GOOD AFTERNOON.

EXAM WILL BE ELECTRONICALLY

WEBSITE -- IT IS MULTIPLE

CHOICE.

YOU'LL GET AN INDICATION OF WHAT

YOU GOT WRONG.

SO YOU CAN THINK ABOUT IT AND GO

BACK.

[INDISCERNIBLE]

BUT THINKING ABOUT IT, THE

QUESTION OF DIARRHEA, I DON'T

KNOW, SOMETIMES IN THIS DAY

AVENUE BIG TIME ADVERTISING, YOU

MIGHT COME UP WITH SOMETHING

LIKE DOESN'T EVERYBODY GET

DIARRHEA SOME TIME.

YOU TAKE SOME MEDICINE, A

DRINKING OF WOKE COKE AND THEN SOME

TEA.

AND THEN YOU RECOVER.

WHAT'S THE BIG DEAL.

OF COURSE THE BIG DEAL AT BOTH

ENDS OF THE AGE SPECTRUM AMONG

THE VERY YOUNG AND AMONG THE

VERY OLD IT'S A HUGE DEAL AND

MILLIONS OF PEOPLE DIE.

WHY DO THEY DIE OF THIS?

>> HOW DO THEY DIE?

AND WHAT CAN BE DONE ABOUT IT?

THERE WAS AN ADVERTISEMENT NOT

SO LONG AGO THAT SUGGESTED

INSTEAD OF DOING WHAT MY GRAND

MOTHER SAID WHICH WAS THE RICE

AND TEA WITH SOME SUGAR, YOU

SHOULD DRINK GATORADE.

DOES GATORADE SOLVE THE PROBLEM

OR DOES IT MAKE IT WORSE.

THEORETICALLY IT MIGHT, BUT IT'S

SOMETHING TO THINK ABOUT.

NOW IN PHYSIOLOGIC SENSE, HOW

MUCH WATER IS GOOD FOR YOU?

HOW DO WE DEAL WITNESS.

WE HAVE 3 FEE 2 FEET OF INTESTINES

AND HOW DOES THAT HUGE

ABSORPTIVE SURFACE COMPENSATE

FOR OUR ENORMOUS NEEDS FOR SALT

AND FOR WATER.

AND IT'S THE IMBALANCE BETWEEN

THOSE TWO THAT IS ULTIMATELY

RESPONSIBLE FOR DIARRHEA.

SO HOW DOES THE INTESTINE DO

THIS.

SO THESE ARE THE GENERAL TOPICS

THAT COME TO MIND, I THINK, WHEN

ONE THINKS OF THE PHYSIOLOGY OF

ABSORPTION ON ONE HAND AND THE

PATHOPHYSIOLOGY OF THIS MAJOR

LETHAL DISEASE.

OH, THIS IS A FAMOUS PHOTOGRAPH

OF A SA SURVIVOR AND HE'S NOT

ADVERTISING GHARID AID BUT

DURE -- GATORADE BUT YOU'LL

UNDERSTAND WHY THOSE BOTTLES

SAVED HIS LIFE.

LET ME INTRODUCE OUR SPEAKERS.

OUR FIRST SPEAKER IS ROGER GLASS

WHO IS DIRECTOR OF THE FOGERTY

CENTER.

ROGER GOT HIS MEDICAL DEGREE AT

HARV

STELLAR GLOBAL NIH-FOCUSED

CAREER IN DEALING WITH DIARRHEAL

DISEASES FROM AN EPIDEMIOLOGICAL

STAND POINT, CLINICAL

PATHOPHYSIOLOGIC AND VIRAL LOGIC

STANDPOINT.

AND SO YOU WILL HEAR WHAT'S

GOING ON GLOBALLY IN ATTEMPTING

TO DEAL WITH THIS ENORMOUS

PUBLIC HEALTH PROBLEM.

ROGER HAS BEEN INVOLVED IN

ENORMOUS ASPECTS OF GLOBAL

DISEASE THROUGHOUT HIS CAREER.

