BSSR Lecture: Environments, Inflammation, Transgenerational Perpetuation of Disparities in Health

GOOD AFTERNOON, AND THANK YOU
FOR COMING TO THE BSSR LECTURE
SERIES.
MY NAME IS MIKE SPITTLE AND I'M
AT OBSSR AND IT IS MY GREAT
PLEASURE TO INTRODUCE YOU TO
DR. TOM McDADE.
BRIEFLY, DR. TOM McDADE IS A
BIOLOGICAL ANTHROPOLOGIST THAT
CONDUCTS RESEARCH ON HEALTH AND
HUMAN DEVELOPMENT IN RELATION TO
SOCIAL.
HE RECEIVED A B.A. AT POMONA
COLLEGE, AND Ph.D. AT EMERY
UNIVERSITY AND WAS A POST DOC
RAL FELLOW AT UNC CHAPEL HILL.
HIS WORK FOCUSES ON THREE
TOPICS.
LSH LIFE COURSE PERSPECTIVE ON
IMMUNE FUNCTION AND THE
REGULATION OF -- AND THE --.
IT IS MY GREAT PLEASURE TO BE
ABLE TO INTRODUCE YOU TO HIM AND
HIS TALK IS CALLED
ENVIRONMENTS, INFLAMMATION,
TRANSGENERATIONAL PERPETUATION
OF DISPARITIES IN HEALTH
THANK YOU.
THANK YOU ALL.
CAN YOU HEAR ME?
IS THIS WORKING?
OKAY.
PLEASE TO BE HERE.
THANKS VERY MUCH FOR THE
INVITATION, AND IT'S GREAT TO
SEE SOME FAMILIAR FACES AND MEET
SOME NEW ONES THAT I'VE KNOWN
OVER E-MAIL OR THE PHONE.
WHAT I'M GOING TO TRY TO DO
TODAY IS TALK ABOUT REALLY ONE
OF THOSE THREADS OF MY WORK BUT
THEY ACTUALLY COME TOGETHER A
BIT IN THIS PROJECT, AND TALK
ABOUT A LIFE COURSE AND WHAT I'M
MOVING TOWARDS AS AN
INTERGENERATIONAL PERSPECTIVE ON
INFLAMMATION AND SOCIAL
DETERMINANTS OF HEALTH.
SO MUCH OF WHAT WE UNDERSTAND
ABOUT HUMAN PHYSIOLOGY, BIOLOGY
DEVELOPMENT AND HEALTH IS DONE
WITH RESEARCH ON LABORATORY
ANIMALS, ANIMAL MODELS AND
CLINICAL SETTINGS IN THE
UNIVERSITY AND OTHER
INDUSTRIALIZED SETTINGS.
AS AN ANTHROPOLOGIST I'M
INTERESTED IN A BROADER
PERSPECTIVE ON HUMAN VARIATIONS
AND HOW THAT MATTERS.
I HOPE YOU'LL TAKE HOME A
COMPARATIVE APPROACH TO
UNDERSTANDING HUMAN BIOLOGY IS
GENERATE INSIGHTS INTO THOSE
BASIC PATHOPHYSIOLOGICAL
PROCESSES THAT WE'RE INTERESTED
IN.
AS AN ANTHROPOLOGISTS IT'S ONE
OF MY PRIVILEGES TO BE ABLE TO
GO TO SOME OF THE PLACES AND DO
THINGS IN INTERESTING PART OF
THE WORLD.
YOU'RE ALL FAMILIAR ABOUT THIS
MINOR REVOLUTION AND OUR
UNDERSTANDING OF HEALTH AND OUR
INCREASING EMPHASIS IN
UNDERSTANDING OF THE EARLY LIFE
ORIGINS OF HALE AND ADULTHOOD.
IT'S BEEN ALMOST 100 YEARS THAT
WE'VE KNOWN FROM DATA COMING OUT
OF THE UK THAT ENVIRONMENTS IN
INFANCY PREDICT LONGEVITY, LIFE
EXPECTANCY, AND OBESE RISK IN
ADULTHOOD.
OVER THE PAST 20 YEARS DAVID
BARKER COMING OUT OF ENGLAND HAS
MOST SUCCESSFUL IN PROMOTING
THIS AS AN IMPORTANT AREA OF
STUDY.
AND THIS IS MORE RECENTLY
CAPTURED PUBLIC IMAGINATION WITH
A COUPLE OFKz
MORE PUBLIC PIECES ON THIS
ISSUE.
THE WAY THE PARADIGM WORKS,
WHICH I'M SURE IS FAMILIAR TO
MOST OF YOU, YOU KNOW, WE USED
TO THINK OF HEALTH IN ADULTHOOD
AS PRIMARILY A PRODUCT OF OUR
INDIVIDUAL GENETIC ENDOWMENT,
OUR CURRENT ENVIRONMENTS AND OUR
LIFESTYLES AND PERHAPS THEIR
INTERACTION, BUT NOW WE'RE
INCREASINGLY COMING TO
APPRECIATE THE IMPORTANT ROLE
THAT ENVIRONMENTAL EXPOSURES
EARLY IN LIFE HAVE IN TERMS OF
PROGRAMMING KEY PHYSIOLOGICAL
SYSTEMS WHICH HAVE SDREKT DIRECT
IMPLICATIONS FOR ADULTHOOD AND
MODERATE THE EFFECTS OF GENES IN
ADULTHOOD.
THE VAST MAJORITY OF THIS
RESEARCH HAS FOCUSED ON EARLY
NUTRITIONAL EXPOSURES AND SUCH,
BUT WE'RE MOVING BEYOND THAT
QUICKLY.
RELATED TO THAT, WE HAVE A
LONG-STANDING TRADITION IN THE
SOCIAL AND BEHAVIORAL SCIENCES
IN APPRECIATING THE IMPACT OF
EARLY ENVIRONMENTAL QUALITY,
EARLY CHILDHOOD ENVIRONMENTS ON
HEALTH, BUT ALSO ON COGNITIVE
FUNCTION, ON SOCIAL FUNCTION AND
EMOTIONAL FUNCTION.
THINGS THAT MATTER TO SOCIAL
ATTAINMENTS THAT WE CARE ABOUT.
FOLKS LIKE JIM PECKMAN, JACK AND
OTHERS HAVE BEEN AGGRESSIVELY
PROMOTING A POLICY AJEB DA BASED
ON THIS LONG-STANDING BODY OF
RESARGE, EMPATHIZING THAT
INVESTMENTS EARLY IN LIFE HAVE
GREATER IMPACT, CREATE GREATER
RETURNS THAN INVESTMENTS LATER
IN LIFE.
THESE FIELDS ARE CONVERGING AND
IT'S A VERY EXCITING TIME, I
THINK, TO BE INVOLVED IN LIFE
COURSE AND INTERGENERAL RESEARCH
RELATED TO HEALTH AND ITS SOCIAL
DETERMINANTS.
THIS IS AN AREA THAT I'M MOVING
TOWARDS AND IF THERE'S TIME AT
THE END I'LL TALK ABOUT TWO NEW
PROJECTS I'M LAUNCHING THAT ARE
RELATED TO THIS.
WE CAN START TO THINK ABOUT
SOCIAL ENVIRONMENTS AND
INEQUALITY OR VARIATION IN THOSE
ENVIRONMENT AND HOW THEY IMPACT
HEALTH IN THAT GENERATION AND
THE FUTURE GENERATION AND THEN
HEALTH ENDOWMENTS AND
ACHIEVEMENTS AND DEVELOPMENTS
THAT ONE GENERATION CAN THEN
HAVE IMPACT ON SOCIAL IMPACT ON
THAT GENERATION AND FOLLOWING
GENERATIONS.
OKAY.
I'M GOING MOVE TOWARD MY
INTEREST IN IMMUNE FUNCTION AND
INFLAMMATION, BUT START BY
TALKING ABOUT A RELATIVELY LARGE
BODY OF RESEARCH ON THE HYGIENE
HYPOTHESIS WHICH HAS SHOWN BOTH
EPIDEMIOLOGICALLY AS WELL AS
MECHANISTICALLY EXPERIMENTALLY
THAT INDIVIDUALS AS ADULTS ARE
HIGHER RISK FOR ALLERGY DISEASES
THAT ARE RELATED TO THE
DISREGULAR LAG OF IMMUNE
PROCESSES AND THAT INDIVIDUALS
WHO HAVE IMPOVERISHED NUTRITION
EARLY IN LIFE AND WHO HAVE LOWER
LEVELS OF MICROBIAL EXPOTION
MOSTLY PROXIED BY THINGS WHETHER
YOU LIVED ON A FARM OR HAVE
OLDER SIBLINGS, THESE KINDS OF
EXPOSURES ACTUALLY PROTECT YOU
AGAINST THESE KINDS OF DISEASES.
THE WORK IS REALLY FOCUSED ON
THOSE TYPES OF ATOPIC DISEASES
AND THE QUESTION I'M GOING TALK
TO YOU TODAY IS WHETHER THIS MAY
MATTER TO INFLAMMATION AND HOW
WE REGULATE THAT.
TEN YEARS AGO THIS WOULD BE A
NICHE QUESTION, BUT RIGHT NOW WE
ARE CURRENTLY OBSESSED WITH
INFLAMMATION I THINK BOTH AT
RESEARCHERS AND IN THE PUBLIC
EYE BECAUSE INFLAMMATION SEEMS
TO BE THE THING THAT'S GOING TO
DO US ALL IN.
IT'S RELATED TO CARDIOVASCULAR
DISEASE, DIABETES, DEMENTIA,
CANCER, A NUMBER OF LARGE
STUDIES HAVE SHOWN THIS AND
CLINICALLY IT'S STARTING TO BE
EVALUATED AS WELL.
INFLAMMATION IS SOMETHING WE
NEED TO BE CONCERNED ABOUT
BECAUSE 15 YEARS AGO OUR
UNDERSTANDING OF IT WAS SUCH
THAT IF YOU DID NOT HAVE AN
INFLAMMATORY SYSTEM YOU WOULD
DIE BECAUSE YOU NEED IT TO HELP
PROTECT YOU FROM INFECTION
DISEASE.
