[MUSIC PLAYING]
MICHAEL KLAG: Good
evening, everybody I
just wanted to take a
moment to welcome you
all to tonight's symposium.
It's going to be an
exciting evening.
My name is Mike Klag.
I'm the Dean of the school.
And as everybody knows,
this is a symposium
in honor of George Graham.
And, in honor of him, but
then in honor also of two
outstanding individuals,
our own Carl Taylor and--
I guess Nevin Scrimshaw
is in a taxi, right?
And hopefully it's a taxi who
knows where our school is.
So my only job, and
after welcoming you,
is to thank everybody who
was involved in this evening
and making it a success.
Our folks from External Affairs,
Monique Forbes-Dickerson,
and everyone else.
And to acknowledge
and compliment
Keith West for
putting this together.
And Keith, as everybody knows,
is a professor in our school.
But not just any professor.
He's the George G.
Graham Professor,
and a former student
of Dr. Graham's.
So he's our first
speaker for tonight.
I'd like to welcome
Dr. West to the podium.
[APPLAUSE]
KEITH WEST: Thank you Dean Klag.
And allow me to extend a very
warm welcome to everyone here,
distinguished visitors, fellow
faculty students, staff,
guest speakers.
It's a very special evening
for a lot of reasons.
It's an intersection
of many points in time.
It's the third Graham
Lecture, in honor of George,
but it's also the Inaugural
Endowed Lectureship
in Dr. Graham's
name that has been
made possible by a generous
grant from The Middendorf
Foundation here in Baltimore.
So that's special all by itself.
And then it happens to
be the 40th anniversary
of the publication of WHO
Monograph on nutrition
and infection--
Interactions of
Nutrition and Infection--
that was published by Nevin
Scrimshaw, and Carl Taylor,
and John Gordon 40
years ago, plus or minus
some standard error here.
It was in 1968.
But as Klaus Kraemer--
I was speaking with him
at Sight and Life, in EB,
a few days ago-- reminded me,
because I was lamenting that
we're really one year off-- and
he said, don't worry about it,
it's the 50th anniversary
of the publication--
the 1959 publication--
in the American Annals of
Medicine on the same title,
nutrition--
Interactions of
Nutrition and Infection.
So it's a 40th, plus or
minus, and it's exactly--
it was March of
1959-- it's exactly
the 50th anniversary,
plus 23 days,
of the anniversary
of the publication
of that lead manuscript.
So I've probably
gone off of my slides
already because I get up
here and I start to chat.
And I'm so excited, I can
hardly speak, as it were.
I've been told that I sound
like Barry White today.
That I should be speaking at
some club, rather than here.
But let me say a few words
about Professor Graham.
He was a Professor of Pediatrics
and International Health
at the School of
Medicine, and here
in the School of Public Health.
He was the founding
director of what
was, for years, the only
division of Human Nutrition.
It was the only division in
the Department of International
Health for a number of years.
He was the first professor
of human nutrition
within the department.
He founded the
Institute of Nutrition
in Lima, Peru in 1961,
where he was working
for years beforehand at the
British American Hospital,
and realized that there was a
lot of malnutrition that needed
to be addressed, that
needed to be understood,
that needed to be treated,
and needed to be prevented.
And so he set about to set
up the Institute of Nutrition
in Lima.
And as its founding
director, which
today stands as one of
the leading nutrition
institutes in the world--
and from where one of our
speakers this evening,
Dr. Claudio Lanata
is a professor
and has traveled all
the way from Lima
to be with us this evening.
Dr. Graham received many
awards and had appointments
on advisory boards.
He was known for his opinions.
He was outspoken.
He was passionate.
And his real his
insistence on evidence--
doing the talking,
rather than people--
earned him many accolades,
and many friends,
and many enemies, and
many people in between.
You had to listen
to Professor Graham
when he spoke because he had
authority behind his voice.
He was a member of the
National Academy of Sciences.
He was on boards with the NIH.
He was on many different
boards of the American
Institute of Nutrition.
He gave congressional
testimonies
about the dangers of
America becoming obese long
before the current epidemic
that we're currently--
that we're facing.
He was a voice calling in
the wilderness at that time,
saying that America needed
to change its eating habits
in the 70s so it would not be
facing an overweight epidemic
in the new Millennium.
He was the-- he received
the Joseph Goldberger
Award from the American
Medical Association.
The Borden Award from the
American Academy of Pediatrics.
These are well-known
nutrition awards.
As well as the E. Leon Garcia
Award from the Pediatric
Society in Peru.
He was a teacher, a mentor.
He was very concerned
about the school--
about the Department of
International Health,
the Division of Human Nutrition.
He had a great
deal of foresight.
And he was the world's
leader in figuring out
how to feed infants
and young children.
His research in Peru stands
even today as citable references
30 years later, 40 years
later, about the consequences
of early malnutrition,
and the benefits
and the interactions
that are observed when
young children are fed
different kinds of diets
in their infancy
and early childhood.
He published over
250 publications.
So he is one of our Hopkins--
he's one of our tall trees
in the Hopkins forest.
And we have a legacy that
we are building in his name,
beginning with the installment
of the George Graham
Professorship in 2005--
for which he was here--
from which funds from
family and friends of him
allowed that to happen.
And it is a lasting tribute
to his contributions.
We've had the George Graham
Professorship Lecture.
I was told I could not
call it a Lectureship when
we started in 2006 because
it was not endowed.
It was coming out of
the Professorship funds,
and so it had to be called
a Professorship Lecture.
And that's what it was for
the first two lectures,
given by Ken Brown in 2005,
and Bill MacLean in 2007.
But now we have a slightly
different landscape.
We now have a
Lectureship in his name.
And this is another tribute to
his stature and contributions
here at the school.
So this is the first
year for that occasion.
And it's a wonderful event
to be then commemorating
the 40th anniversary of the
WHO Monograph on Interactions
of Nutrition and Infection.
We have-- that
has been published
in a number of
languages over the years
and really has
served as a platform
for understanding what we
knew about this interaction,
up to that point in time.
And it has served as
a source of vision
for guiding the research over
the past 40 years and beyond.
It's one of those
special publications
that we have all read
and been familiar with,
and we're very thankful
for it being written.
And I just point out
that it was really
50 years ago that the first
publication with this title
came out from Scrimshaw,
Taylor, and Gordon.
So we have Charles Stephensen
talking about the effects
of malnutrition on infection--
the first part of this
vicious cycle, as it were--
who is a research scientist
at the USDA Western Human
Nutrition Research Center,
and an adjunct professor
at the University of
California, Davis.
We have Claudio Lanata talking
about the effects of infection
on nutritional
status of the host.