ASK OUR SECOND SPEAKER IS MARK

DAWDAWNDONOWITZ WHO IS A PROFESSOR AT

JOHNS HOPKINS.

HE GRADUATED FROM HOPKINS IN GAS

TROENGASTROENT ALL -- AS A SOPHISTICATED

LEVEL WHICH THEN PROVIDES NEW

TARGETS FOR UNDERSTANDING OAF

THERAPY AND DEVELOPMENT OF -- OF

THERAPY AND DEVELOPMENT OF NEW

AGENTS, DRUGS TO DEAL WITH THESE

VERY COMPLICATED AND LETHAL

DISEASES.

BOTH OF OUR GUESTS HAVE RECEIVED

ALL KIND OF HONORS AND

ACHIEVEMENTS AND WE'RE GRATEFUL

TO BOTH OF THEM FOR TAKING TIME

TO BE HERE TODAY.

SO ROGER PERHAPS IF YOU WOULD

COMMENCE.

>> I'M DELIGHTED TO BE HERE.

MY PROFESSOR IS IN THE BACK,

DIDN'T GO TO A BALL GAME TODAY

SO NICE TO BE HERE.

YOU MIGHT WANT TO ASK, WHY DOES

ANYBODY WORK ON DIARRHEAL

DISEASES AND TALK ABOUT IT IN

THE AFTERNOON AT TEA TIME.

SO I WOULD START WITH THIS SLIDE

BEFORE I GO ON TO LET YOU KNOW

HOW I GOT INVOLVED IN THIS CRAZY

SUBJECT.

I WAS A STUDENT IN THE HISTORY

OF SCIENCE AS AN UNDERGRADUATE.

THIS SLIDE WAS PRESENTED TO US

IN MY HISTORY OF SCIENCE CLASS

BEING BROAD STREET PUMP.

YOU CAN SEE HERE IN THE PUMP THE

PUMP HANDLE, THIS IS AN OUTBREAK

OF CHOLERA IN 1854 WHERE JOHN

DID THE FIRST MAP OF CHOLERA,

CALLED A GHOST MAP IN A NEW

BOOK.

HE PLOTTED OUT CASES AROUND THE

PUMP AND DECIDED THE PUMP WAS

SPOPTD IN BAD WATER.

BECAUSE OF THIS WE HAVE THE

HISTORY OF EVEN TEAM ALL,

STARTING -- EPIDEMIOLOGY,

STARTING WITH THE SCRIPT OF

EPIDEMIOLOGY AND GLOBAL HEALTH

WHICH CAME BY SHIPS,

QUARANTINING SHIPS.

THERE'S EPIDEMIOLOGY IN THIS ONE

SLIDE.

AS A YOUNGSTER AND UNDERGRADUATE

I SAID IF ONLY THE PUMP IS

INVOLVED, IF I GO TO SOME PLACE

WHERE THEY HAVE CHOLERA I CAN

GET AWAY BY JUST TAKING THE

HANDLE OFF THE PUMP.

DOESN'T THAT SEEM REASONABLE.

SO I DID GO OUT TO BANGLADESH,

PEND FOUSPENT FOUR YEARS THERE AND FOUND

THE PUMPS IN THE PUMP HANDLES,

$1000 MILLION PROJECT TO PUT

PUMPS INTO THE FIELD AREA TO SEE

IF WE COULD STOP CHOLERA WHICH

WAS THE NATURAL THING TO DO.

JOHN SNOW TOLD US ABOUT THIS 150

YEARS BEFORE.

AND LO AND BEHOLD, PUTTING IN

PUMPS, TWO WELLS AROUND THE

FIELD AREA MADE NO DIFFERENCE IN

THE INCIDENCE OF CHOLERA.

WHAT THEY DID DO WAS SOMETHING

TOTALLY UNEXPECTED.