THERE'S BEEN A CHANGE IN OUR
CONCEPTUALIZATION OF
INFLAMMATION THAT'S GOING TO
FEATURE PROMINENTLY IN THE STORY
I'LL TELL TODAY.
WHAT HAS LED TO THIS?
SOME OBSERVATIONS COMING OUT OF
CARDIOVASCULAR EPIDEMIOLOGY
WHICH HAS SHOWN THAT IF YOU
MEASURE A KEY BIO MARKER OF
INFLAMMATION, IF UH YOU MEASURE
IT AND DETECT IT AT LEVELS THAT
WERE CONSIDERED UNDETECTABLE BUT
WITH NEW ASSAYS THAT ARE
SENSITIVE WE CAN MEASURE IT, IT
PROVIDE ADDITIONAL PREDICTIVE
RISK FOR CARDIO VAS YOU CAR
DISEASE THAN TRADITIONAL
MEASURES.
HERE YOU HAVE YOUR RATIO
CHOLESTEROL TO HDL.
AS THIS GOES DOWN, YOUR RISK OF
HEART ATTACK GOES DOWN, BUT ALSO
YOUR LEVEL OF CRP INDEPENDENTLY
OF YOUR LIPID LEVEL HIGHER LEVEL
ASSOCIATED WITH HIGHER RISK.
THAT'S A KEY FEATURE OF THIS.
IN THE POPULATION IN DEMOGRAPHIC
SCIENCES INFLA MAKS HAS ALSO
GOTTEN ATTENTION BECAUSE A PAPER
HAS HAVE PROPOSED THAT LIFE
EXPECTANCY IS DUE TO REDUCTIONS
IN INFECTION DISEASE, MORBIDITY
WHICH IS IN TURN LOWERED BURDENS
OF INFLAMMATION THROUGHOUT AN
INDIVIDUAL IS'S LIFE COURSE AND
WHAT THEY CALL HAS LED TO THE
DEVELOPMENT OF A COHORT
MORBIDITY PHENOTYPE.
IF YOU REDUCE IN CHILDHOOD YOU
REDUCE THE OVERALL LIFETIME
BURDEN OF INFLAMMATION AND
THEREFORE SINCE INFLAMMATION IS
CONTRIBUTOR TO CARDIO VASULAR
VASCULAR DISEASE -- THOSE DATA
ARE NOT WITHOUT SOME
CONTROVERSY.
NO MEANS A DONE DEAL.
NONETHELESS, IT'S AN IMPORTANT
PART OF OUR CURRENT
UNDERSTANDING OF INFLAMMATION.
THIS IS WHAT I'M CALLING THE
CHRONIC LOW-GRATE FLAN MAGS
x INFLAMMATION MODEL. MOD --çV
WITH THIS IS A STUDY OF CR BIO
VESHLT.
IT'S HEAVILY CITED -- THESE ARE
A SET OF FOUR INDIVIDUALS WHO
ARE SAMPLED AT THREE OR FOUR DAY
INTERVALS OVER SEVEN WEEK PERIOD
AND THE DOTS JUST CONNECT THEIR
VALUES.
SO WHAT YOU SEE, THE INDIVIDUALS
HERE AT THE BOTTOM THERE'S A
LITTLE BIT OF NOISE BUT PRETTY
CONSISTENTLY THEY'RE LOW AND
LOWER THAN THESE TWO INDIVIDUAL
AT THE TOP.
IF YOU JUST DO ONE SNAPSHOT IN
TIME YOU'LL BE ABLE TO
DIFFERENTIATE THESE TWO.
THIS MEASURE SHOULD HAVE SOME
PROGNOSTIC VALUE.
THE ASSUMPTION IS THAT ONE
INDIVIDUAL MEASURE OF CRP WILL
IDENTIFY AND SEPARATE THESE
INDIVIDUALS.
THAT'S AN IMPORTANT PART OF THE
PHYSIOLOGY OF THE SYSTEM AS WELL
AS HOW WE LOSE USE IT
EPIDEMIOLOGICALLY.
IN TERMS OF PHYSIOLOGY, HERE'S
HOW THE MODEL WORKS.
BODY FAT IS VERY IMPORTANT
SOURCE OF PROINFLAMMATION
CYTOKINES.
THOSE ENTER GENERAL CIRCULATION
AND THEN THEY GO THE LIVER,
CELLS IN THE LIVER PRODUCE --
-- IN TURN PROMOTE THE
PRODUCTION OF CRP.
CRP ENTERS GENERAL CIRCULATION
AND THEN IT HAS THESE EFFECTS
THAT ALL LEAD TO THE INITIATION
AND PROGRESSION OF
ATHEROSCLEROSIS.
THESE PROCESSES ARE INDEPENDENT
OF OTHER PATH PHYSIOLOGICAL
PROCESSES RELATED TO LIPIDS
AND -- THIS IS THE MODEL THAT
UNDERLIES MUCH OF THIS RESEARCH.
OKAY.
WHAT DO THESE TWO HAVE IN
COMMON?
FROM THE LOOK OF HIM AROUND THE
MIDDLE, UM, PROBABLY HAS PRETTY
HIGH LEVELS OF CRP.
VISCERAL ATA POST TISSUE AROUND
THE MIDDLE IS MOST IMPORTANT --
HE PROBABLY HAS ELEVATED CRP,
SHOULD BE INCREASING HIS RISK
FOR CARDIOVASCULAR DISEASE AS
WELL AS OTHER BAD THINGS.
THIS IS A HORSESHOE CRAB.
BEEN ON THE PLANET SINCE THE
DAYS OF THE DINOSAURS, ALSO HAS
VERY HIGH CONCENTRATIONS OF CRP
AND THAT'S BECAUSE THE IMMUNE
SYSTEM OF THE HORSESHOE CRAB
DEPENDS ON PATTERN RECOGNITION
MOLECULES AS A FIRST-LINE
DEFENSE AGAINST INFECTIONS.
IT DOES NOT HAVE AN ELABORATED,
SPECIFIC HUMERAL AND
LYMPHOCYTE-DRIVEN SYSTEM LIKE
MAMMALS DO.
C REACTIVE PROTEIN WAS
DISCOVERED IN 1930 FOR ITS
ABILITY TO BIND TO
[INDISCERNIBLE] REGION.
IT WAS FIRST DISCOVERED AS -- IT
PLAYS AN IMPORTANT ROLE IN ALL
ORGANISMS THAT HAVE IT.
THIS IS WHAT THE MODEL LOOKS
LIKE.
IT'S NOT A CHRONIC ACTIVATION,
IT'S A ACUTE PHASE OR A CUTELY
RESPONSIVE MODEL WHERE YOU HAVE
BASICALLY UNDETECTIBLE LEVELS OF
C REACTOR PROTEIN.
YOU GET CHALLENGED WITH A
BACTERIUM, A VIRUS, OR AN INJURY
THAT HAS TO BE DEALT WITH, AND
LEVELS OF CRP INCREASE BY THREE
OR FOUR ORDERS OF MAGNITUDE
WITHIN 24-48 HOURS AFTER
EXPOSURE.
THAT PROVIDES A VERY RAPID
FRONTLINE OF DEFENSE AGAINST THE
INFECTION AGENT, AND THEN AS THE
INFECTION STARTS TO RESOLVE AND
IS MORE SPECIFIC IMMUNE DEFENSES
START TO COME ONLINE WHICH CAN
TAKE FOUR, FIVE DAYS TO COME ON,
THE CONCENTRATION OF C REACTIVE
PROTEIN DROP DOWN TO BASELINE.
THAT'S AN ACUTE PHASE MODEL.
THEN, AGAIN, IN TERMS OF
MECHANISM AND PHYSIOLOGY, YOU
HAVE A PATHOGENIC CHALLENGE,
PROINFLAMMATORY MEDIATORS LIKE
IL 6.
THESE INDUCE THE LIVER TO
PRODUCE MORE CRP.
THEY ALSO CROSS THE BLOOD BRAIN
BARERIER AND IP DEUCE THE
SYMPTOMS WE ASSOCIATE WITH
INFLAMMATION LIKE FEVER OR
TIREDNESS.
CRP ACTIVATES COMPLIMENTS,
PROMOTES THE ACTIVITY OF
[INDISCERNIBLE] CELL WHICH IS
CAN CLEAR YOUR BODY OF THESE
INFECTION DISEASES AND IT TAGS
THEM SO THEY'RE RECOGNIZED BY
THE BODY OF BEING FOREIGN AND
HELPS US CLEAR OUR BODY OF
THINGS LIKE THIS.
THAT'S THE ACUTE PHASE MODEL.
WE HAVE THIS SITUATION WHERE WE
HAVE A PHYSIOLOGICAL SYSTEM THAT
IS RESPONSIVE TO TWO DOMAINS OF
STIMULI.
ONE BEING PATHOGENS AND THE
OTHER BEING BODY FAT, AND THEY
SHARE A COMMON PHYSIOLOGICAL
PATHWAYS WE RELATED TO CYTOKINES
WHICH LEAD TO THE ACTIVATION OF
INNATE IMMUNE PATHWAYS AS WELL
AS PERHAPS INCREASING RISK FOR
CARDIOVASCULAR DISEASE.
NOW THE PROBLEM IS, WE ONLY
STUDY THE SYSTEM IN PEOPLE LIKE
THIS, RIGHT?
SO WE WERE LOOKING AT THIS
PATHWAY, BUT THE WAY THE SYSTEM
FUNCTIONS, THE WAY IT HAS
EVOLVED T WAY IT FUNCTIONS IN
OTHER MAMMALS AND VERTEBRAS
INVOLVES PRIMARILY THESE KINDS
OF"
IN STUDYING THIS SYSTEM ONLY INN>
RELATIVELY PRIVILEGED AFFLUENT
POST EPIDEMIOLOGICAL TRANSITION
SETTINGS WITHOVER NUTRITION AND
LOW LEVELS OF ARTIFICIAL DISEASE
WE CONSTRAIN THE RANGE OF
ENVIRONMENTAL VARIATION WHICH
MAY BE CRITICAL IN UNDERSTANDING
THIS SYSTEM IN A MORE
COMPREHENSIVE WAY.