Claudio is a Senior
Researcher at the Institute
of Nutrition in Lima, Peru.
I decided to keep it
in English because I
would destroy the Spanish.
And so he's going
to complete that--
the other part of that circle.
And then we have our
own Professor Bob Black,
Chairman of our Department
of International Health,
and Edgar Berman
Professor-- also
the Director of the Institute
of International Programs--
who's going to bring those
two paths together and try
to give us a little bit more
vision of the way forward.
And how we can make this
area of interactive--
interactions between
nutrition and infection
continue to be a vibrant area
for research in the future.
Then we will have a conversation
with Nevin and Carl.
Nevin-- I won't go
through all this other
than to say that Nevin is
truly one of the, if not the,
father of modern
nutrition today.
He has published
over 650 papers.
He's been on-- he's
been the founding member
of a number of institutions.
With the UN University,
he is the Editor-in-Chief
of the Food Nutrition Bulletin.
The list goes on and on.
He's one of the greats in
modern science in nutrition.
He started the
Institute of Nutrition
in Central America and
Panama, NCAP, which
has for years published numerous
papers about the importance
of nutrition and child health.
And we're just delighted
that he's coming.
He's not here yet,
but he's coming.
He's a Laureate of the World
Food Prize, and so forth.
So when he comes,
I'll be much relieved
when I see his face actually
walk through the door.
And then we have Carl.
Carl Taylor, who is the
founder and first director
of our Department of
International Health.
And, have I got that right, Tim?
I think, yes.
We've got Carl who
is the first director
and founder of our department.
It's the first department
of international health
of its kind in any school of
public health in the world.
And so it all started here.
Life begins here
in public health.
And in international health.
And the students every
year feel that, I think.
Dr. Taylor worked
for 30 years in India
as the director of the
Presbyterian Mission Hospital.
He was the founder and the lead
researcher for the Narangwal
Project, which set the
stage for how we understand
nutrition and infection
interactions in the South
Asian context.
We've learned enormous amounts.
We studied the Narangwal Project
when I was a mere student here
in the late 70s and early 80s.
Carl was the director of the--
the Chair of the department
from up until 1983,
'84, at which point
Bob Black took over.
And Carl went to China
to direct UNICEF,
where he spent the next four
years leading the UNICEF
charge in China.
He is the recipient
of numerous awards,
including the US Presidential
Award for Service
to Children in the World Who
are in Especially Difficult
Circumstances.
He's co-authored a book with his
son, Daniel, who's also here--
we're delighted that
Dan is here with Carl--
called Just and
Lasting Change that
was published by Johns
Hopkins University Press.
He's a teacher and a
mentor to thousands of us
who are in International Health.
And we are thrilled that
Carl is here, as well.
I'd like to also just
finish by saying that
tonight's proceedings are
going to be incorporated
into a special commemorative
book on Interactions
of Nutrition and Infection 40
Years later, or 50 Years Later,
whichever title of--
whichever way we go--
along with the first
chapter of the Monograph
that was published 40 years ago.
I'd like to welcome
the Grant family here.
Carol, welcome.
It's very nice to have you.
These proceedings
are being videoed,
so we'll have this up on YouTube
probably by 10 o'clock tonight.
We'll have this book that
captures the early foreword,
a later foreword, that Carl
and Nevin are going to write,
the papers from
Charles and Claudio,
plus the comments
of the evening.
So make some good
comments and questions.
And they will be published
by Sight and Life.
We have permission from
WHO to republish portions
of the original WHO Monograph
as a special commemoration
of the evening, and
the event itself.
And I'd like to
recognize Dr. Klaus
Kraemer from Sight and Life.
Sight and Life is
publishing this all for us.
And if you fill
out your card, and
drop it in the box at
the end of the evening--
either here or
upstairs-- you will
be sent, when it is--
when it comes out,
a free copy of this
commemorative publication.
Sight and Life has
also kindly agreed
to put the proceedings
into a special proceedings
issue of the Sight and Life
newsletter, which reaches about
10,000 people around the world.
So we'll start off the
evening with Charles
talking about malnutrition
and infection.
And then we'll round
it up with Claudio
talking about the role of
infection on malnutrition.
And then catch this
Bob, we're gonna
have Bob bring it together.
[AUDIENCE LAUGHING]
I actually tested
that beforehand.
I was afraid the arrows
were going to, like,
go the other way.
[AUDIENCE LAUGHING]
And then we'll
have a conversation
with Nevin and Carl.
These are supposed to be
lazy-boy chairs, you know,
where we were going
to have a floor lamp
and soft lighting with
paintings coming down to make
it look like a living room.
But this is as close as
we've got to a living room.
And we'll enjoy a conversation
with Carl and Nevin.
And then a reception at the top
of the hop on the 9th floor.
And there are surprises
up there, as well.
So everyone is invited to the
9th floor for a very, very
nice reception--
Peabody Wind Ensemble,
wine, and so forth.
I have stopped my
comments, at this point,
and would like to welcome
Dr. Charles Stephensen--
Charles, where are you?
Here you are-- to the podium
to talk about the first half
of this vicious cycle.
[APPLAUSE]
CHARLES STEPHENSEN:
Oops, static electricity.
Well thank you Keith
for that introduction,
and I'd like to thank
Johns Hopkins for the--
and the Middendorf foundation,
and George Graham Lectureship--
for inviting me to, sort
of, be the lead-off batter
here tonight.
And thank you all for coming.
I remember-- so I was a student
here about the same time
Keith was, and the last
time I was in this building,
or in this room, it looked
quite a bit different.
And I was--
I think I was listening to Leon
Gordis talk about hepatitis A--
is my last memory of this hall.
So this is my topic.
And since I'm going to talk
about effect of malnutrition
on resistance to
infection, we do
need to start with a little
primer on the immune response
to infection.
And this graph is out of
one of my favorite books
published in the mid-70s,
Pathogenesis of Infectious
Disease by Cedric Mims.
And it shows, on the top
there, the infection--
let me try the pointer.
So this represents infection
by a mucosal pathogen.
It may be short
lived and cleaned up
by the innate immune system,
represented at the bottom
by that monocyte, which
will differentiate
into a macrophage
in this neutrophil.
And then here we have
bacterial or viral replication.
And one of the things
I noted about the--
in reading the Monograph--
is that there were a lot of very
well-conducted animal studies.
And I think they had three
common characteristics.
One, there were good solid
nutrition interventions,
some of them with single
nutrient deficiencies,
for example, pair-fed controls.
Lots of different
pathogens, lots
of different animal species.
Good microbiological endpoints
and pathological endpoints.
So at the time of the
publication in 1978,
much of the information here--
So an initial infection, perhaps
through a process of invasion
through mucosal surfaces
becoming a systemic infection
and also showing
virus replication,
sort of systemically.