THEY PRESENTED ARSENIC

CONTAMINATED WATER TO AN ENTIRE

POPULATION, AND NOW THE HIGHEST

LEVELS OF ARSENIC IN THE WORLD

TODAY ARE IN THESE POPULATIONS

WHO ARE GIVEN THIS MICROBIAL

FREE WATER AS PART OF A CHOLERA

CONTROL PROGRAM.

SO I LEARNED A LOT IN THIS

EXPERIENCE, SOMETIMES TAKING

HANDLE OFF PUMP THAT MIGHT BE

GOOD FOR OTHER REASONS BUT NOT

FOR THE PREVENTION OF CHOLERA.

BUT WHAT I DID ALSO LEARN WAS

THAT CHOLERA WAS, IS A RAPIDLY

FATAL DISEASE AND BY USING ORAL

THERAPY, YOU COULD ACTUALLY

PREVENT SEVERE DIARRHEA IN

CHILDREN AND ADULTS IN THE

FIELD.

AND BRING THEM BACK TO HEALTH.

AND THIS TO ME IS ONE OF THE

REASONS I'M AT FOGERTY.

THIS LESSON FROM AN INVESTMENT

IN GLOBAL HEALTH PROBABLY LESS

THAN $10 MILLION OF U.S.

INVESTMENT IN DEALING WITH

CHOLERA, LED TO THE IDEA THAT

TODAY WE USE ORAL THERAPY FOR

THE TREATMENT OF EVERY PERSON

CHILD WHO HAS A DIARRHEAL

ILLNESS.

SO WE'VE BENEFITED IN THE U.S.

TREMENDOUSLY BY THIS DISCOVERY

THAT WAS NOT MADE TO TREAT

AMERICAN CHILDREN, IT WAS REALLY

MADE TO PREVENT DIARRHEA IN

BANGLADESH IN CHILDREN WITH

CHOLERA AND ADULTS.

SO VERY IMPORTANT FINDING.

I ALSO LEARNED WHILE I WAS THERE

THAT CHOLERA WAS NOT THE MOST

IMPORTANT DIARRHEAL DISEASE IN

BANGLADESH, AND IN FACT THERE

WAS MORE CASES OF VIRUS THAN

CHOLERA.

THERE'S A PICTURE OF THE DOCTOR

IN THE RIGHT CORNER AND IT'S

REALLY THE MOST IMPORTANT CAUSE

OF SEVERE DIARRHEA IN CHILDREN.

IT INFECTS ALL CHILDREN IN THE

FIRST FEW YEARS OF LIFE.

IT'S NOT -- IT'S A DEMOCRATIC

VIRUS IT AFFECTS THE RICH AND

POOR, BANGLADESH, EVEN IN

AMERICA ALL KIDS GET IT.

IN THE REPUBLIC IT'S AN EQUAL

OPPORTUNITY VIRUS IT'S NOT JUST

A DEMOCRATIC VIRUS.

FIRST INFECTIONS ARE SYMPTOMATIC

AND NATURAL IMMUNE FEE AND

LIMITED STAINS IN CIRCULATION.

MY SON WAS THE FIRST VIRUS IN

CDC WHEN MEANT SANITATION AND

HAND WASHING BY MY WIFE DID NUT

TO GO PREVENT MY OWN SON FROM

GETTING ROTO VIRUS.

SANITATION IS NOT GOING TO MAKE

A DIFFERENCE.

THIS IS WHY WE'VE GOT INVOLVED

WITH VACCINES.

THE DISEASE THAT'S

INDISTINGUISHABLE FROM ANY FORM

OF CHILDHOOD DIARRHEA, VOMITING

DEHYDRATION AND IN SOME CASES

SHOCK THAT LEADS TO DEATH.

HERE'S A POOR CHILD HARD TO SHOW

A CHILD WITH DIARRHEAL DISEASE.

WELL WHEN YOU THINK ABOUT THE

ATM MACHINE OF GLOBAL HEALTH,

AIDS, TB AND MALARIA.