FOR THAT REASON, I'VE BEEN
LOOKING AT INFLAMMATION AND ITS
CORE LETS IN BOW LI YEAH,
PHILIPPINES AND ECUADOR AS WELL
AS THE UNITED STATES, AND I'M
GOING TO BE TALKING ABOUT TWO
STUDY WE'VE BEEN DOING ONE IN
PHILIPPINES AND ONE IN ECUADOR.
THIS SURVEY BEGAN IN THE EARLY
80s.
INITIALLY STARTED AS AN
INVESTIGATION OF MA TERRIBLE AND
CHILD HEALTH AND THE PREDICTORS
OF CHILD SURVIVAL AND BREAST
FEEDING AND GROWTH IN LOW-INCOME
DEVELOPING WORLD SETTINGS LIKE
THE PHILIPPINES.
IT DID THAT VERY WELL, WAS AN
IMPORTANT STUDY IN DEMONSTRATING
THE HEALTH BENEFITS OF BREAST
FEEDING AT A TIME WHEN FORMULA
USE WAS ON THE RISE ARNGSD THEN
THE STUDY ENDED.
IT WAS DESIGNED TO -- IT BEGAN
WITH A RECRUITMENT OF MORE THAN
THREE THOUSAND WOMEN FROM 30
RANDOMLY-SELECTED NEIGHBORHOODS
AROUND SABU CITY WHICH WAS THE
SECOND LARGEST METROPOLITAN AREA
IN THE PHILIPPINES.
EVERY WOMAN IN THIS WHO WAS
PREGNANT DURING A FIXED WINDOW
OF ENROLLMENT WAS ASKED TO
PARTICIPATE AND OVER 95% OF THEM
DID SIGN UP.
THEY WERE INTERVIEWED,
MEASUREMENTS WERE TAKEN OF THEM
AND THEIR HOMES AND THEIR
NEIGHBORHOODS AND THEN AT THE
DELIVERY OF THEIR BABY, THEY
WERE WEIGHED AND THEN EVERY TWO
MONTHS FOR THE FIRST TWO YEARS
OF THEIR OFFSPRING'S
WERE VISITED IN THE HOME, BABY
WAS A BIGGED, LENGTH WAS
MEASURED, INFORMATION COLLECTED
ON BRAETS FEEDING, DIET, HOW THE
MOM WAS DOING, LEVELS OF
INFECTION DISEASE.
STUDY WAS DESIGNED TO END THERE,
BUT ST THE STUDY WAS DONE IN
COLLABORATIVE WITH COLLEAGUES
C TOUCH WITHES, THE AND THEY KEPT.
PARTICIPANTS TO SEE HOW THE KIDS
WERE DOING.
THEN HERE IN 98 AND 99 WHEN THE
KIDS WERE 14 AND 15 I WAS DOING
A POST DOC AT UNC CHAPEL HILL.
IT WAS ABOUT THE TIME THAT THIS
IDEA THAT WE NEEDED TO PAY MORE
ATTENTION TO EARLY ENVIRONMENTS
AS PREDICTORS OF HEALTH AND
PHYSIOLOGICAL FUNCTIONS OF
ADULTHOOD STARTED TO COME
ONLINE.
WE REALIZED THIS DATASET WAS THE
BEST IN THE WORLD FOR LOOKING AT
THESE KINDS OF QUESTIONS GIVEN
THE HIGH RESOLUTION OF PROSE
PROTECTIVELY COLLECTED DATA WE
HAVE IN INFANCY.
WE DID A LITTLE BIT OF WORK
HERE, BUT, UM, GENERATED A BUNCH
OF PROJECTS TO DO A MAJOR
FOLLOW-UP AT 2005 WHERE WE COULD
FIND 1885 OF THE ORIGINAL
PARTICIPANTS WHO WERE IN THEIR
EARLY 20s AT THE TIME.
WE DID A FULL SEX SOCIAL
DEMOGRAPHIC SURVEY OF THEM AND
WE ALSO COLLECTED BLOOD AND
SALIVA SAMPLES.
THESE ARE THINGS WE MEASURED IN
THOSE SAMPLES.
I'LL TALK ABOUT THOSE IN A
MOMENT.
OKAY.
SO THIS IS WHAT CRP LOOKS LIKE
IN THE PHILIPPINES COMPARED TO
ANN HAEN'S DATA.
I'M SHOWING YOU HERE IS DATA
FROM ANN HAENS AGE AND SEX
MATCH.
THESE ARE YOUNG ADULTS IN THE
UNITED STATES AND OVERALL THE
LEVEL OF CRP IN FILIPINO YOUNG
ADULTS IS.2 OR.3 MILLIGRAMS PER
LITTER COMPARED TO.9 MILLIGRAMS
PER LITTER THE UNITED STATES.
CONSISTENTLY IN THE U.S. WE SEE
WOMEN TEND TO HAVE HIGHER THAN
MEN, THAT'S NOT SO IN THE
PHILIPPINES.
THIS SEEMS COUNTERINTUITIVE TO
US.
HERE WE HAVE THE PHILIPPINES
WHICH HAS MORE INFECTION
DISEASE.
THE UNITED STATES IS IN THE --
INFECTION DISEASE STILL THE
NUMBER TWO SOURCE OF MORTALITY
IN THE PHILIPPINES, SO THERE WAS
A BURDEN OF INFECTION THAT IS
HIGHER THAN IN THE UNITED
STATES.
SO IF CRP IS INVOLVED IN
INFLAMMATION, MAYBE YOU MIGHT
EXPECT IT TO BE HIGHER BUT THAT
WAS NOT THE CASE.
ONE OBVIOUS POSSIBILITY BASED ON
WHAT I'VE SAID BEFORE ABOUT THE
ROLE OF BODY FAT IN PROMOTING
THE PRODUCTION OF CRP IN
ACTIVATING INFLAMMATION PATHWAYS
IS DIFFERENCES IN BODY FAT
DISTRIBUTION.
AMERICANS ARE HEAVIER THAN FILL
PIN KNOWS.
IN 2005, THE AVERAGE WAIST SIR
KIM FRENS WAS 70 COMPARED TO
ALMOST 89 CENTIMETERS IN THE
UNITED STATES.
MAYBE THAT EXPLAINS THE
POPULATION DIFFERENCE.
HERE WE HAVE THAT COMPARISON
BASED ON WEIGHT SUR
CIRCUMFRANCE GROUP.
AMERICANS PRODUCE MORE CRP THAN
FOLKS IN THE PHILIPPINES DO.
THERE'S SOMETHING ELSE GOING ON
HERE, AND MY$(D
WHETHER EARLY ENVIRONMENTAL
FACTORS MIGHT EXPLAIN THAT THIS.
THERE IS ANOTHER POSSIBILITY AND
I ALWAYS USED TO GET THIS
QUESTION AND I'M HAPPY TO HAVE
AN ANSWER THAT GENETIC
DIFFERENCES ACROSS THE
POPULATIONS CAN NOT EXPLAIN THE
DIFFERENCES IN CRP.
INFLAMMATION THERE ARE SNPs AND
ALLELES THAT MATTER TO
INDIVIDUAL DIFFERENCES AND
INFLAMMATION.
I HAVE A COLLEAGUE IN UNC CHAPEL
HILL WHO DOES GENETIC COMPLEX
DISEASES AND BECAME A
COLLABORATOR ON THIS PROJECT AND
IN 2005 SHE USED THE DNA CAMP V
SAMPLE AND LOOKS AT -- THESE ARE
DISEASES, GENES THAT HAVE BEEN
PREVIOUSLY ASSOCIATED IN THE
UNITED STATES AND IN WESTERN
EUROPE WITH HIGHER OR LOWER
LEVELS OF CRP AND WE FIND A VERY
SIMILAR PATTERN OF ASSOCIATION
WITH N THE PHILIPPINES.
WE EXPLAIN SMALL AMOUNTS OF
VARIANCE IN CRP, FOUR OR FIVE
PERCENT AND THEY'RE NOT DRAMATIC
POPULATION DIFFERENCES IN THE
LEVEL OF PROAND ANTIINFLAMMATION
SNPs ACROSS THE TWO SETTINGS.
THE GENES MATTER BUT NOT TO THE
STORY I'M TELLING YOU HERE
TODAY.
ALL RIGHT.
SO NEW EARLY ENVIRONMENTS
MATTER?
SO DO EARLY ENVIRONMENTS MATTER?
SO THE MODEL IS THAT I'M GOING
TAKE YOU THROUGH SHEER THAT WE
KNOW AS AN ADULT YOUR LEVEL OF
BODY FAT, YOUR LEVEL OF
PATHOGENIC EXPOSURES, BOTH THESE
THINGS MATTER TO YOUR
CONCENTRATION OF CRP AS WELL AS
BEHAVIORAL THINGS.
MIGHT THERE BE ANALOGOUS
EXPOSURES EARLY IN LIFE IN
INFANCY THAT MAY PROGRAM THE
SYSTEM OR HAVE A DIRECT EFFECT
IN THE SYSTEM ON SOME MEANINGFUL
WAY?
THIS IS A MODEL THAT'S GUIDING
MY SELECTION OF VARIABILITIES
AND IN TERMS OF TIMING WHEN
WE'RE LOOKING AT THESE
EXPOSURES, A PRIORITY THERE ARE
VERY GOOD REASONS TO THINK THAT
THE FIRST YEAR IN PARTICULAR BUT
PROBABLY THE FIRST TWO YEARS OF
LIFE IN INFANCY ARE CRITICAL
PERIODS OF DEVELOPMENT OF THE
IMMUNE SYSTEM.
THIS FIGURE SHOWS YOU THAT.
THIS IS THE POINT TO TAKE AWAY.
WHAT THE TOP FIGURE IS AN E NUM
RATIVE REPRESENTATION OF WHERE
ASPECT OF THE IMMUNE SYSTEM ARE
THROUGHOUT THE LIFE COURSE AND
THIS IS A FUNCTIONAL MEASURE.
