

it's not every day it's only five days
it's a short time only thirty minutes and

then we're measuring by no
function using that your G. and

we're also measuring visual function
using this optic kinetic tracking and

so here you see that this is
a virtual system consisting of four.

Puter monitors where the the animal
sits in the center of those monitors and

the monitors create a virtual drum
that rotates around the animal and

we can change the spatial frequency
the width of the stripes here or

we can also change the contrast of those
stripes so for this experiment we have

four treatment groups and in active
control tried the treadmill control and

then two diabetic groups one that's
inactive and one that is on a treadmill.

So when we look at these animals we
find that the treadmill exercise is

beneficial So this is looking at this
also trying potential response again

here's our control groups here you can see
the diabetic animal who has the delay that

we've talked about and when we run these
animals on the treadmill that delay

is decreased maybe it's a little easier to
see in the quantification down here are to

control groups the significant
delay in the diabetic inactive and

the protective effect with
the treadmill exercise

now we can look at this using another.

Planet are looking at another type
of stimulus called flicker and

this isolates actually the cone
pathways and it's often often used.

Clinically and

we can here see this nice delay in
the diabetic animals that are inactive and

a nice significant preservation in
the diabetic animals that have exercise so

there seems to be having
a significant benefit to the retina.

And then we also looked at visual
function so here we're looking at visual

acuity thresholds across
the weeks of S.E.Z. our control

groups are at the top there very stable
and then you can see that the diabetic

animals that are inactive are showing
a decrease and the diabetic animals

on the treadmill are showing some benefit
although this didn't reach significant

between these two groups however in
our contra sensitivity measures we do.

Significance where you can see that
the treadmill group has significantly

better contra sensitivity than
the animals that did not have exercise.

So we wanted to investigate what
the mechanism of this exercise

benefit is and one potential.

Candidate is a brain Dr neurotrophic
factor and so to look at B.D.N.F.

or to potential rare we gave
the rats B.D.N.F. track B.

receptor agonist called an A twelve and
we would give this to the animals two and

a half hours before they started running
and this is because this is allows

kind of the peak activity
all of agonist and

it's important to note that this
agonists is specific for track B.

but does not affect track a or track C..

OK Thank you.

And when we give these animals
the A twelve it seems to

block the a fact so here I'm showing
you results of the flicker in your G.

and you can see that this is all diabetic
animal So here's our interactive animal

Here's our animal with that active and
has the vehicle so

you can see that it has a faster
implicit time it's better but

then when we use the a in a twelve with
the active group you can see that it

completely blocks the response and it's
not any different than the control groups.

We can see a very similar type of response
if we look at the contrast sensitivity so

here we have the inactive diabetic group
with the vehicle Here's the active group

that has improved contrast sensitivity and
then when we use the A N A twelve with

the active group we get
a complete blockage.

Right so that is one potential
mechanism but exercise like diabetic.

Diabetes is very complex there's
a lot of stuff that is going on and

it's possible that there's other
mechanisms for the protection and so

one of the other things that we're looking
at is the potential role of dopamine so

definitely it is important for
visual function and in fact

it's been shown that different dopamine
receptors are needed for different aspects

of visual function such as spatial
frequency and contrast sensitivity.

In addition we know that don't
mean is decreased in S.T.

zeroed in models and it turns out the
dopamine is that is decreased in the on I

but it's also decreased in other parts
of the body in diabetes as well and

importantly don't mean seems to
be modulating with exercise and

it's depended on the exercise intensity.

So first I want to show you that
if we give diabetic animals.

Which is a precursor to dopamine we can
actually prevent those early changes so

here again I'm showing you the last twenty
potentials this is that dim flap and

the bright flash response if you can
see the delay that with the D.M..

With a dim flash in the diabetic
animals and when we give them L.

dopa we can consume significantly
preserve that response and

here's the quantification of that.

And with the bright flash we
see as a hint of the same sort

of response even though
it isn't significant.

And similarly if we look at the visual
function looking at visual acuity or

contracts and stiddy we see some very
significant effects when we give L.

dopa So here are control groups and
then we have our diabetic group

on this just given vehicle and you can see
the decline that we've already noted and

then we give them L. dopa we have
signals significant preservation.

Contrast sensitivity we also see
significant preservation in fact

the animals with the L.

dopa are very similar to the controls
until this last time point so

it appears that dopamine is
an underlying mechanism to

this dysfunction that we're seeing in
the early stage diabetic retinopathy but

we think that exercise made it one way
to increase the dopamine levels so

here I'm showing you better
mints of dopamine and

don't pack that had been performed by
the OF own lab so this is the dopamine and

packed a pack is
a metabolite of dopamine and

you can see the levels of dopamine in
the inactive in the just the treadmill

control and then the diabetic animal
has a significant decrease and

then when we look at the animals
that had treadmill exercise

they have significantly more dopamine and
pack.

So an important question that we have
is does the track the antagonist

treatment would actually
alter the dopamine levels and

that is something that we're
trying to determine right now.

Right so what kind of conclusions can we
draw from these results Well it appears

a dim flash also try potentials reveal
early retinal dysfunction in diabetic

retinopathy in both rats and humans
treadmill exercise preserves visual and

retinal function and early stages
of diabetic retinopathy I don't.