FOR CHILDREN, IN FACT,

RESPIRATORY DISEASE AND DIARRHEA

ARE THE MOST IMPORTANT CAUSES OF

DEATH IN CHILDREN AND ROTO VIRUS

IS THE MOST IMPORTANT CAUSE IN

THAT PROFILE.

I WENT BACK TO CDC AFTER THREE

YEARS WITH THE DOCTOR IN HIS

LAB.

IN GOVERNMENT LABS YOU ALWAYS

HAVE TO BE CHEAP AND LAZY.

CHEAP BECAUSE YOU DON'T HAVE A

LOT OF MONEY AND LAZY BECAUSE

YOU DON'T HAVE A LOT OF PEOPLE

TO HELP.

SO THE QUESTION WAS HOW CAN WE

DETERMINE THE IMPORTANCE OF ROTO

VIRUS AS A NATIONAL PROBLEM

WITHOUT SOME DATA.

THE HEAD OF CDC WELCOMING ME

BACK FROM NIH.

I TALKED TO HIM ABOUT AN HOUR

WITH ROTO VIRUS THE WORK AT

BANGLADESH, THE WORK AT NIH AND

HE SENT ME A THANK YOU NOTE TO

COME BACK AND DIRECTED IT TO ME

IN CHARGE OF THE RETRO VIRUS

LABORATORY.

SO HE DIDN'T KNOW THE DIFFERENCE

AFTER I SPOKE WITH HIM BETWEEN A

ROTO VIRUS AND RETRO VIRUS.

I REALIZE I HAD AN EDUCATIONAL

PROBLEM AHEAD OF ME.

I USED MY MEDICAL OFFICES TO

CONSTRUCT THIS DATA FROM NCHS

DATA OF HOSPITALIZATIONS.

AND I GUESS THIS ISN'T WORKING

ANYMORE.

BUT WHAT YOU CAN SEE IN THE

UPPER SLIDE HERE IS A

SAW-TOOTHED CURVE OF 200

THOUSAND DIARRHEAL

HOSPITALIZATIONS OF CHILDREN

EVERY YEAR FOR A VARIETY, A GRAB

BAG OF CAUSES.

MOSTLY CAUSES UNKNOWN.

INTO SEASONALITY NOW WE KNOW TO

BE ROTO VIRUS FROM CONFIRMATORY

TESTS IN LABORATORIES.

IT'S VERY SIMILAR TO THE STUDIES

DOWN BY THE DOCTOR'S GROUP USING

THE DC CHILDREN'S HOSPITAL.

THAT WINTER PEAK IS PRIMARILY

THIS KIDS FROM SIX MONTHS TO TWO

TO THREE YEARS OF AGE.

THAT'S ROTO VIRUS AND IT

REPRESENTS ABOUT 30,000

HOSPITALIZATIONS A YEAR.

ABOUT A THIRD TO 50% OF ALL

HOSPITALIZATIONS OF CHILDREN.

THIS IS AN IMPORTANT SLIDE ALSO

BECAUSE IF YOU THINK ABOUT THE

USE OF A VACCINE OR THE

INTRODUCTION OF A VACCINE WHICH

WE DID IN 2006 IN THIS COUNTRY,

YOU'D EXPECT IN THE FIRST YEAR

TO FLATTEN THIS CURVE IN ONE OR

TWO YEARS AFTER VACCINE

INTRODUCTION TO FLATTEN THIS

CURVE IN TWO OR THREE YEARS

AFTER INTRODUCTION.

AND YOU CAN ACTUALLY SEE AN

IMPACT IN HOPEIZATIONS WITHIN

TWO OR THREE YEARS FOLLOWING A

GOOD IMMUNIZATION PROGRAM.

SO WE WENT ON TO DEVELOP THE

DISEASE BURDEN OF ROTO VIRUS FOR

THE U.S.

AND THIS IS DATA THAT WAS

PRESENTED ULTIMATELY TO THE

ADVISORY COMMITTEE ON

IMMUNIZATION PRACTICES AT CDC,

AS THE RATIONALE ABOUT WHY THE

U.S. SHOULD BE INTERESTED IN

PREVENTION OF ROTO VIRUS.