I'LL TALK YOU THROUGH IT.
ON THE X AXIS IS AGE GOING FROM
BIRTH TO 20 YEARS.
THE Y AXIS IS PERCENT OF ADULT
LEVEL.
THIS IS WHERE YOU'RE AT, AT AGE
20.
AS AN INFANT YOUR NUMBER OF T
AND B CELLS ARE TWO TO THREE TO
FOUR TIMES HIGHER DESPITE THE
FACT THAT YOU ONLY WEIGH TEN
POUNDS THE ABSOLUTE NUMBER OF
CELLS ARE HIGHER.
THE SIZE OF THE THYMUS IS DOUBLE
IN INFANCY THAN WHAT IT IS FOR
US IN THE ROOM RIGHT NOW.
THE FUNCTION OF THESE CELLS, OF
THE LYMPHOCYTES IS UP REGULATED.
THEY'RE SENSITIVE TO ACTIVATION
AND THAT'S WHAT THIS IS SHOW
YOU.
IF YOU XROOIM PRIME THESE CELLS
THEY WILL REPLICATE AND DIVIDE.
THERE ARE ASPECTS OF THE IMMUNE
SYSTEM OF THE SPECIFIC IMMUNE
SYSTEM THAT ARE VERY ACTIVE IN
INFANCY.
THIS MAKES SENSE IF YOU THINK
ABOUT WHAT THE IMMUNE SYSTEM HAS
TO ACHIEVE.
YOU'RE BEING BORN INTO AN
INFECTION DISEASE ECOLOGY THAT
YOU CAN NEVER ANTICIPATE BECAUSE
MICROORGANISMS EVOLVE SO QUICKLY
ON THE ORDER OF DAYS OR PERHAPS
WEEKS OR HUMANS EVOLVED ACROSS
GENERATIONS THAT ARE 15-30 YEARS
LONG.
WE CAN'T COMPETE ON THAT LEVEL.
WE HAVE TO LEARN THROUGH A
SERIES OF VERY COOL PROCESSES
THAT SORT OF EMBODY DARWINIAN
PROCESSES WITHIN OUR OWN BODIES,
WE HAVE TO LEARN ABOUT OUR
INFECTION DISEASE ECOLOGY AND
THAT'S WHAT'S GOING ON IN
INFANCY.
THAT'S WHY THESE PROCESSES ARE
UP REGULATED.
THIS POINTS TO INFANCY AS A
CRITICAL PERIOD OF EDUCATION OF
THE IMMUNE SYSTEM WHERE
ENVIRONMENTS MAY HAVE
DISAPPROPRIATIONAL LONG-TERM IP
PACT.
THAT'S THE PART WHERE I'M
LOOKING IN INFANCY.
ALSO I HAVE DATA FOR THE FIRST
TWO YEARS, SO THAT'S THE
IMPORTANT PART OF WHY I'M DOING
THAT.
THIS IS WHAT WE HAVE IN TERMS OF
OPERATIONALIZING AND TESTING
SOME OF THESE PIE POT CEASE.
FROM THIS STUDY WE HAVE MEASURES
OF BIRTH WEIGHTS MEASURED,
LENGTH OR WEIGHTS, WHETHER THE
GESTATIONAL AGE AND WHETHER THE
BABY WAS DELIVERED PRETERM OR
NOT.
SOCIO ECONOMIC STATUS FOR
PEOPLE.
WE HAVE WEIGHT GAIN AND LENGTH
GAIN OF THE INFANT, DURATION AND
PATTERN OF BREAST FEEDING.
MULTIPLE LEVELS OF CLEANLINESS
AND SANITATION AND SELF-RECORDED
OR MOM-REPORTED SYMPTOMS OF
INFECTION DMZ THE INFANT.
COMPARABLE MEASURES IN ADULTHOOD
THAT PRIOR RESEARCH IN THE U.S.
AND
MATTER TO INFLAMMATION THAT WE
CAN CONTROL FOR.
SOME OF THESE MAY BE ON THE
CAUSAL PATHWAY BUT THE RESULTS
DON'T CHANGE WHETHER WE INCLUDE
THESE OR NOT.
THIS IS WHAT WE FOUND5
RESPECT TO BIRTH WAITHD AND CRP
IN ADULTHOOD.
INDIVIDUALS WHO WERE BORN WITH
LARGER BIRTHWEIGHTS HAVE LOWER
CRP AS YOUNG ADULTS.
I'M MODELLING HERE THE
PROBABILITY OF ELEVATED CRP.
THE RESULTS ARE THE SAME IF I
PRESENT THE ACTUAL CRP
CONCENTRATIONS.
LIKE IF THERE'S A QUESTION I CAN
TELL YOU WHY I DECIDED TO -- IT
HAS TO DO WITH DISTRIBUTION BUT
THE RESULTS ARE ESSENTIALLY THE
SAME.
AS BIRTH WEIGHT GOES UP,
PROBABILITY OF HIGH CR P P GOES
DOWN.
THIS IS IMPORTANT BECAUSE THERE
ARE LOTS OF STUDIES THAT HAVE
SHOWN THAT BIRTH WEIGHT IS
ASSOCIATED WITH CARDIOVASCULAR
RISK IN ADULTHOOD.
THIS SUGGESTS THAT INFLAMMATION
COULD BE A MECHANISM THROUGH
THAT WHICH THAT -- THIS CANNOT
EXPLAIN THE POPULATION
DIFFERENCES IN CRP ACROSS THE
U.S. AND PHILIPPINES.
FILIPINOS IN GENERAL GIVE BIRTH
TO LOWER BIRTH WEIGHT BABIES.
SO IF ANYTHING SHE SHOULD HAVE
HIGHER CONCENTRATIONS OF CRP
COMPARED TO AMERICANS THIS IS
NOT PART OF THE BIGGER STORY
THAT I'M TRYING TO TELL YOU
HERE.
ALTHOUGH I THINK IT IS
IMPORTANT.
RI YEAH MORBIDITY IN INFANCY IS
AN IMPORTANT PREDICTOR OF CRP.
THIS IS, I THINK, MORE
INTERESTING, AND WHAT I'M
SHOWING YOU HERE IS THAT THIS IS
THE NUMBER OF INTERVALS, THE
INTERVIEWER WENT INTO THE MOM'S
HOME AND ASKED THE MOM OVER THE
PREVEEDING SEVEN DAYS HAS YOUR
BABY EXPERIENCED SYMPTOMS OF
DIARRHEA INFECTION.
THIS IS THE NUMBER OF INTERVALS
IN INFANCY DURING WHICH THE MOM
SAID YES.
IT'S NOT A COMPLETE CENSUS OF
DIARRHEA MORBIDITY IN INFANCY
BUT IT'S HIGHLY CORRELATED WITH
THAT.
BABIES WHO HAD HIGHER LEVELS OF
DIARY YEAH IN INFANCY HAVE LOWER
LEVEL OF CRP AS AN ADULT.
INTERVIEWERS WENT INTO THESE
HOMES AND OBSERVED THE HOMES.
ONE OF THE THINGS THEY LOOKED
FOR WAS WHETHER BABIES WERE AT A
STAGE OF CRAWLING AND WHETHER
ANIMAL FEE IS IS WAS PRESENT ON
THE HOME.
MANY OF THESE HOMES WERE OPEN.
THIS IS A TROPICAL ENVIRONMENT.
PIGS, FOWL, DOGS WERE ALOUD TO
ROAM FREELY IN AND OUT OF THE
HOME.
IT WAS NOT UNLIKELY THAT BABIES
WOULD COME IN CONTACT WITH
ANIMAL FEE IS I FI IS IS.
THE NUMBER OF TIMES THE
INTERVIEWER CAME INTO THE HOME
AND SAW THAT THIS SITUATION WAS
HAPPENING.
A HIGHER FREQUENCY OF CONTACT
WITH FEE CALL MATERIAL, LOWER
CRP AS AN ADULT.
ALSO A HIGHER SEASONAL
ENVIRONMENT WITH A RAINY SEASON
AND DRY SEASON.
THAT SEASONALITY IS ALSO
ASSOCIATED WITH SEASONALITY
INFECTION DISEASE BURDEN.
A LOT OF THE EARLY WORK ON THIS
STUDY WAS ASSOCIATED WITH
SEASONALITY AND TRANS AND
INFECTION DIARRHEA AND HOW
BREAST FEEDING CAN BUFFER
INFANTS FROM THAT SITUATION.
INFANT BORN IN THE DRY SEASON
ACTUALLY EXPERIENCE MORE
INFECTION DISEASES IN THEIR
FIRST YEAR OF LIFE BECAUSE THE
ALIVE FOR MORE OF THE NON-DRY
SEASON, RIGHT.
LITTLE COUNTERINTUITIVE.
KIDS BORN IN THE DRY SEASON IF
YOU LOOK AT HOW THAT ASSOCIATED
WITH INFECTION DISEASE EXPOSURE,
THEY HAVE MORE AND THEY ALSO
HAVE LOWER CRP AS AN ADULT.
SO WE HAVE THREE MEASURES OF
MICROBIAL EXPOSURE IN INFANCY.
EACH ON ITS OWN I WOULDN'T PUT
TOO MUCH STOCK IT BUT EACH HAVE
DIFFERENT LEVELS AND STRENGTHS
TO THEM AS MEASUREMENT
CONSTRUCTS AND THEY SUGGEST THAT
LOWER LEVELS OF MICROBIAL
EXPOSURE ASSOCIATED WITH HIGHER
CRP AND THAT'S INDEPENDENT OF
PRENATAL UNDERNUTRITION OR LOWER
BIRTH WEIGHT.
THE MECHANISMS ARE NOT KNOWN.
THIS IS SOMETHING THAT WE'RE
STARTING TO LOOK AT AND I'LL
TALK ABOUT IN A MOMENT, BUT ONE
POSSIBILITY IS THAT THERE'S
HIGHER LEVEL OF PROINFLAMMATORY
SIGNALING, IL 6 IN PARTICULAR.
IL 10 DISRUPTS IL 6.