This sort of information
was well developed,
and we knew a lot about what
specific deficiencies could
do in animal models.
And I think there were 53--
vitamin A is my
favorite vitamin--
and I think there were
50-some vitamin studies.
Nowadays, what
we've, since 1968--
we are focusing on this
part of the graph, I guess.
It is up there behind me.
I can see it--
the immune response
to infection.
And we knew relatively little
about cellular immunology
at that point, and
we know a lot now.
And so the experimental animal
studies tend to reflect that.
And so this evening, I'm going
to talk about innate immunity
and adaptive immunity.
And they're not really
two separate systems,
but adaptive immunity we
defined in the 60s, 70s, 80s.
And identified, for
example, T lymphocytes,
and antigen-presenting
cells, which
present antigen to
T lymphocytes, which
provide help to B lymphocytes
in producing antibody.
And the innate
immune system, we've
learned a lot more about
since the, sort of, early 90s.
And we knew about these
phagocytic cells, which
were discussed-- well,
have been discussed
since the early 20th century.
And data on the effect of
malnutrition on these cells
was presented in
the 1960 Monograph.
But now we know a lot about
how these cell types, including
other actors in
innate immunity, which
can include epithelial
cells at mucosal surfaces,
stromal cells, cytokines,
chemokines, lipid
mediators like prostaglandins
and leukotrienes.
There's a whole network of
mediators of inflammation
that are triggered by
the initial response,
in recognition of a pathogen
by a specific group of pattern
recognition receptors, in
the innate immune system--
that we didn't know anything
about until the 1990s.
So this immune
response to infection,
which here is coming
up around day 5, really
starts about an
hour after infection
in recognition of the pathogen
by the innate immune system
and triggering inflammation.
And then the innate
immune system
really links to the
adaptive immune system,
and triggers the
memory response.
So I am going to
differentiate a little bit
and show some examples between
the innate and adaptive
immune system, and
effect of nutrition
on these different cell types.
So in deference to Keith's
preoccupation with 40 years,
I stopped my review
of the literature
in 2008, as indicated
on this slide.
He was worried about
that months ago.
So chapter 3 and chapter
4 in the Monograph
really describe the effect
of malnutrition on resistance
to infection-- in
chapter 3, which is big,
and it has several
very long tables.
And chapter 4 is really
talking about immune function,
and it's very slim.
So there's a description
of synergism and antagonism
between nutrition,
malnutrition, and a pathogen.
So synergism would be
increased severity of infection
with malnutrition, but there
is little mechanistic data.
And so, as I've
already mentioned,
a current focus particularly
in animal studies,
not so much in human studies,
is on mechanism and mechanism
of immune function.
But we also know a
lot about mechanism
of action of nutrients that
we didn't know anything
about 40 years ago.
And much of the data came
from observational, clinical,
and community studies.
Whereas, I think a major
advance between then
and now is the application of
randomized controlled trial
methodologies in the
community, in the clinic,
to look particularly
at specific--
well I was going to say,
specific micronutrient
deficiencies, but at
least specific nutrition
supplementation.
So vitamin A, zinc, multiple
micronutrients, and so on.
So that's a big difference
now and has given us
a lot of valuable information.
And I mentioned the
earlier animal studies,
their endpoints.
And now we're more
focused on mice
than a diversity of species.
We can knock-in
or knock-out genes
of interest related to nutrient
metabolism or immune function.
And so, again, a lot
of mechanistic studies
are going on.
So there's not quite a synthesis
of that information yet.
And, very briefly, chapter 4
talked about immune function,
as I mentioned.
And so on the right
there, in 2008,
you can see we have B
cells, cytotoxic T cells,
various subsets
of T helper cells
that are pro-inflammatory
in response
to specific types of pathogens,
or T regulatory cells
that down-regulate
inflammation, gamma delta T
cells, and the list goes on.
And then as I've mentioned,
the innate immune system
we know a lot more about that
just in the past 15 years
than we did 20 years ago.
And one other point I wanted
to highlight is, so on the left
here, you see protein
energy malnutrition
impairs protective immunity.
That's clearly shown
in the 1968 Monograph
but we've had a nutrition
transition that was--
Keith alluded to earlier.
So that now we're
not only interested
in sort of under-nutrition,
malnutrition,
but we're also starting
to think about,
instead of protein
energy malnutrition,
the idea of dietary
restriction sort
of in a calorie-rich
environment.
So that's a difference
in focus, and that
leads to a difference--
another difference.
And maybe this is
cheating a little bit,
but we've been focusing
on infectious diseases,
but now we're also interested in
chronic inflammatory diseases,
which also obviously
involve the immune system.
So I'm not going to
be comprehensive.
And so this is an
idiosyncratic view
of what I think the
differences are, then and now.
And so I really
picked three examples.
And one example that's a change
in thinking for all of us,
I think, is that some nutrients
that previously were thought
of as calorie
sources are now being
differentiated and analyzed.
And fat-- generically "fat"--
does more than provide energy.
Fatty acids can
modulate inflammation,
and so I'll show you an example
from the innate immune system.
So this is a circa 1970-ish
view of the macrophage,
in black, which phagocytosis
a foreign body, or a pathogen
kills it with lysozyme
and reactive oxygen.
And that can be impaired
by malnutrition.
But part of the revolution
in innate immunity
is identifying the
mechanisms by which
bacteria lipopolysaccharide
can activate macrophages.
We knew monocytes were
activated to become macrophages.
We didn't know how to activate
pattern recognition receptors.
Toll-like receptor 4 is the
one that's activated by LPS,
and it regulates transcription
of genes like TNF alpha,
IL 1 beta, and cyclooxygenase
2, which itself then metabolizes
arachidonic acid
to leukotrienes--
well, to prostaglandins.
And these are mediators
of inflammation.
So just as an example of how
fat is no longer just calories.
This is an in vitro
study that shows
that saturated fatty acids
themselves can actually
activate toll-like receptor 4.
If you think about
lipopolysaccharide,
it has a lipid component of
short-chain fatty acids--
lipid A-- so it itself
has a lipid component.
But this experiment shown
here, from Dr. Dan Wang's lab,
shows that the
toll-like receptor 4--
in the red box at the
top, on the left--
is activated by LPS.
But it can also be activated
by saturated fatty acids--
or saturated fatty acids can
enhance the activation of LPS.
And there's a lot of complicated
immunology in the cytoplasm
there.
But if you get down to the--
so I'm going to skip that--
but if you get down
to the nucleus,
the activation of
toll-like receptor 4
is activating gene transcription
and, in this case, COX-2.