NOW NOTE TWO THINGS IN THIS

FIGURE.

ONE IS THAT WE DON'T HAVE A LOT

OF DEPTH FOR ROTO VIRUS I DEATHS FOR ROTO 
VIRUS OF

VACCINES.

IT'S NOT TO PREVENT DEATH BUT TO

PREVENT THE HUGE BURDEN OF

HOSPITALIZATIONS.

ABOUT 5% OF ALL HOSPITALIZATIONS

OF AMERICAN CHILDREN ARE FOR

ROTO VIRUS.

AND ALMOST EVERY CHILD GETS THIS

DISEASE.

ALSO THERE'S A BIG DIFFERENCE

BETWEEN THE MEDICAL COST OF

HOSPITALIZATIONS AND DOCTOR

VISITS AND THE INDIRECT COSTS.

THESE ARE COSTS OF A MOTHER

STAYING HOME FROM WORK FOR THREE

OR FOUR DAYS.

IT'S THIS DIFFERENCE BETWEEN THE

MEDICAL COST AND THE INDIRECT

COSTS WHICH DETERMINES IN PART

THE VALUE OF THE VACCINE.

IN THE U.S. WE CONSIDER BOTH

MEDICAL AND INDIRECT COSTS

EUROPEANS DON'T CONSIDER THE

INDIRECT COSTS AS BEING

IMPORTANT.

IN THE PRICING OF VACCINES.

SO VERY FEW EUROPEAN COUNTRIES

HAVE YET EMBRACED THIS VACCINE.

GLOBALLY, THE VALUE OF THE

VACCINE WILL BE QUITE DIFFERENT

IN THE DEVELOPING WORLD AND IN

THE U.S.

AS I SAID IN THE U.S. AND EUROPE

AND AUSTRALIA, VERY FEW DEATHS

BUT IN INDIA IT'S BETWEEN 100

AND 120,000 DEATHS OF CHILDREN

EACH YEAR FROM ROTO VIRUS.

IN SUB-SAHARAN AFRICA ANOTHER

HUNDRED THOUSAND.

SOME TENS OF THOUSANDS IN LATIN

AMERICA.

BUT SO IT MEANS THAT A VACCINE

THAT WILL BE A LIFESAVER FOR

CHILDREN IN LOW INCOME COUNTRIES

ARE 85% OF THE DEATHS OCCUR IN

REALLY LOW INCOME COUNTRIES.

WHEREAS IN THE DEVELOPED

COUNTRIES, IT WILL ONLY BE AN

ECONOMIC VALUE.

IMPORTANT TO THINK ABOUT THE

HISTORY OF THE VACCINES THAT

THEY DEVELOPED.

SO GLOBALLY ABOUT 5% OF CHILDREN

WILL DIE OF CHILDHOOD DEATHS

WILL BE FOR ROTO VIRUS, WITH 152

CHILDREN WORLDWIDE.

THE VIRUS ITSELF IS MADE UP OF

11 INDIVIDUAL SEGMENTS OF DOUBLE

STRANDED RNA.

SOME OF THESE, TWO OF THESE AT

LEAST ON THE OUTER CAPS THAT ARE

IMPORTANT FOR VACCINE SERO TYPES

AND WE THINK FOR NEUTRALIZATION.

THE SPIKE, THE RED SPIKE AMOUNT

JUDGES -- AND THE YELLOW WHICH

IS A FL GLIE GLYCOPROTEIN.

THERE ARE FOUR OR FIVE SERO

TYPES WE CALL THEM GENE ONE TO

FOUR AND DIRECTION OF OTHER

STRAINS AROUND THE WORLD.

IT'S THESE FOUR OR FIVE MAIN

STRAINS WHICH REALLY HAVE TO BE

THE TARGET FOR IMMUNIZATION.