THERE ALSO COULD BE CHANGES IN
THE PHENOTYPES OF T CELLS IN
PARTICULAR LIKE P REGULATORY
CELLS THAT PRODUCE A LOOT OF
ANTI-INFLAMMATORY ACTION.
SO MEK NISICALLY WE DON'T KNOW
EXACTLY WHAT'S GOING ON, IF
THERE'S ANY IMMUNOLOGISTS OR
MOLECULAR BIOLOGISTS IN THE
AUDIENCE, MAYBE YOU HAVE IDEAS.
CONCEPTUALLY, THIS IS WHAT I
THINK IS GOING ON.
IN A HIGH PATHOGEN ENVIRONMENT,
YOU CAN IMAGINE THESE RED ARROWS
AS KROEB Y'ALL CHALLENGES AND
EXPOSURE IN INFANCY DURING THIS
CRITICAL PERIOD OF IMMUNE
DEVELOPMENT, AND SO YOU GET A
CHALLENGE, THE SYSTEM BECOMES
ACTIVATED AND THEN IT TURNS
ITSELF OFF, AND YOU DO THAT OVER
AND OVER AND OVER AGAIN.
SO YOU HAVE LOTS OF
OPPORTUNITIES, LOTS OF
EDUCATIONAL OPPORTUNITIES FOR
YOUR SYSTEM TO.COM IN RESPONSE
TO THE LOCAL INFECTION DISEASE
ECOLOGY.
TO THE EXTENT THIS IS A
SENSITIVE PERIOD PHENOMENON,
THOSE PATHWAYS CARRY FORWARD
INTO ADULTHOOD AND THEN WHEN
YOU'RE EXPOSED TO A
PROINFLAMMATORY STRESSOR IN
ADULTHOOD, YOU NOUNT A QUICK AND
EFFICIENT RESPONSE THAT THEN
BECOMES SHUTDOWN WHEN THE
INFECTION HAS RESOLVED OR THE
ISSUE IS RESOLVED.
SO IT'S A VERY EFFICIENT ON AND
OFF KIND OF DYNAMIC.
IF YOU'RE IN A MORE SANITARY
HIGH GEE NICK LOW PATHOGEN
ENVIRONMENT, YOU HAVE FAR FEWER
OPPORTUNITIES FOR THIS KIND OF
EDUCATIONAL PROCESS TO UNFOLD
AND THEN PERHAPS AS AN ADULT
LACKING THOSE WHILE EDUCATED
REGULATORY PATHWAYS WHEN THERE'S
AN INFLAMMATORY STIMULUS T
SYSTEM ACTIVATES, BECOMES
OVERACTIVATED OR BECOMES SLOW
TORE TURN ITSELF OFF OR KIND OF
MEANDERS IS IS NOT VERY ACUTELY
REGULATED, IT'S SORT OF ALWAYS
ON AT A CHRONIC LEVEL.
SO WAS THERE ANY EVIDENCE FOR
THIS?
THIS IS MY INTERPRETATION OF WHY
THERE MAY BE LOWER CP IN THE
PHILIPPINES BUT DO WE HAVE ANY
EVIDENCE TO SUPPORT THAT?
SO ONE SOURCE OF EVIDENCE IS
THAT IN THOSE 2005 BLOOD SAMPLES
WE MEASURED THE CRP IN AND I
JUST TOLD YOU ABOUT, WE ALSO
MEASURED IL 6 AND IL 10 AS PROAN
ANTI-INFLAMMATORY CYTOKINES,
RESPECTIVELY.
THE DOTS SHOW YOU PREVIOUSLY
PUBLISHED VALUES FOR POPULATIONS
ALL OVER THE WORLD BUT MOSTLY IN
WESTERN EUROPE AND THE UNITED
STATES.
THESE ARE VALUES FROM HEALTHY
ADULTS.
THERE'S A TON OF WORK USING
CLINICAL POPULATIONS, SO WE
GRADUATE OPPORTUNITY SPENT A LOT
OF TIME MINING THE LITERATURE
AND FINDING STUDIES THAT HAD
HEALTHY CONTROLS AND WE
SUMMARIZED THAT AND THE AVERAGE
IL 6 CONCENTRATION ACROSS THESE
STUDIES IS 1.9 MILLIGRAMS PER
LITTER AND AVERAGE IL 10 IS
3.17.
IN THE PHILIPPINES IL 6 IS LOWER
AND IL 10 IS HIGHER.
THIS IS PARTICULARLY
INTERESTING.
THIS IS QUITE A BIT HIGHER.
THERE COULD BE A DIFFERENT
AMBULANCE OF
PROTOANTI-INFLAMMATORY CRY TOE
KIND SIGNALLING IN THE
PHILIPPINES THAT MAY EXPLAIN THE
TYPE CONTROL IN THE LOWER LEVELS
OF C REACTIVE PROTEIN.
THAT'S MY INTERPRETATION FOR
THIS MODEL.
GOING FORWARD, WE WANTED TO DO A
STUDY OF CRP BIO VARIABILITY IN
ENVIRONMENT CHARACTERIZE BID
HIGHER LEVELS OF INFECTION
DISEASE.
WE DID THIS IS ECUADOR LAST
SUMMER.
THIS IS THE MOD UNTIL THE UNITED
STATES T CHRONIC LOW-GRADE
INFLAMMATION MODEL I WAS TELLING
YOU ABOUT.
IF YOU ARE BORN INTO A VERY
SANITARY ENVIRONMENT, WHEN THEN
WE KNOW AT LEAST CORRELATIONALLY
AS AN ADULT YOU'RE
A PATTERN OF CRP PRODUCTION LIKE
THIS WITH BETWEEN VARIATION AND
RELATIVELY STABLE WITH
INDIVIDUAL VARIATION OVERTIME.
WE HAVE NO IDEA WHAT THOSE
DYNAMICS LOOK LIKE IN A PREEPI
TRANSITION POPULATION THP.
THERE ARE TWO STUDIES THAT HAVE
LOOKED THAT IN THE UNITED
STATES.
TWO STUDIES OF CRP BIO
VARIABILITY PERIOD BOTH IN THE
UNITED STATES BOTH WITH THE SAME
CONCLUSION, BUT WHAT DOES IT
LOOK LIKE IN THE EK DOR YAN
AMAZON?
WE DON'T KNOW.
IT COULD BE WE GET A PATTERN
LIKE THIS OR THIS, OR THIS
PATTERN BUT EVERYTHING IS
SHIFTED UP WHICH IS IN FACT WHAT
THE COHORT MORBIDITY HYPOTHESIS
WOULD SUGGEST.
WE WANTED TO FIGURE THAT OUT.
WE DESIGNED A STUDY AND
IMPLEMENTED IT IN ECUADOR.
I'M GOING TO SHOW YOU THE
RESULTS IN A MINUTE.
THIS IS FROM ONE OF THE STUDIES
OF CRP BIOVARIABILITY IN THE
UNITED STATES.
THESE ARE INDIVIDUALS ON THE X
AXIS AND THEIR CRP.
THIS IS OVERzL
EACH DOT REPRESENTS A CRP VALUE
FOR THAT INDIVIDUAL.
EACH INDIVIDUAL HAS MULTIPLE
SAMPLES AND THIS LINE REPRESENTS
THREE MILLIGRAMS PER LITTER.
THAT'S THE COMMONLY USED CUT
POINT TO IDENTIFY RYE HIE RISK
CRP CONCENTRATION.
YOU SEE THERE'S SEPARATION HERE.
THERE ARE INDIVIDUALS FOR WHOM
CRP IS CONSISTENTLY ABOVE THIS
THREE MILLIGRAM PER LITTER
THRESHOLD AND A NUMBER OF
INDIVIDUAL WHO IS FLIRT WITH
THAT LINE DOWN HERE.
THERE'S A LOT OF AGAIN BETWEEN
INDIVIDUAL VARIATION AND NOT AS
MUCH WITHIN.
SO WHAT DO WE SEE IN LOW LAND
ECUADOR.
THE STUDY WE DID WITH THE SHOAR,
THEY'RE IN THE AMAZON BASIN --
ANDES MOUNTAINS RUN HERE, BUT
THE ACTUAL BASIN OF SOUTH
AMERICA BEGINS ON THE EAST COAST
OF THESE MOUNTAINS.
TROPICAL RAIN FOREST, THEY LIVE
IN A SYSTEM OF „iRIVERS, VERY FEW
ROADS, NO RUNNING WATER, NO
ELECTRICITY AND HYPER INFECTION
DISEASE.
THEY'RE HORTICULTURAL LIST,
LITTLE BIT OF HUNTING AND
FISHING.
HIGH DEGREE OF CHILD DEATH DUE
TO INFECTION DISEASES AND THE
MAIN SOURCE OF ILLNESS ARE
[INDISCERNIBLE].
WE DID THIS STUDY WITH 52
ADULTS, 18-50 YEARS OF AGE.
FOUR WEEKLY SAMPLING INTERVALS.
WE VISITED THEM EVERY WEEK TO
THE DAY AND WE COLLECTED A DRY
BLOOD SPOT SAMPLE.
THIS IS RELATED TO ONE OF THE
MAJOR AREAS OF MY RESEARCH WHICH
IS THE DEVELOPMENT OF MINIMALLY
INVASIVE METHODS THAT ALLOW US
TO STUDY HUMAN PHYSIOLOGY IN THE
AMAZON.
WE COLLECT THE SAMPLE BY NICKING
THE PERSON'S FING FINGER WITH
THE LAN SET AND WE PUT THE BLOOD
ON TO THIS FILTER PAPER.
THE BLOOD DRYS ON THE CARD AND
BECOMES PRESERVED EVEN AT
TROPICAL TEMPERATURES.
WE SHIP THE SAMPLES BACK TO THE
LAB OR PUNCH THEM OUT AND PUT IN
THE BUFFER.
WE MAKE WHOLE BLOOD AGAIN AND
THEN ADD THEM TO AN ASSAY PLATE
AND DO A SANDWICH
[INDISCERNIBLE] AND THEN WE
GENERATE A CALIBRATION CURVE AND
GENERATE THE CONCENTRATION OF
CRP IN EACH OF THESE SAMPLES.