So COX-2, if you put a reporter
construct in a cell line that
is expressing toll-like receptor
4 as a model system activated
with LPS--
low level of LPS--
you get 100% of this driving
expression of luciferase.
So you get a 100% expression.
This is enhanced by
saturated fatty acids,
and can be diminished by
polyunsaturated fatty acids.
So in addition--
so in this case,
the dietary fat may be
acting as a pathogen.
So this is an
excursion into the area
of chronic inflammatory disease.
And another activity of
polyunsaturated fatty acids
of marine origin, so long-chain
omega-3 fatty acids like EPA--
shown in the blue on the right--
is it can be a direct competitor
of another essential fatty
acid, arachidonic acid, which
is the precursor through the COX
and LOX enzymes of 2- and
4-series prostaglandins
and leukotrienes that
mediate inflammation.
So the membrane levels
of these two fatty acids
depend entirely on diet.
So if your intake
of EPA goes up,
the composition of the membrane
in this granulocyte changes.
And when these
enzymes are activated,
there's a precursor now, not
only arachidonic acid but EPA.
And EPA-derived 3- and 5-series
prostaglandins and leukotrienes
are much less inflammatory.
And also, because
of the competition,
there's fewer 2 and--
2-series prostaglandins
and 4-series leukotrienes
produced from arachidonic acid.
So EPA can be anti-inflammatory
in this context.
And there's a lot of
clinical trial data showing
that in chronic inflammatory
disease, for example arthritis,
if you have granulocytes
in your joints,
you can take EPA from
fish oil supplements.
Pet foods now have EPA and
fish meal components, fish oil
components, for the same reason.
You can decrease
leukotriene production,
which can subsequently
decrease production
of pro-inflammatory cytokines.
So if you look at the percent
of EPA in the monocyte membrane,
it's inversely correlated
with production of IL 1 beta
and TNF alpha.
So this is a good thing
for inflamed joints.
If you go too high
this will decrease
the bactericidal activity
of these same cells.
So there's a plus and a minus.
So protein energy
malnutrition, example 2.
I hope someone's timing me.
OK.
So I have another hour, or so?
I'm doing a-- OK.
Protein energy malnutrition
and dietary restriction,
as I mentioned earlier, can
affect adaptive immunities.
So I'm going to
talk about T cells
in the thymus, where
T cells come from.
So we know, and knew in
1968, that protein energy
malnutrition impairs T
cell-mediated immunity.
I guess we didn't know it was T
cell-mediated necessarily then.
But in children
with malnutrition,
if you can image the thymus
in infants, it's smaller.
The number of recent thymic
emigrants, new naive T cells,
is lower.
The T cell areas of
lymph nodes is smaller.
And if you look at T
cell-mediated response,
like delayed type
hypersensitivity response,
on the right, you can
see a lower response
in kids with malnutrition.
That's data from work
in Ghana, I believe--
Charlotte Newman
in the early 1970s.
So the kids with the
worst malnutrition
have the lowest DTH score--
area of induration there.
And thymic function
and this DTH response
can recover pretty quickly
when malnutrition is treated.
So what's the mechanism here?
And these are data from a
paper from 1998 in Nature
that shows that T cell
immune deficiencies is
induced by starvation--
OK, we knew that--
but also reversed by
the hormone leptin.
So leptin is a hormone
that's involved in sort
of long-term energy balance.
It's produced by adipose tissue.
If you have lower
adipose stores,
or you have lower
serum leptin levels,
it sort of reflects energy
reserves of the body,
and it's lower in protein
energy malnutrition.
Mice without leptin, or its
receptor, have thymic atrophy.
T cells have leptin receptors.
And leptin promotes T cell
survival, proliferation,
and differentiation.
So in the top left,
figure A there,
those are human
lymphocytes in culture.
And the bottom two lines are
no, or a very little bit of,
additional leptin.
A 100-fold more for
the middle line.
And the highest line is the
highest level of leptin.
So you alleviate the leptin
deficiency in cell culture
and you get better
lymphocyte proliferation.
On the right-hand side, you
see an experiment in mice.
On day 0, there are
four groups of mice,
and the mice were
starved for two days.
And you can--
that's body weight.
So body weight
drops by almost 30%.
And then recovers rapidly
by day four or five.
And then during that
weight loss period,
animals were immunized to induce
a delayed-type hypersensitivity
skin test response, which
we saw has diminished
in children with PEM,
and later challenged,
on day six or seven.
And then the other intervention
was leptin, or sham, treatment
during the sensitization period.
So the bottom bar graph
shows, on the far left,
this is our negative control--
well-nourished but
no immunizations, so
no DTH response.
This is our positive control--
well-nourished,
robust DTH response.
This is the starved animal
without leptin, so diminished
DTH response.
Then leptin treatment
restores that response.
So T cells respond
to energy reserves.
T cells, and other
cells in the body,
also have receptors for,
for example, amino acids.
And, at least in studies
with avian species--
chickens-- the thymus
is reduced and T cells
are diminished in number
by protein malnutrition.
But bursa cells,
B cells, are not.
And it seems that
the T cells don't
up-regulate a high affinity
receptor for amino acids.
And so seem sort of predestined
under protein restriction
to not fare well compared
to other immune cell types.
In humans these are data--
historical data,
really-- looking
at survival rates of
children in Gambia
from Sophie Moore
and Andrew Prentice.
And kids that were born in the
harvest season, birth weights
are good.
Or in the hungry season,
birth rates are low.
Same mortality or
survival curves
here, but when they
hit 20 years of age--
the hungry season-- now adults
have a higher mortality rate.
If you look at a
study of infants
from 1 to 50 weeks
of age, looking--
Imaging the thymus,
you see the kids--
this is hungry season
minus harvest season.
So if you see a negative,
that's a smaller thymus
in the hungry season.
So thymic deficits
early in life.
On the bottom, fewer
numbers of recent emigrant
T cells circulating
in the blood.
So definitely a
thymic impairment.
And so immunologists would
suspect this later difference
in mortality might be due to
impaired adaptive immunity
but we don't have this data.
But if we jump to our
current concern with obesity
and look at some
non-human primates
that are sedentary
and overweight,
and we put them on a
calorie restriction
diet-- the black bars-- and
look at the same endpoint,
so these are males and females.
So if you look at
one or the other,
the number-- the percent
of naive T cells,
so recent emigrants,
from the thymus
is now better in the
calorie-restricted group
than the sedentary obese group.
If you look-- with
another method
of recent thymic emigrants,
you see the same thing.
And if you see T cell
receptor heterogeneity,
it's better in the
calorie-restricted group, which
means you have a better
repertoire of T cell receptors
to respond to
different antigen type.
So that's a good thing.
So this is sort of--
Aristotle would
be happy, I guess.