NOW, BEYOND THAT, AS WE'VE GONE

OUT AND STARTED LOOKING AT

STRAINS AND PLACES LIKE INDIA,

WE'VE IN FACT FOUND HUGE DIVERSE

TEASTHERESE INDIVERSITIES IN TRAINS.

WE STARTED FINDING BOVINE HUMAN.

THEY CAN GET TOGETHER AND MIX

LIKE A DECK OF CARDS AND WE FIND

STRAINS COMING IN FROM CATS,

MONKEYS, FROM RABBITS, FROM

PIGS.

AND IT REPRESENTS A DIFFERENT

WAY FOR THESE VIRUSES TO EVOLVE

OVER TIME.

WELL, HERE'S DR. KAPICIAN WHEN

HE STARTED WHO IN LATE 70'S AND

SEVERAL 80'S WITH RUTH BISHOP

WHO FOUND THE VIRUS AND TOM WHO

NAMED IT BECAUSE OF ITS

WORLDWIDE APPEARANCE AND AL

KAPIKIAN.

ROTO FIELD WAS THE VACCINE I

WORKED ON WHILE I WAS HERE AND

HAVING A REBIRTH WAS A

REASSORTMENT STRAIN, A STRAIN

THAT WAS NATURALLY ATTENUATED

FOR MAN BUT REASSORTED TO GIVE

THE FOUR MAIN SERO TYPES.

THIS IS AN INCREDIBLE NOVEL

INVENTION.

IT WAS LICENSED IN 1998 TO GREAT

FAN FARE.

I WAS AT CDC AT THAT TIME AND

WITHIN TWO MONTHS, WE HAD

INCORPORATED THIS FIRST DIARRHEA

SAX SEEN FOR VACCINE INTO THE IMMUNIZATION

FOR AMERICAN CHILDREN.

WE WERE EXCITED, THIS WAS GOING

TO MAKE A MAJOR DIFFERENCE IN

THE WORLD BECAUSE OF THE HIGH

BURDEN OF 600,000 DEATHS WE

ESTIMATED AT THAT TIME.

WE ALSO GOT BILL GATES

INTERESTED IN THIS U IN 1998 HE

HAD A CHILD TWO YEARS OLD THAT

JUST RECOVERED FROM ROTO VIRUS.

I HAD DINNER WITH HIM.

I HAD TO MAKE A PITCH, I HAD

ABOUT FIVE MINUTES TO MAKE MY

PITCH AND MY PITCH WAS, WHERE DO

I POINT THIS.

HELP.

THERE WE GO.

HERE'S MY PITCH.

MY PITCH WAS WE KNEW A LOT ABOUT

ROTO VIRUS, DISEASE BURDEN WAS

HUGE.

WE KNEW HOW TO DEVELOP THE

VACCINES AND PROMOTE THEIR

TESTING AND LOW INCOME

COUNTRIES.

WE THOUGHT WE COULD ACHIEVE A

TREMENDOUS REVOLT GLOBALLY IN

FIVE TO SEVEN YEARS.

AND WE COULD MEASURE AN IMPACT

IN TWO OR THREE YEARS AFTER

INTRODUCTION.

SO WE HAD A REALLY NICE IDEA OF

HOW TO PUSH FORWARD A PLAN.

AND HE DID AND HE THOUGHT THIS

WAS A GREAT IDEA AND HE TALKED

ABOUT ROTO VIRUS ALL THE TIME.

AND HE HAD BEEN INCREDIBLY

INVESTED IN THESE, IN THE ROTO

VIRUS ACTIVITY.

WELL AL AND I AND RUTH BISHOP

GOT AN AWARD FOR GRADED

CONTRIBUTION TO VACCINOLOGY AND

GLOBAL HEALTH.

THAT AWARD LASTED ABOUT --

MONTHS AND AT THAT TIME THIS

HUGE PROBLEM OCCURRED THAT WE

NEVER ANTICIPATED.

I LOST MY HAIR OVER THIS

FIGURING OUT THIS PROBLEM.