THIS KIND OF DATA COLLECTION OR
SAMPLE COLLECTION APPROACH
ALLOWS US TO GAIN ACCESS SESZ TO
PEOPLE IN PLACES LIKE THE EK
ECUADOR AMAZON AND GET A SAMPLE
EVERY WEEK.
HERE'S WHAT WE FOUND.
SO AGAIN WE HAVE PARTICIPANT ON
THE X AXIS, CRP CONCENTRATION ON
THE Y.
HERE'S THE THREE MILLIGRAM PER
LITTER THRESHOLD AND EACH
DIAMOND REPRESENTS A VALUE FOR
THAT PARTICIPANT.
PARTICIPANT OVER HERE ON THE
RIGHT HAS VALUES STACKED UP LIKE
THIS.
SORTED BY OVERALL AVERAGE ACROSS
VIMGS.
DOES THIS LOOK DIFFERENT TO YOU?
THERE ARE NONE OF THOSE, RIGHT?
THERE ARE NO INDIVIDUALS WHO
CONSISTENTLY PRODUCE CRP ABOVE
THREE MILLIGRAMS PER LITTER.
IN FACT, ONLY A THIRD OF THE
INDIVIDUAL, 17 PEOPLE, PRODUCED
ONE CRP VALUE ABOVE THIS
THRESHOLD, AND ON THE OTHER
WEEKLY INTERVALS THEY PRODUCED
VALUES THAT WERE VERY LOW, IN
MOST CASES LESS THAN ONE
MILLIGRAM PEARLY LITTER.
VERY DIFFERENT PATTERN OF
VARIATION.
THERE IS NO CHRONIC LOW-GRADE
MAGS IN THIS SETTING.
THERE'S ANOTHER WAY TO REPRESENT
THIS.
THIS IS GOING ACROSS TIME.
SO WEEK
THESE ARE THE 17 INDIVIDUALS FOR
WHOM AT LEAST ONE SAMPLING
INTERVAL HAD AN ELEVATED CRP.
WEEK TWO, THERE ARE ABOUT SIX
INDIVIDUAL WHO IS HAVE ELEVATED
CRP, BUT THE NEXT WEEK EVERY
SINGLE ONE OF THOSE HAS A LUE
LESS THAN THAT HIGH-RISK
THRESHOLD.
IF YOU WERE DOING A CROSS
SECTIONAL STUDY AND SAMPLED AT
WEEKLY TWO, YOU WOULD SAY ABOUT
A THIRD OF THIS POPULATION HAS
HIGH-RISK CRP, THAT MATCHES TO
THE U.S.
BUT YOU WOULD MISCLASSIFY EVERY
SINGLE ONE OF THOSE INDIVIDUALS
BY VIRTUE OF DOING CROSS
SECTIONAL STUDY DESIGN.
SO TO MY MIND THAT IS ACTUALLY
PRETTY COMPELLING EVIDENCE FOR A
DIFFERENT SET OF REGULATORY
DYNAMICS THAT INDIVIDUALS IN THE
EK DOR YAN AMAZON CAN PRODUCE
HIGH CRP BUT ALSO VERY LOW CRP.
THE UNITED STATES IT SEEMS LIKE
PEOPLE CAN PRODUCE HIGH CRP BUT
A LOT OF PEOPLE CANNOT PRODUCE
THAT LOW VALUE AND THOSE ARE THE
INDIVIDUALS WHO ARE PROBABLY AT
ELEVATED RISK FOR CARDIOVASCULAR
DISEASE.
I TRACE THAT BACK TO EXPOSURES
EARLY IN LIFE.
SETTING UP THE DYNAMICS OF THIS
SYSTEM.
THIS DOES HAVE SOME IMPLICATIONS
FOR HOW WE UNDERSTAND
INFLAMMATION AS IMPLICATIONS FOR
OTHER THINGS WE CARE ABOUT.
MAYBE WE SHOULDN'T THINK ABOUT
EARLY ENVIRONMENTS MATTERING
DIRECTLY TO INFLAMMATION IN
ADULTHOOD BUT THINK ABOUT HOW
EARLY ENVIRONMENTS SET UP THE
DYNAMICS OF A SYSTEM, HOW THEY
SET UP HOW THE SYSTEM IS
REGULATE AND THE CONSEQUENCES OF
DIFFERENTIAL PHENOTYPES,
DIFFERENTIAL PATTERNS OF
REGULATION MATTER IN RESPONSE TO
STRESSORS IN ADULTHOOD, AND IN
ORANGE HERE, WE HAVE A SET OF
PROINFLAMMATORY STIMULI THAT ARE
WELL-ESTABLISHED AND IN MANY
CASES OF HIGH INTEREST TO SOME
OF US.
BODY FAT, I TALKED ABOUT,
PRODUCED ABOUT UP REGULATED
INFLAMMATION.
SMOKING IS A STRESSOR, VACCINE
IS A VERY NICE EXPERIMENTAL PAR
TIME FOR ACTIVATING AN
INFLAMMATORY RESPONSE.
INFECTION ACTIVATED
INFLAMMATION, PREGNANCY IS AN
INFLAMMATION EVENT.
THERE'S A LOT OF INTEREST IN
PSYCHOSOCIAL STRESSOR AND THEIR
IMPACT ON INFLAMMATION.
PERHAPS ALL THESE THINGS ARE
MODERATE, THEIR IMPACT ON THE
INFLAMMATION RESPONSE AND
IMPLICATIONS FOR DISEASE MAY BE
MODERATED BY HOW YOUR BODY
REGULATES INFLAMMATION IN
RESPONSE TO EARLY ENVIRONMENT.
I'M GOING TO SHOW YOU SOME
PRELIMINARY DATA THAT SUGGESTS
THAT'S THE CASE.
GOING BACK TO THIS ORIGINAL
OBSERVATION THAT IN THE UNITED
STATES WE PRODUCE MORE CRP THAN
FILIPINOS DO PER UNIT OF BODY
FAT.
IT COULD BE THAT IN THE
PHILIPPINES BASED ON HIGHER
LEVELS OF EXPOSURE TO MICROBES
THERE ARE MORE ROBUST SET OF
ANTIINFLAMMATION -- EVERYBODY
THOUGH BODY FAT IS A
PROINFLAMMATORY INPUT YOUR BODY
IS BETTER ABLE TO KEEP THAT
STIMULATION IN CHECK.
PERHAPS THAT'S WHY WE HAVE LOWER
CRP THERE ETCH AT THE SAME LEVEL
ODD BODY FAT.
IN ECUADOR, WE FIND THE SAME
THING.
SMALLER SAMPLE HERE.
ONLY 50 PEOPLE TOTAL TO 10-15
PEOPLE IN EACH OF THESE CELLS
AND AGAIN AT EVERY LEVEL OF
WEIGHT CIRCUMFERENCE WE HAVE
LOWER LEVELS OF CRP IN ECUADOR
THAN THE UNITED STATES.
WHAT ABOUT STRESS?
SO I'VE DONE SOME WORK ON STRESS
AND INFLAMMATION AND PUBLISHED A
PAPER WITH JOHN AND COLLEAGUES
R– ADULTS IN C HICAGO.
OF OLDERV
WE FOUND STRESS [INDISCERNIBLE]
HIGHER CRP AMONG OLDER ADULTS
CONTROLLING FOR EVERYTHING.
OKAY.
SO THAT'S INTERESTING.
THERE ARE SOME GOOD REASONS TO
UNDERSTAND HOW THIS MAY HAPPEN,
WHICH I CAN GET INTO IF THERE
ARE QUESTIONS.
WE ALSO HAVE A PSS.
WEED A ADMINISTERED IT TO OUR
FILIPINO PARTICIPANTS.
PUTTING ASIDE THE QUESTION ABOUT
THE -- I CAN STILL ANALYZE THE
ASSOCIATION BETWEEN VARIATION
AND PERCEPTIONS OF STRESS AND
CRP IN THE PHILIPPINES AND I'VE
DONE THAT HERE.
THERE IS A POSITIVE ASSOCIATION
BUT IT'S VERY WEAK AND IT'S NOT
STATISTICALLY SIGNIFICANT.
SO THAT'S INTERESTING, BUT WHAT
IF THIS OTHER ISSUE OF EARLY
ENVIRONMENT MODERATING THE
IMPACT OF STRESSORS IN
ADULTHOOD, HOW MIGHT THAT INFORM
WHAT WE DO HERE?
I TRIED TO TEST THAT EXPLICITLY.
I DID THIS LAST WEEK SO IT'S NOT
FULLY FLESHED OUT.
I JUST TOOK ONE OF THE VARIABLES
THEY SHOWED BEFORE, MATTER TO
CRP IN ADULTHOOD AND RAN AN
INTERACTION.
SO HERE WE HAVE PERCEIVED STRESS
IN INTERACTION WITH SEASON OF
BIRTH PREDICTING CRP.
IF YOU WERE BORN NOT IN THE DRY
SEASON -- THIS MEANS YOU HAVE
LOWER LEVELS OF INFECTION
EXPOSURE IN THE FIRST YEAR OF
INFANCY -- THEN YOU START TO SEE
A PATTERN OF ASSOCIATION THAT
LOOKS LIKE CHICAGO.
HIGHER STRESS, HIGHER CRP.
IF YOU WERE BORN IN THE DRY
SEASON, HIGHER LEVEL OF
MICROBIAL EXPOSURE IN INFANCY,
PERHAPS ROBUST„i ANTIINFLAMMATION
IN PLACE THERE'S NO ASSOCIATION
AND IF ANYTHING IT'S NEGATIVE.
ON THEIR OWN NEITHER OF THESE
LINES ARE SIGNIFICANT BUT THE
INTERACTION IS.
THERE IS IS DIFFERENT PATTERN OF
ASSOCIATION BETWEEN THESE
VARIABLES.
THEY COULD TRACE THIS BACK TO
EARLY ENVIRONMENTS.
PREGNANCY.
PREGNANCY INDUCES A LOT OF
CHANGES IN A WOMAN'S IMMUNE
SYSTEM AND HOW SHE REGULATES
IMMUNE FUNCTION.