The golden mean.
Too much is bad.
Too little is bad.
So we're thinking
more about balance now
than deficit and adequacy.
And finally, Keith, I'm
getting to vitamin A.
And I'll wrap up
in three minutes.
So vitamin A and, again,
this is an example--
vitamin A sort of
serving as an example.
So I want to mention that there
are community intervention
trials that have given
us a lot of data.
We have new mechanistic
information.
We know how vitamin A
works in the immune system.
And we're looking at adaptive
immune endpoints and vitamin A,
the active metabolite retinoic
acid effects antigen presenting
cells, T cells, and B cells.
And in 1986, Dr. Summer, and
West, and other co-authors
from this institution, published
a study that showed about 30%
lower mortality in Indonesia
with vitamin A supplementation,
compared to control villages.
They were not
placebo-controlled,
and that observation was
seminal and led to a very--
to several placebo-controlled
intervention trials.
The results of which
are shown here.
So the relative-- lower relative
risk of death in the vitamin
A supplement group
compared to placebo group
from primarily infectious
diseases in infants
and young children.
The same thing has been
seen in clinical trials
with some infections,
but not others.
So this shows that the mortality
from measles, on the top right
graph there, is lower in the
vitamin A group-- the red bar.
The duration of
post-measles pneumonia
is lower in the bottom graph.
However, this is not a
universal observation
in that anybody with
pneumonia is necessarily
going to improve.
And I mention this just to
highlight the fact that,
one thing I think we need to
do, is look at the mechanism,
particularly in
human studies, more.
And this is a study done in
Peru that basically showed--
So I was involved, others
in this room were involved.
Vitamin A supplementation
slows recovery
in children hospitalized
with pneumonia.
They all got out of the
hospital at the same time.
But if you look at blood
oxygen saturation in the--
let me get these right--
the vitamin A group, it
recovered more slowly
after hospital admission
than the placebo group.
The percent of children
with retractions
reflected that in the need
for supplemental oxygen.
So a final word about mechanism.
And this is just to highlight
a little bit of data
from animal studies.
In 1987, Pierre
Chambon and Ron Evans
were working separately--
identified the retinoic acid
receptor.
This is the receptor we
knew about, retinoic acid.
So as of 1987, we knew how it
worked in the immune system
and in other cell types.
So in ex vivo cell culture
studies with primary cells,
you can take naive
T cells, shown here.
Let them interact with
antigen, and they'll
develop a phenotype--
a T Helper 1
cell protects against
intracellular pathogens.
This is a big
oversimplification, forgive me.
Th2 cells will defend against
extracellular pathogens
like vibrio cholerae,
for example,
or respiratory viruses, and
promote the IgA response.
And just, in brief,
retinoic acid--
indicated here as RA--
can act on
antigen-presenting cells
to decrease IL 12 production,
which drives Th1 development.
So that's-- vitamin A is
diminishing the Th1 response,
potentially retinoic
acid itself.
If you look at the Th1 cell,
can decrease interferon gamma
production.
Interferon gamma
can down-regulate--
down here-- Th2 development.
And there are some
other direct effects
of retinoic acid on this T cell
that drive Th2 development.
So one of the responses
driven by Th2 cell
is a secretory IgA response
at mucosal surfaces
to a pathogen like the vibrio
cholerae, or in this case,
influenza A virus
infection in mice.
So vitamin A deficiency, as
you now expect, would decrease.
And high vitamin A increases
influenza-specific solitary IgA
response--
and shown here.
So this is the
flu-specific salivary IgA.
And it's really
because there are
fewer IgA vaccine-specific
IgA cells in submucosal
in the salivary
gland, in this case.
So it's really impaired the
cell-mediated immune response.
And I guess just one final
cautionary comment, again.
I guess I'm always looking
for the black cloud surrounded
by the silver lining but--
If you think about balance
in the immune system,
if you're improving
something, some response,
you're potentially causing
pathology in another situation.
So in mouse-- simple mouse model
of asthma that's driven by Th2
cells, if you--
vitamin A deficiency
will actually decrease.
And high vitamin A
increase the severity
and increase the
number of eosinophils,
increase IgE, increase
IL 4 and IL 5, and so on.
That's not by any means a
perfect model of asthma.
So in conclusion, I
guess the one thing
I think about is, if you're
thinking about deficiencies--
so nutritionists have
all seen this slide.
This is level of
vitamin A intake.
Deficiency, we're
commonly defining by risk
of impaired retinal function.
We now know there's increased
risk of infection or death
from infectious diseases,
at least in some subgroups.
It may be worth looking
at immune dysregulation
as a potential sort of toxic,
or a high-level side effect,
of vitamin A and
some other nutrients.
So as I've said,
nutritional deficiencies,
as we learned from
the Monograph in 1968,
are definitively
associated with severity
of infectious diseases,
risk of death.
And since then, we've
learned a lot of things.
So just the three I highlight is
that the randomized controlled
intervention trials
have shown us
a lot about single nutrients.
We have a lot of mechanistic
data from animal models.
We don't have much mechanistic
data from human studies,
and I think that's
an interesting place
to put some effort in.
And that's it.
[APPLAUSE]
KEITH WEST: Thank you
very much, Charles.
That really gets us
off on a good footing.
I think we'll go through the
rest of our vicious cycle
and bring that to
some coherence,
and then open up for
questions and answers.
So with that, I'd like to ask
Dr. Claudio Lanata, who's also
a alumnus of this institution.
Claudio got his
MPH here in 1980--
3?
'83-- and has done great
work since that time.
And of course, comes from the
Institute of Nutrition in Lima.
So you have two
institutional homes here.
CLAUDIO LANATA: Thank you.
Thank you, Keith.
Really an honor and
pleasure to be here.
Yes, I was a student
in this room.
Several of you were my teacher.
And it's really great
and an honor to be here.
So let's start
this presentation.
And I'm going to end the cycle,
and talking about infection
as a risk for reduced
nutritional effect.
So as soon as these
lights are coming.
Yeah it's coming.
KEITH WEST: Oh it's coming.
CLAUDIO LANATA: Yes, all right.
Thank you.
OK.
This is Peru.
And just to bring you a
bit of a nice celebrity
party in the highlands of Puno.
And this is the place
where George mother came.
So George has a
combination of US and Peru.
And it's a nice summary that
Keith gave us about him.
And they talk about
George in nutrition,
but also he's a very
[INAUDIBLE] in his opinion.
So he got into politics
a lot, as you can see.
And thanks to his
political connections,
he was able to give us
this beautiful institute
because he convinced
the Peruvian government
to donate to us the
piece of land when
we built this Nutrition
Research Institute, where
we are working.
And this is George last
visit to our place.