AM LOST A LOT OF ANGST I WOULD

SAY.

AND WITH 15 CASES THAT WERE

IDENTIFIED AS A VACCINE ADVERSE

EVENT AND THEN A COUNTRY WHERE

FEW CHILDREN DIE OF ROTO VIRUS.

THIS WAS AN ADVERSE EVENT THAT

COULD MOVE THE SURGERY OR

POSSIBLY DEATH OF AMERICAN

CHILDREN OR CHILDREN IN THE

DEVELOPING WORLD.

WHEN WE EXAMINE THIS MORE

CAREFULLY, IT WAS REALLY A SMALL

PEAK OF CASES AFTER THE FIRST

DOSE, PERHAPS THE SECOND.

AND BECAUSE OF THIS, THE VACCINE

WAS REMOVED FROM USE IN THE

UNITED STATES.

WELL, WHEN WE EXAMINED WHAT WAS

GOING ON, WE COULD NEVER FIND A

REAL CAUSE OF IT BUT WE DID

THINK 50% OF CHILDREN WHO GOT

THEIR FIRST VACCINE BETWEEN

THREE AND SIX MONTHS OF AGE HAD

80% OF THE INTUSSUSCEPTION

WHEREAS 20% VACCINATED ON

SCHEDULE HAD INTUSSUSCEPTION.

BECAUSE OF THIS TEN-FOLD RISE OF

INCIDENCE.

WE RECOMMENDED THAT ALL FUTURE

LIVE ORAL VACCINES ONLY BE GIVEN

TO CHILDREN UNDER THREE MONTHS

OF AGE.

SO IT WAS APPARENTLY EVERYTHING

WAS IN OBSERVATION AND THAT'S

BEEN HELD EVER SINCE.

SO WE TRIED TO RESURRECT THIS

VACCINE AND MEETING WIT W.H.O.

BECAUSE SAVING ONE DEATH -- IS

WHITE AN EQUILIBRIUM.

IF YOU WOULD LOVE TO INTRODUCE

THE VACCINE BUT WHEN HE HAD THE

FIRST CASE OF INTAW SA INTAW INTUFS SAW IN
TAW SAW INTUSSUSCEPTION.

SEVEN YEARS LATER TWO NEW

VACCINES ARE ON THE MARKET

TODAY, ONE FROM GSK AND ONE FROM

MERCK, A HUMAN STRAIN THAT'S

BEEN PASSAGE FOR ATTENUATION AND

A TRAIN SIMILAR TO THE

RESUSVIRUS EXCEPT WITH A BOW

VEIN BACKGROUND.

THESE WENT THROUGH THE CLINICAL

CHILD.

THESE ARE CALLED THE PAPER OF

THE YEAR FOR CLINICAL CHILD IN

MORE THAN 60,000 CHILDREN EACH.

NOW THE MERCK VACCINE ROTO TECH

IS DEVELOPING BOVINE, THREE

DOSES, IT SHEDS POORLY BUT IT'S

WORKED VERY WELL.

I WON'T GO INTO SPECIFIC.

THE GSK VACCINE, THE ATTENUATED

IS GIVEN AT EITHER OF THE LIQUID

PREPARATION BUT IT GROWS WELL

AND IS SHED.

SO WE HAVE TWO VACCINES, BOTH

HIGHLY EFFECTIVE.

AGAIN, WITHIN A MONTH

AND-A-HALF, THESE WERE

RECOMMENDED.

THE ROTO TECH WAS RECOMMENDED

FOR USE IN ALL AMERICAN CHILDREN

AND WE'VE HAD A NATIONAL

IMMUNIZATION PROGRAM IN THE U.S.

SINCE 2006.

BUT WHAT HAPPENED?

WE GO BACK TO OUR SAW TOOTHED

SLIDE THAT I SHOWED YOU AT THE

BEGINNING.