THIS IS VERY IMPORTANT BECAUSE
THE FETUS IS ONLY 50%
GENETICALLICALLY RELATED TO HER.
THERE HAS TO BE SUPPRESSION OF
IMMUNE PROCESSES THAT WOULD
OTHERWISE REJECT THE FETUS.
CHANGES IN DYNAMICS ARE PART OF
THIS PROCESS.
IN 2005 WHEN WE COLLECTED OUR
BLOOD SAMPLES, THERE WERE ABOUT
80 WOMEN WHO WERE PREGNANT AT
THE TIME OF THIS SURVEY AND WE
COLLECTED BLOOD FROM THEM BUT IN
ALL THE ANALYSIS I'VE SHOWED YOU
I'VE ELIMINATED THEM FROM THE
SAMPLE BECAUSE THEIR CRP RZ UP
AND THEIR DYNAMICS ARE
DIFFERENT.
IT'S A VERY INTERESTING SUBSET
OF WOMEN TO LOOK AT.
THESE ARE
GOING FEATURE IN A GRANT
APPLICATION TO JUSTIFY
ADDITIONAL RESEARCH.
VERY PRELIMINARY AND WHAT I'VE
DONE HERE IS TAKEN WOMEN AND
DIVIDED THEM JUST ON MEDIUM
SPLIT ON WHETHER THEY HAD HIGH
OR LOW CRP AT THE TIME OF THE
BLOOD COLLECTION AND WHETHER
THEY HAD HIGH OR LOW IL 10.
I'M FEATURING IL 10 HERE BECAUSE
PART OF THE STORY I'M DEVELOPING
IS THAT IL 10 IS A VERY
IMPORTANT AEN INFLAMMATORY
SIGNAL.
IT'S LIKE DRIVING 100 MILES PER
HOUR WITH YOUR FOOT ON THE
ACCELERATOR.
IF BRAKES ARE WORKING YOU CAN
SLOW DOWN AND KEEP THINGS IN
CONTROL.
BETTER THAN GOING 100 MILES PER
HOUR DOWN THE HIGHWAY WITH NO
BRAKES AND NO WAY TO KEEP THINGS
IN CHECK.
I'M GOING TO SHOW YOU A SLIDE
ABOUT CARDIOVASCULAR DISEASE IN
A MINUTE THAT HELPS ME JUSTIFY
THIS APPROACH.
HERE'S THE DISTRIBUTION AMONG
WOMEN WHO ARE BORN INTO LOW
MICROBE HOUSEHOLD.
I TOOK THE VARIABLE I SHOWED YOU
BEFORE AND DID A MEDIAN SPLIT.
ABOUT A QUARTER HAVE LOW CRP.
ABOUT A THIRD HAVE HIGH CRP AND
LOW IL 10.
SO I'M INTERPRETING THIS AS
INCONTROLLED INFLAMMATORY STATE.
A THIRD HAVE HIGH CRP AND HIGH
IL 10.
I'M INTERRUPTING THIS AS A
CONTROLLED INFLAMMATORY STATE.
NOW, IF WE LOOK AT WOMEN WHO
WERE BORN INTO HOMES 20 YEARS
AGO WITH A HIGHER LEVEL OF
MICROBIAL EXPOTION THEY'RE MUCH
MORE LIKELY TO BE IN THIS WELL
CONTROLLED INFLAMMATORY STATE.
SO DOES THIS MATTER?
I MEAN, THIS IS INTERESTING.
ONE OF THE THINGS THAT'S COOL
ABOUT TO THIS TO ME THE S YOU'RE
PERTURBING THE SYSTEM AND THE
DYNAMICS OF THE RESPONSE IS VERY
INTERESTING.
DOES THIS HAVE ANY HEALTH
CONSEQUENCES?
THE THING THAT GOT ME THINKING
IN THIS DIRECTION IS THE STUDY
OF, UM, CARDIOVASCULAR DISEASE.
THESE WERE PATIENT WHO IS
PRESENTED TO HOSPITAL WITH A
HEART ATTACK.
THEIR BLOOD WAS DRAWN AND THEY
WERE FOLLOWED FOR SIX MONTHS,
AND THE OUTCOME IS DEATH OR
SUBSEQUENT HEART ATTACK, AND AT
BASELINE, INDIVIDUALS WHO HAD
LOW IL 10 AND HIGH CRP HAD THE
WORST OUTCOMES, FAR AND AWAY THE
WORST.
ONE IN FIVE OF THEM WAS DEAD.
PEOPLE HAD THE BEST OUTCOMES HAD
HIGH CRP.
THIS IS CONSISTENT WITH THE IDEA
THAT INFLAMMATION IS GOOD FOR
YOU IN CERTAIN CIRCUMSTANCES.
BUT THEY ALSO HAD HIGH IL 10.
THE PEOPLE WHO DID BEST HAD
INFLAMMATION BUT A CONTROLLED
INFLAMMATORY STATE.
SO MIGHT THIS APPLY ALSO TO AN
IMPORTANT HEALTH YOUTH COME
OUTCOME FOR ADULTHOOD IN WOMEN
AND THE BIRTH WEIGHT OF YOUR
BABY?
INDIVIDUALS IN THIS
WELL-CONTROLLED INFLAMMATORY
STATE HAVE AN AVERAGE BIRTH WAIT
WEIGHT THAT IS MORE THAN A
HUNDRED GRAMS HIGHER THAN WOMEN
IN POORLY CONTROLLED
INFLAMMATORY STATE OR WOMEN WITH
NO ACTIVE INFLAMMATORY ACTIVITY,
AGAIN SUGGESTING THAT
INFLAMMATION IS DOING STHIENG
GOOD BUT YOU WANT TO CONTROL IT.
ENOUGH TO MOTIVATE US TO PURSUE
A MORE LIFE COURSE AND EVEN
INTERGENERATIONAL APPROACH TO
THE STUDY OF INFLAMMATION, AND
THIS IS OUR WORKING MODEL, AND,
UH, THIS IS THE LIFE COURSE
HERE, AND WE HAVE AN
INFLAMMATORY PHENOTYPE WHICH
DEVELOPS IN INFANCY CHILDHOOD
INTO ADULTHOOD AND A LOT OF
INTEREST HOW N HOW THAT MATTERS
TO AGING.
INFLAMMATION IS KEY IN PREGNANCY
AND IT CAN BE -- THAT SETS UP
THE NEXT GENERATION WITH RESPECT
TO THESE PROCESSES AS WELL.
WE CAN TRACE AN INDIVIDUAL'S
INFLAMMATORY PHENOTYPE BACK TO
HER INFANCY AND PRENATAL
NUTRITIONAL ENVIRONMENT, POST
NATAL INFECTION ENVIRONMENT, AND
THERE'S A LOT OF INTERESTING
RESEARCH ON THE ROLE OF
PSYCHOSOCIAL STRESSORS IN
CHILDHOOD THAT I DIDN'T TALK
ABOUT MATTERING TO THE
DEVELOPMENT OF INFLAMMATION AS
WELL.
I HAVE BROADER INTERESTS IN
SOCIAL DISPARITIES AND
INEQUALITIES.
THESE ARE ALL EXPO E SURES THAT
ARE PARTITIONS IN DIFFERENT WAYS
BY SOCIO ECONOMIC PROCESSES.
I THINK I'LL PROBABLY END THERE.
I HAVE TWO STUDY PUTTING IN
MOTION THAT TESTS VARIOUS
ASPECTS OF THIS MODEL.
IF THERE ARE QUESTIONS ON THAT
I'D BE HAPPY TO FEATURE THEM BUT
I WANT TO LEAVE TIME FOR
QUESTIONS SO MAYBE WE SHOULD DO
THAT.
THANK YOU.
[APPLAUSE]
>> [LOW AUDIO].
>> ALMOST ALL THE DELIVERIES
WERE IN THE HOME OR A LOCAL
BIRTH CENTER.
>> [LOW AUDIO].
>> YEAH, VERY VIEW, VERY VIEW
C-SECTIONS BUT THAT I THINK IS A
VERY INTERESTING POSSIBLE ROUTE.
THERE'S A LOT OF PARTICULARLY
WITH RECENT INTEREST IN MICROBUY
YOEMS AND CROSS GENERATIONS.
DOING SOMETHING LIKE THIS IN THE
UNITED STATES WOULD BE VERY
INTEREST
INTERESTING [INDISCERNIBLE].
YES.
>> [LOW AUDIO].
>> MM-HMM.
>> [LOW AUDIO].
>> MM-HMM.
YEAH.
>> [LOW AUDIO].
>> MM-HMM.
YEAH.
>> [LOW AUDIO].
>> SO I THINK THERE ARE TWO
THINGS THERE.
ONE IS THERE IS A LOT OF
RESEARCH AND INTEREST IN THE
UNITED STATES, IN PARTICULAR ON
INFECTION AND THE REGULATION OF
INFLAMMATION ON GESTATION
PREDICTING PRETERM DELIVERY BUT
ALSO LOWER BIRTH WEIGHT.
IN THE UNITED STATES LOWER BIRTH
WEIGHT IS ALMOST ALWAYS
ASSOCIATED WITH EARLY BIRTH.
WE DON'T HAVE THE DATA TO
ADDRESS IT.
BUT WITH RESPECTED TO LEVEL OF
PRENATAL AND POST NATAL EXPOSURE
THAT MIGHT MATTER TO US IN THE
U.S. VERSUS THE PHILIPPINES.
PHILIPPINES IN THE 80s, THE
LEVEL OF EXPOSURE TO THE KINDS
OF MICROBES PROBABLY ORDERS A
MAGNITUDE GREATER THAN WHAT
HAPPENS ON THE UNITED STATES
EXCEPT ON A RURAL FARM WHERE
YOU'RE ACTIVELY ENGAGED WITH
ANIMALS.
I DON'T THINK THIS WILL TRACK
FOR DISADVANTAGE, BUT THAT'S A
VERY TESTABLE HYPOTHESIS ON
SOMETHING THAT I WOULD LIKE TO
LOOK AT.