That's George, and that's Mary
Peña, our current director,
Hilary Creed.
That's Ron Kleinman
who is member
of the advisory board with
Ken Brown, who also was part
of Hopkins before,
and the whole crowd
of the Instituto
in honoring George
in one of his last visits.
And I also, before
going into the topic,
want to thanks George
because I didn't
have any idea
about the Instituto
when I was studying
medicine in Peru.
As many times it happens.
So I had to take a--
I was doing epidemiology,
and there was a course
about readings in nutrition.
And I thought, my gosh, I
always hear nutrition, you know.
And it's good to have some
idea before going back to Peru.
So let me take this course--
elective course-- in nutrition.
But you have to have the OK
from the professor in charge
of the course.
And you have to get
an appointment for him
to give the OK for
you to sign in.
So I walk into George
office, like this picture,
and he talked to me
in perfect Spanish--
Peruvian Spanish.
And knew all my family--
you are from this-- my god!
I'm completely surprised.
That's how I got to know the
Instituto where finally I work.
So thanks for that course.
It changed my life.
All right, getting back to
this fantastic work that was
[INAUDIBLE] in that--
really breakthrough
review, 40 years ago.
That review, as has
been said, concentrated
looking on effects on nutrition
from diseases well known
at that time--
typhoid, TB, measles.
And the whole series--
I mean really very
exalted review--
that you did in every little
inch that you can measure,
in terms of different
animals and various protozoa,
helminthic bacteria, everything.
But as Charles has
said, mostly were
based on clinical studies, as
well as laboratory animals.
Very detailed studies looking
on metabolic nutrient balance
and some micronutrients.
But there were no
longitudinal studies.
I mean epi was not around
much in those times.
So very few really long-term
studies carefully done
were conducted at the
time of that review.
But I pick a particular topic,
and I'm going to build on that.
One of the subjects
they review, which
was presenting in the Monograph
as a negative finding,
was that they were describing
the growth of children where
they were given antibiotics.
But they were
frustrated because when
they stop these
antibiotics, the child
go back to not growing well.
But when the child were given
those daily antibiotics,
they show that they
improve their growth,
as compared to placebo.
Interestingly, when they change
to other type of antibiotics,
like penicillin,
that effect didn't
existed so they were really
touching the composition
of the microflora in the gut.
And what are the consequences of
having all the junk in our gut,
as I will discuss later.
And I think they
were really touching
this bacterial overgrowth that
exists in the gut of children
in developing
country, which is now
called by many the "tropical
barrier" for delivering
good antigens to the gut,
in the area of vaccinology.
We are dealing with that.
And indeed, children
in poor countries
are permanently exposed
to unsanitary conditions.
They eat, drink,
and swallow millions
of millions of microorganisms
daily, in their daily diet.
That creates a
burden on nutrition
because the body has to fight
with all of these visitors
and keep them under control.
And we will see what happens.
And let me start
by a wonderful work
that William Checkley
did in our cohort in Peru
with a group of--
some of them are here--
showing how the first
encounter of a human body
with a parasite
like cryptosporidium
affected growth on children.
And once they were
infected, and if they
also in those
infections had diarrhea,
they gained less weight,
as compared to controls.
But when children were infected
without having diarrhea,
they also had an effect--
was less marked than when
diarrhea was around.
But given the fact that the
asymptomatic infections were
much more common and frequent,
the total burden on nutrition
was more important the
asymptomatic component
than the diarrhea associated
burden with crypto.
They also show that the effect
is long-lasting particularly
if the child is infected
early on in infancy,
and if they were already
stunted at the time
of their first infection.
So this has been validated.
There has been study in another
cohort in Brazil showing more
of a similar result.
But very interesting,
the effect was
different by species.
So the gut is not always
treating everybody the same.
So in the two to three
months after infection,
both of these type
of cryptosporidium
had the same effect.
But in the follow-up period
of three to six months
after infection, only
one subtype of crypto
had a long-lasting
effect on nutrition.
And again, in this
cohort in Brazil,
the greater effect
on nutrition was
about asymptomatic infections
than symptomatic diseases.
In another study
in Guinea-Bissau,
very interestingly,
very similar weight loss
associated with
crypto infection,
but again a gender issue.
So our gut also
reacts different,
by different
parasites, but gender
seems to be also an
important variable that
takes care of another
thing in the Monograph.
Gender came that strong
as a potential covariate
to be looking into the effects.
And this is the crypto--
and there are still a lot to
know how exactly it works,
but one of the theories is that
it cover up your gut surface
in a way that will
not only create
some degree of inflammation,
but just by mechanical effects,
it may create malabsorption
and fighting also
with the nutrients, having this
effect in you-- in the gut.
And going out to picking very
close relatives with Giardia.
And I'm willing to bet if I make
a little test on all of you,
I will get a majority
of you saying
that Giardia is the same.
Is a pain in the neck, but
it creates a lot of problems.
Again, in this
cohort done in Peru,
obviously from birth many
children are infected with
Giardia, re-infected, some
of them could be infected
for a year--
secreting weekly the parasite,
but it doesn't affect growth.
And it did not have
any risk of diarrhea.
Not at all.
We have another study
with it, with Bob Gilman
who is sitting here.
And we-- [INAUDIBLE] publishes
one of my tragics in life.
A lot of papers
need to be written.
And nice to be in this school
because we welcome student
who has abilities to do
data analysis because we
have a lot of data that
needs to be published.
So you're welcome.
We had the same effect.
But interesting in
that study, in contrast
to the one that
has been published,
is that we also look on
fat malabsorption, glucose
malabsorption, and several
other indicators of Giardia.
It was thought the
mechanism by which Giardia
could be producing
nutritional impact,
and none of those
indicators was associated
with Giardia infection.
So how could that happen?
Because in the same
city, if I take
a group of gringos who
hasn't leave the US,
and bring them to Lima,
one of their nasty diarrhea
they get by traveling
there is caused by Giardia.
So it's not the
Giardia that is there.
It's not pathogenic.
It's something
happening that makes
a difference between these two.
So this is hypotheses.
It seems to be that early
exposures to area infections
in children may activate
the immune system in order
to make them tolerant
to these pathogens.
While if you acquire this
infection later in life,
then you are really
susceptible, and then you
develop lung disease.
And there is animal
data endorsing this.
There is a rat model in which
you can infect these rat very
early in life.
Nothing happens to them.
They keep-- no disease.
They grow normally.
But if you take the same
rat and infects them
after a critical age, you may
even not only make them sick,
but kill them, by the
same strain of Giardia.
So a very interesting
change in age
related to this
mechanism of tolerance.
And that brings me to how--
I mean, Charles was
talking about mechanisms.