Know a protective in diabetic
retinopathy and both B.D.N.F.

and dopamine signaling may undergrad
the protective affects of exercise

in D.R. So based on these conclusions

where are we headed next well one of
the things we'd like to know is whether or

not these same functional defects
are happening in a type two diabetic model

of course Type two diabetes is
much more common than type one so.

We're looking at a non obese type two
model called the goto cause Iraqi rat.

We of course want to know whether or

not those hydro signs can detect reactors
oxygen species in diabetic retinopathy

and we're also working to translate
our findings to the clinic so

we just received a small pilot grant from
the Department of ophthalmology at Emory

to look out a small group
of human diabetic patients

to see if our early detection methods.

Sed and if treating with doping mean
will actually change their dysfunction.

So finally I'd just like to acknowledge
on the many people in my law that have

contributed to this work
are collaborators here.

C.V. and honor is the center for
visual and cognitive rehab that's over at

the V.A. that I'm a part of and
a lot of the exercise work was actually.

Inspired by the work being done
over there by these folks and

of course to acknowledge
our funding thank you very

much.

So.

That we're giving as
a precursor to mean we're just

giving it systemically as an IP
injection You can also give it lonely so

you can actually mix it in with
their water and give it that way.

So.

You know people often associate L.-Dopa
with like the levodopa drugs that

Parkinson's patients get which
have a lot of side effects

we don't see any side effects in our
animals and you know I am actually

thinking a lot about this because of
our little human study I'm not sure

that there's really too much
evidence that levodopa lol.

Doses actually has many side effects for

healthy individuals individuals
that aren't Parkinson's patients so

probably the patients of course
don't have the neurons and

that So that's a whole good reason
that you're giving them the.

But that also changes or dopamine
receptors profile in their expression and

then when you give it so there's it's
really it just becomes very complicated so

a lot of the side effects
that I think we see and

patients that have P.D. may be
somewhat due to their disease and so

hopefully if we were giving it to
other individuals we would see those.

Yes.

Yes I would say it appears but
really there has not been an extensive

examination of that because it's hard
to detect are less right it's hard

to detect on oxidative stress so there's
actually a number of retinal diseases that

have oxidative stress is part
of that disease process so

I am hopeful that using the hydro signs
non-invasively in our animals where

allow us to trap the level of our last
through the progression of the disease

which would be really informative to
understanding how this pathology actually

progresses.

Yes Yes absolutely absolutely So
I think it

makes total sense that you would use some
sort of antioxidant agent and that's

something else that we're investigating
in the lab but there's many out there so

I think this is kind of the beauty of if
you can detect the disease much earlier I

think it opens up the window for all kinds
of things that could be protective but

many of the neuroprotective
agents that we test in the lab

were all like my experiments I showed you
we can test super early right but then we

get to the clinic and we say OK let's test
I'm we're not to talk to the disease so

early and so they're not nearly as
successful and so if we can back it up and

actually detect it much earlier a lot of
the newer protective agents whether you're

talking about exercise or an antioxidant
you know a multi vitamin type

formulation are a really non toxic
are not that big of a deal to to do and

so the patients could really benefit from

that.

OK.

Well.

Thank you.

Right.

So the exercise question first so
the exercise that were suggesting.

That our that our data suggest might be
beneficial is actually like a rock for

a person so the C.D.C.'s you know is is
suggesting that people just take a walk

every day and it doesn't have to be you
know a race walk it doesn't have to be

a marathon pace type of a you know you
have to be a marathon runner to benefit so

you know I don't think that
there's clear evidence of exactly

what type of exercise is most beneficial
now and that's something that's that's

a gap in the knowledge in the field and
something that certainly at the you know

what we're talking about that like how do
we address that it's really important.

Elderly people can certainly exercise so
one of the things that Joe Nocera in

the C.V. and on is doing is he has studies
that are just looking at aged healthy

individuals exercising in the benefits of
that to their memory they do great and

this is they actually are doing a spin
class so they're you know on bicycle so

it's very safe they're stable there's no
concern about them falling that kind of

thing they're monitored very closely and
because it's a class type of environment

they're actually very good at coming and
so they actually stay with the program as

the dropout rate is extremely low so
all that's really positive I think that

if we do it right I think people
might actually sign up to do that.

So your other question about
the comparison of the techniques

I might actively try.

I did do that in the lab right now trying
to compare determine what's most sensitive

what makes the most sense to actually
try to push forward in the clinic so

you know I could spend another half hour
just talking to you about what I think

was is Bast what the limitations are there
certain limitations to certain things

that your G. is done mostly right now and

with a big gone spill device
that not many places have and

so I'm very excited about a handheld
device that a company has right now

that you could just hold in front of
the eye and use a skin electrode and

we're getting ready to test that right now
if that can do the same thing that this

other one does that's huge that's you
know really allows us to move into

outpatient clinics and other places that
could could really use the screening

so.

Thank you.

So.

We haven't done that yet and
we should a sudden know myopia question.

Yeah it's a good question but
I don't know.

So maybe part of the outdoor
activity that people are showing

is beneficial to children is actually
partly due to exercise I don't know but

they haven't shown an exercise component
you know the questions I didn't seem to be

correlated with that protection a deceives
to be the bright light exposure so

we'll see.

Thank you.