A LOT OF LIT KRA RA CHUR ON THE
HIGH JEEB HYPOTHESIS AND THE
IMMUNE PATHWAYS RELATED TO THAT
SUGGEST THAT IT'S NOT
NECESSARILY OVER INFECTIONS.
SO, OF COURSE, I HAVE A
FOUR-AND-A-HALF YEAR OLD AND
EVERY TIME HE CAME HOME WITH A
COLD I WAS LIKE GREAT, ONE NOTCH
DOWN ON THE RISK FOR ASTHMA.
[LAUGHTER]
IT'S PROBABLY NOT THAT.
THOSE THINGS ARE CORRELATED BUT
WHAT'S PROBABLY LACKING IS
EXPOSURE TO COME ON
MICROORGANISMS THAT ARE IN DIRT
AND ROTTING VEGETABLE MATERIAL
AND WATER THAT'S NOT BEEN
BLEACHED.
THINGS THAT HAVE BEEN PART OF
THE MAMMALIAN ENVIRONMENT FOR MA
LIN YEAH THAT IN POST
EPIDEMIOLOGICAL POPULATIONS AND
POST EPI HYPER HYGIENIC
ENVIRONMENTS THAT WE'VE
ELIMINATED FROM OUR DIETS, FROM
OUR ENVIRONMENT.
I THINK EVEN IN SOCIALLY
DISADVANTAGED CIRCUMSTANCES IN
THE UNITED STATES, PEOPLE ARE
MOSTLY DRINKING TAP WATER, NOT
ENGAGE SOIL THE WAY PEOPLE IN
OTHER PARTS OF THE WORLD DO.
THAT IS A TESTABLE HYPOTHESIS.
>> [LOW AUDIO].
>> PROBABLY NOT MUCH.
I DON'T THINK THAT THERE'S --
THIS'S NO EVIDENCE TO SUGGEST
THAT VACCINES REALLY MATTER TO
THE KINDS OF THINGS THAT I'M
TALKING ABOUT BUT IF THEY DO
MATTER THEY MAY PUT INDIVIDUALS
AT RISK NOR HIGHER
[INDISCERNIBLE] THE WAY THEY
ACTIVATE THE IMMUNE RESPONSE IS
BY [INDISCERNIBLE] WHICH HAVE
BEEN ASSOCIATED WITH ALLERGY AND
ASTHMA.
WE DO HAVE INFORMATION ON
VACCINES IN THIS STUDY BUT THEY
DON'T SEEM TO EXPLAIN ANY
VARIATION HERE.
THEY DO MATTER.
THEY, UM, ARE NOT EXPLAINING
WHAT I'M SHOWING HERE, BUT
INTERESTINGLY ALONG THOSE LINES
SORT OF WHAT CAN WE DO TO PRIME
SOME OF THESE PATHWAYS.
THERE ARE CLINICAL TRIALS IN THE
UK WHERE PEOPLE AS AN ADULT WHO
SUFFER FROM EXTREME FORM OF
ALLERGY OR ASTHMA HAVE BEEN
GIVEN EXTRACTS OF PARASITES OR
SOME OF THE MICROBES THAT I'M
TALKING ABOUT AND IT'S SHOWN
THAT IT'S ALLEVIATED SOME
SYMPTOMS.
I THINK THAT'S INTERESTING.
MY CRITIQUE IN THAT WOULD BE
IT'S PROBABLY TOO LATE.
IF YOU WANT A BANG FOR YOUR BUCK
I THINK YOU TO DO IT EARLIER IN
LIFE.
BUT THEY DO SHOW SMALL EFFECTS.
>> QUESTIONS, ANYMORE QUESTIONS?
>> YEAH.
>> [LOW AUDIO].
>> YEAH.
MM-HMM.
[LAUGHTER]
RIGHT.
RIGHT.
>> [LOW AUDIO].
>> THIS IS SOMETHING I WOULD
LOVE TO DO.
I THINK ANOTHER CLASS OF PEOPLE
TO LOOK AT IN THIS REGARD OR
IMMIGRANTS WHO MAY HAVE GROWN UP
IN A CERTAIN ENVIRONMENT AND
COME TO THE UNITED STATES.
THAT WOULD BE VERY INTERESTING
CASE STUDY.
THERE'S GOOD OPPORTUNITY HERE
BECAUSE THERE ARE A LOT OF
STUDIES, A LOT OF DEMOGRAPHICS
SOCIAL SCIENCE POPULATION
STUDIES MOVING FORWARD OVER THE
PAST FIVE YEARS AT HEALTH HRS,
THAT ARE USING THIS BLOOD SPOT
METHOD THAT ARE MEASURING CRP
AND HAVE HISTORIES OF WHERE
PEOPLE GREW UP, WHETHER THEY
WENT TODAYCARE OR NOT, WHETHER
OLDER SIBLINGS, WHETHER THEY
WERE ON A FARM, IMMIGRANT.
WE CAN TEST THESE HYPOTHESES.
I'M WAITING FOR DATA SO I CAN DO
SOME OF THOSE THINGS.
>> [LOW AUDIO].
>> THERE ARE DEFINITELY SOME
SELECTION.
I DON'T WORRY SO MUCH ABOUT
MORTALITY SELECTION IN THE
PHILIPPINE STUDY.
IT WASN'T AS HIGH AS THE
ORIGINAL INVESTIGATORS THOUGHT
IT MIGHT BE.
I'M SURE YOU NOTICED THAT
ORIGINAL END WAS 3,300 AND WE
WERE AT 885 IN 2005.
MOST OF THE LOSS HAPPENED IN THE
FIRST TWO YEARS OF LIFE AND IT
WAS DUE TO MIGRATION.
IT WASN'T DUE TO LACK OF
PARTICIPATION OR ENTHUSIASM FOR
THE STUDY BUT A LOT OF PEOPLE
MOVE OUT OF SABU, MOVED TO THE
UNITED STATES, HONG KONG AND WE
DIDN'T HAVE THE FUNDS TO FOLLOW
THEM UP.
THE BIAS IS THAT WE HAD PEOPLE
THAT ARE MORE LIKELY TO STAY IN
SABU, SO THEY WERE A LITTLE LESS
EDUCATED
AND NOBLE.
YEAH.
>> [LOW AUDIO].
>> HMM.
MM-HMM.
>> [LOW AUDIO].
>> YEAH.
YEAH.
>> [LOW AUDIO].
>> THAT'S GREAT.
I THINK WE'RE ONE OF MY GOALS IS
TO GET PEOPLE TO ASK THESE
QUESTIONS AND TO GENERATE
HYPOTHESES AND TEST THEM USING
RESOURCES LIKE THAT WHICH I
ACTUALLY WAS NOT AWARE OF.
THERE'S A LOT OF RESEARCH ON THE
HYGIENE HYPOTHESIS IN THE
CONTEXT OF ALLERGY AND
IMMUNOLOGY.
I WANT TO EXPAND THAT OUT.
IF INFLAMMATION REALLY MATTERS
TO ALL OF THESE THINGS WE CARE
ABOUT, THEN THESE SAME KINDS OF
EXPOSURES EARLY IN LIFE SHOULD
MATTER, AND SO WE SHOULD STUDY
THEM.
MAYBE IT ONLY APPLIES IN THE
PHILIPPINES AND PLACES LIKE THAT
NOT SO MUCH HERE, BUT WE SHOULD
FIGURE THAT OUT OR TRY TO.
>> [LOW AUDIO].
>> MANY MM-HMM.
YEAH.
>> [LOW AUDIO].MM-HMM.
YEAH.
>> [LOW AUDIO].MM-HMM.
YEAH.
>> [LOW AUDIO].MM-HMM.
YEAH.
>> [LOW AUDIO].MM-HMM.
YEAH.
>> [LOW AUDIO].-HMM.
YEAH.
>> [LOW AUDIO].
>> RIGHT.
RIGHT.
>> [LOW AUDIO].
>> YEAH.
>> RIGHT.
SO YES AND NO.
SO, UM, IT'S BASED ON DATA FROM
THE U.S., LARGE EPIDEMIOLOGIC
COHORTS AND IT ALSO MAPS ON THE
THIRD OF THE DISTRIBUTION --
THAT RECOMMENDS THE USE OF THAT
[INDISCERNIBLE].
ONE OF THE REASONS THAT I USED
THIS CUP POINT APPROACH IN THE
PHILIPPINES IS THAT THE
DISTRIBUTION HAS SHIFT SOD FAR
LEFT THAT I DON'T THINK THREE
MILLIGRAMS PER LITTER IS
MEANINGFUL THERE.
I USED THIRD TILES.
THE CUT POINT FOR THAT WAS .7
MILLIGRAMS PER LITTER.
THAT WAS A WAY TO THINK OF
RELATIVE RISK.
DO THINK THE LEVEL REALLY
MATTERS AND THAT IS ONE OF THE
THINGS THAT WE'VE JUST BEEN FUND
BID NIA TO LOOK AT AMONG THE
MOMS.
SO THE MOMS WHO WERE ORIGINALLY
RECRUITED INTO THE STUDY ARE NOW
IN THEIR 50 AND 60s AND 70s AND
THEY'RE AGEING IN THE
CARDIOVASCULAR LIST.
WE'VE MEASURED THEIR CRP BEFORE,
WE'RE GOING TO MEASURE IT AGAIN
AND WE'LL BE ABLE TO SEE WHAT
THE IS CUT POINT THAT PREDICTS
RISK IN THIS ENVIRONMENT, BUT
WE'RE ALSO GOING TO GIVE THEM A
VACCINE ARK FLU VACCINE ARK
SUBSET OF THEM AND MEASURE THE
DYNAMIC OF THE RESPONSE TO THE
VACCINE AND SEE IF THAT'S A
BETTER PREDICTOR OF
CARDIOVASCULAR RISK THAN JUST
YOUR ARCH CRP LEVEL.
I'LL BE GOING TO THE PHILIPPINES
IN ABOUT THREE WEEKS TO GET THAT
OFF THE GROUND.
>> THANK YOU VERY MUCH.
[APPLAUSE]
>> THANK YOU.