And we are I think moving
forward on that concept.
And there is a whole now
new wing of attention
to the mechanism of immunology.
And in this area, there
is a new key player--
number 10 in soccer--
which is dendritic cells.
And it looks like
these cells are
the key player in order to keep
some kind of order in the gut.
They are [INAUDIBLE],,
capturing everything--
Fruit.
Every foreign antigen
that is delivered
is captured by these
dendritic cells.
And they have, like, a computer
saying, oh I know them, fine.
Not to worry.
Don't overreact.
And keep this under control.
So that mechanism of
capturing that works even
in the crypt, or in the
patch, and the Peyer's patch
cells on M cell dependent
uptake of different antigens,
the dendritic cells seems
to be very important.
And they do
condition imprinting,
and these [INAUDIBLE]
effect in immunology.
So they are very
early on activated.
And there has been
studies in neonates
in developing countries
showing how quickly they
start acting in the gut of--
on developing countries,
particularly when
they're exposed to
so many pathogens
that are being acquired
by these individuals.
And they recognize it.
They kind of, OK you work
in this neighborhood.
I know you now.
I keep you under control.
Don't cross the line.
I will keep you under control.
But I won't overreact
like this is.
So very interesting role.
And I think we need more
to learn about them.
And obviously vitamin A
is crucial in that role.
So then dendritic cells do have
a key relationship with vitamin
A, and I think Charles
alluded to that,
for their correct function.
They also travel
all over the body,
bringing the antigens they
have capturing and delivering
to the appropriate effective
cells, either in the spleen
or in the mesentary
[INAUDIBLE] in order
to build this appropriate
immune response.
So this is fine for immunology,
but what about nutrition?
This has a cost, obviously.
All this work.
It has been exhausting.
And so I think the body is
really actively involved
in keeping all these
foreign antigens--
food, microorganisms--
under control.
And immunotolerance is not
really an immune suppression
that we used to think
a few years ago.
It's just that they are so
activated-- so early activated,
that the response
creates that tolerance.
It just maintains
them under control.
And it's fascinating.
I mean, in children in
developing countries,
it has been measured that they
are producing 3 to 5 milligrams
of secretory IgA per
day, in the gut in order
to fight all these infections.
And there is different
responses in the upper gut
and in the colon.
And if you look on the
types of dendritic cells
sitting in the small bowel,
or in the large bowel,
they are quite different
species because they
have to deal with
different bacteria
and different environment.
That also explains
why the gut has
such a strong
immunological memory,
able to respond to antigens.
Even though, when you are
looking on serology markers,
they have disappeared
a long time ago.
They do response.
And the cholera vaccine
trial in Bangladesh
has been very nice
example of that.
And what I'm trying
to make in this
is that it is an important
nutrition burden that needs
to be studied and quantified.
I think this is
something that we
need to keep making
progress to understand
the cost for nutrition
of living in poverty.
And I took Abdullah's
review of this graph just
to show that obviously
poverty is very complicated,
relates to under nutrition
by several mechanisms--
in which infectious
disease, low birth weight,
and inadequate dietary intake--
by that, not only on
the nutrition quality
but also in the microbiology
can [INAUDIBLE]..
And we are working in
Peru now on food hygiene
and how to bring a better diet
to children, to bring down
the bacteria exposure
in their daily intake
because it has a problem.
And I think everybody has heard
about Leonardo Mata famous
studies in Santa Maria Cauqué,
where he was one of the first
in the group there to
demonstrate that this line was
a growth curve on a normal child
in the reference population.
This was the group of
children they study.
And this dotted line
was an individual child
that obviously end up dying.
And they were very nicely
showing, how at the beginning,
they were kind of
protected mostly
because the amount
of breastfeeding
these children were receiving
was massive at that time.
But as soon as they started
getting weaning foods,
they start getting
a lot of diarrhea,
and respiratories, and a whole
bunch of diseases that end up--
and some of them killing them.
And many of them have really
a very low growth curve,
keeping them undernourished,
and also psychomotorically
retarded.
So diarrhea was recognized
very early then,
and it has been
always quoted as one
of the best examples
of an infection cause
in the nutrition.
Abdullah Baqui and Bob Black
review 23 prospective studies
looking into this issue.
21 of the 23 show
an impact on weight.
The two that did not were
done in Taiwan and Australia.
So they probably were
having a different diet
quality than the rest of the
developing country studies.
From 30, say that--
studies that had data,
you can see the weight
loss attributable to
diarrhea, around 40 grams
lost weight per day.
30 studies looks on length.
Four didn't show any effect.
But eight had again around
0.08 millimeters of length
lost per day.
But Abdullah couldn't
do a meta analysis.
Why?
Because these studies
are very hard to compare.
There are different case
definitions, different methods,
different mechanics by which the
different variables were taken,
and they were
analyzed differently.
So very hard to
combine together.
And that prompted again William
Checkley, who is sitting here,
to--
and I don't know how
he did it, but he
was able to really grasp
nine longitudinal data,
original databases,
from different studies
from five countries that
had frequent anthropology
and diarrhea surveillance.
And they analyzed
incidence and prevalence,
and look on the
amount of disease
that the children had in
the first two years of life
to predict stunting at 20
month, four month of age.
Control for several variables,
and you can see here,
it is a linear relationship.
The higher number of
episodes of diarrhea,
the higher your chance of
being stunted at 20 month, four
months of age.
And the same thing-- the
more prevalence the number
of days of your life that
you have diarrhea with,
also the higher your chance
of developing stunting
at 20 month, four month of age.
And this is the odds of becoming
stunted at 24 months of age,
if you have an increase of five
episodes of diarrhea or more
per year in the first
two years of life.
It's not huge.
It's 1.13, but significant.
Not too different if
you look on prevalence.
Interestingly, that study
also showed beautifully
that this catch-up growth
that has been described
doesn't exist that often
in terms of length.
And very few children who were
stunted at six months of age
recover at 24 months of
age in these nine studies.
And this was done
in analysis that
control for regression
towards the mean, which
was a major problem in the
original studies of how
to interpret this data.
And this bring me
back to a diagram
that our friends put together
in 1968 Monograph, in which they
were considering-- this
is total body nitrogen,
and this is the
nitrogen balance.
So they were thinking, OK
you have an infection here.
You will start losing weight.
And your total balance
of nitrogen is gone.
And it's because you're
losing, and by consuming,
a lot of your energy.
And then if you catch up, you
recover from the infection,
and you're having
a good diet, you
will be able to build a
positive balance of nitrogen.
And therefore, your total
body nitrogen will recover.
These are normals.
If you are really
malnourished-- the C letter--
you will lose body mass,
and you may barely catch up.
I think they need a photograph
here because some of them
don't go back to the baseline.
At a low [INAUDIBLE]
matter, diagram
show they continue coming down.
But they also thought that
some people could lose but then
gain, and keep gaining,
positive nitrogen balance.
So they will be able to
really catch up and recover
the malnutrition.
And I think that is what
is being now looked.
This doesn't seem to
be that often happening
in developing countries.
Why?
Because of quality of diet.
And this is a nice study
that Bob, and Diego
Lopez [INAUDIBLE]
and Ken Brown did
in Lima, in which they
were studying children
who were having different types
of quality of diet, normally.
Not during illness.
All the time.
And they look all
these children who
were having a better amount of
calories per day, per kilogram.
If they have diarrhea,
no matter what
was the prevalence
of diarrhea, there
was no impact on
growth velocity.
But if they were on a middle or
lousy diet, the more diarrhea,
the less weight gain
they were having.
So you can, in a way, by
this catch up phenomena
that was very, very
nicely published
in the concepts
in that monogram,
you really can revert
this metabolic effect
on diarrhea on nutrition.
Mechanisms has been studied--
reduction of energy consumption
because of poor appetite
and vomiting.
There was a major
grant from USDA
which was called Feeding During
Diarrhea, because in the 80s,
some people thought that the
mothers in developing countries
were so stupid that they were
going to dilute the diet when
the child has diarrhea,
and really support him
with a very awful diet.
Since that didn't happen--
normally the mother is
recognized that the child has
lost appetite, and they
reduce the volume of food,
but they don't change--
they don't change--
and this particular recipe that
is very lousy for nutrients.
So that doesn't
seem to be the case.
There is reduced absorption
of nutrients because
of the structure of
the cells increase
motility and malabsorption,
that we were discussing before.
Some issues on permeability
to test sugar-- that brings up
potential chronic
disease because some
of this diarrhea by that
increase permeability,
expose antigens to
inside the lumen,
into the interstitials,
that shouldn't be there.
And suddenly it triggers
a whole of reactions
and chronic inflammation
that was never before.
There a lot of loss of
nutrients, particularly zinc,
copper, vitamin A--
there's a whole chapter
of vitamin A in the urine and
all the metabolism of vitamin A
in infection, as well as
increased utilization.
I think diarrhea,
enterotoxigenic E. Coli,
Rotavirus, and dysentery illness
are the best examples, as well
as persistent diarrhea,
how these diseases are
more serious.
Changing gears.
What about respiratory
infections?
Are they the same?
And here we have much less data.
There has been much
less number of studies
on respiratory disease
looking into this interaction.
Again in the review that
Abdullah and Bob did,
they only found eight
studies and four of them
has found an impact.
The others did not.
And not of any respiratory
infection, but mostly
the lower, more severe.
Some of them with
similar amount--
a bit greater loss of weight
per day as the diarrhea studies,
but only two studies.
In terms of linear growth,
three or five studies--
again with more severe
disease-- had an effect.
They have documented
that there is reduction
of food intake mostly because of
fever and severity of illness.
Obviously because respiratory
illness not necessarily
destroys the gut tissue.
But we need more studies.
And I think that's
the major message
on respiratory diseases.
I don't think this interaction
has been looked that carefully
with this type of disease.
Obviously TB is an exception.
It was included in the review.
It long recognized as a
cause of severe wasting
and negative nitrogen balance.
Interestingly,
chemotherapy improved
nutrition status, especially
when good nutrition support
is given.
But there is no more
studies showing that also,
in that infection--
chronic infection like TB,
there is an anabolic
block that developed
b in some patients that
makes them refractory even
to nutritional support.
So again, there is a
need to understand better
these mechanisms by which some
of these chronic infections
do have a much more strong
effect on nutrition.
And they become
refractory for a time
for nutritional rehabilitation.
And obviously, it was not
existing in the 1968s,
but the HIV/AIDS
infection and TB
has made things much
more worse for nutrition.
Measles was
recognized importantly
as a cause of kwashiorkor
in undernourished children
in the review.
Anorexia is refusing to eat.
Catabolic effect, protein-losing
enteropathy was described.
In the latest years
after the review,
I think they recognize that
acute and persistent diarrhea,
due to a long time after the
initial episode of measles,
because there is a
persistent immunosuppression
in these patient, which
was not known in the 60s.
And a whole of
interaction with vitamin A
makes the vitamin
A a key element
in the treatment
of measles cases.
Malaria was also mentioned.
Very few studies
in the '68 review.
But I think there's
nice data now
that has been emerging
from trials, particularly
preventive trials, like
pyrimethamine and chloroquine
prophylaxis versus placebo
that has shown that children
in Ghana, Gambia, and
Nigeria increased growth
when they were given these
prophylactic medication.
Not only because
of the medication,
because the insecticide-treated
bed nets had the same effect.
So just avoiding this
infection with the mosquito
do have a nutrition benefit.
And a very nice study
in Vietnam, not just
a trial but an
effectiveness type trial,
because it was done under
programmatic conditions
over five years.
They also has seen a very
positive nutrition effect
by controlling malaria.
And this is my last--
obviously HIV/AIDS makes
everything look awful.
The effects starts intra-uterus.
It's a high risk of
intrauterine growth retardation
and low birth weight.
Children in Africa that
are infected at birth,
even if they are
asymptomatic, they
do have a very bad
growth compared
to the non-infected children.
There are several mechanisms
directed by the virus,
as well as the HIV-induced
secondary infections.
And this wasting seems
to be related again
to all these inflammatory
and immunological mechanism
that Charles was describing,
especially this interleukins
that seems to be very
crucial for anorexia.
And several micronutrient
deficiencies
has also been described with
HIV/AIDS in these children.
So in conclusion,
I think since 1968,
we have now a lot of
well-conducted epidemiological
studies and clinical trials
that has documented very clearly
the importance of
infections on nutrition
in developing countries.
But I think with
few exceptions, I
could say that these effects
may be transient and not lasting
if these children are well-fed.
And I think that's a very
important message, because I
think we have a lot
to do by improving
dietary intake of children
in developing countries,
and help them deal
with this burden
of infectious, and
noninfectious agents,
they have to be
fighting all the time.
So the nutritional
cost of living
in poor and healthy
environment with high intake
of microorganism and
asymptomatic infections,
I think we need to look
at that more carefully
and measure how much
cost the body is
paying to deal with
these conditions
in poor environments.
So I want to finish by
thanking Nevin, Carl,
and John for stimulating
40 years of research.
Very exciting.
And I'm sure that this
will continue hopefully
in the next 40
years by many of you
guys sitting here doing
key research to finalize
the understanding of
all this interaction.
Thank you very much.
[APPLAUSE]