THE BLUE ARE HOSPITALIZATIONS

WHERE CHILDREN HAVE SUBMITTED A

SPECIMEN FOR TESTING FOR ROTO

VIRUS, AND THE REDS ARE THE

RESULT OF THEIR TEST.

WHAT YOU CAN SEE IS THAT ONCE

THE VACCINE WAS INTRODUCED IN

2006, TWO YEARS LATER WE HAVE

ABOUT HALF AS MUCH DIARRHEA

HOSPITALIZATION, SPECIMENS SENT

TO THE LABORATORY AND ROTO VIRUS

DETECTIONS HAVE GONE DOWN ALMOST

BY 90% OR MORE.

SO IT'S AN INCREDIBLE IMPACT.

SMALL STUDIES AROUND THE U.S.

HAVE SHOWN THE SAME IMPACT, 90

TO 95% REDUCTION IN

HOSPITALIZATIONS OR EMERGENCY

DEPARTMENTS.

VERY INTERESTING.

HOW DO WE GET A 95% REDUCTION IN

HOSPITALIZATIONS WITH ONLY 70 OR

7 5% OF CHILDREN ARE IMMUNIZED.

HOW DOES THAT HAPPEN?

THIS LED TO AN UNDERSTANDING

THAT THERE IS REALLY A HERD

PROTECTION OF THOSE CHILDREN WHO

ARE NOT IMMUNIZED ARE PARTIALLY

PROTECTED.

IT'S NOT ONLY THE PROTECTION

THAT WE SEE IN THE ROTO VIRUS

SEASON, THAT PEAK OF THE YEAR,

WHEN CHILDREN DESERVE THE FOUR

YEARS, IT'S ALSO IN CHILDREN

FIVE TO 14 YEARS.

WE NEVER REALLY THOUGHT THAT

THESE KIDS HAD ROTO VIRUS AS THE

CAUSE OF THEIR DIARRHEA.

HOW ABOUT ADULTS, HOW ABOUT

THEIR PARENTS.

WE NEVER THOUGHT OF THEM HAVING

ROTO VIRUS ACROSS THEIR DIARRHEA

EITHER BUT WE HAVE SEEN ROTO

VIRUS IN ADULTS AND THE ELDERLY.

SO WE ESTIMATED THIS IS A STUDY

BY LOBMAN IN JID WE ESTIMATE

THERE'S ANOTHER 20-25% OF THE

BENEFIT OF THE VACCINE THAT

OCCURS BY PREVENTING DIARRHEA IN

THESE ROTO VIRUS DIARRHEA IN

THESE OLDER AGE GROUPS.

IT ALSO SAYS THE TRANSMISSION IS

FROM THE INFANT TO THE OLDER

SIBLINGS TO THE PARENTS TO THE

GRANDPARENTS.

SO WE ACTUALLY HAVE IDENTIFIED A

MODE OF TRANSMISSION BY

INTRODUCING A VACCINE.

WELL IN MEXICO, HERE'S ANOTHER

STUDY.

THE FIRST TIME WE'VE SEEN THE

ROTO VIRUS COULD PREVENT DEATHS.

REMEMBER WE MADE THESE WONDERFUL

I WOULD SAY BOGUS ESTIMATES OF

THE DEATH RATE, 600,000, 500,000

DEATHS.

BUT IT'S ALL EXTRAPOLATION FROM

HOSPITAL SURVEILLANCE.

WE DON'T REALLY KNOW WHY KIDS

DIE OF THIS.

HERE IN MEXICO, VACCINE WAS

INTRODUCED IN TO 07 I 2007 IN AGE.

THESE ARE CHILDREN THAT DIE

ABOUT 2000 A YEAR.

AFTER THE VACCINE WAS

INTRODUCED, WITHIN TWO YEARS

THERE'S A REDUCTION FIRST OF

CHILDREN UNDER ONE AND THEN

CHILDREN UNDER ONE AND TWO.

A 40% REDUCTION OF DIARRHEAL

DEATH.

IT ALSO SAYS SOMETHING WITH

HEALTH EQUITY, THESE VACCINES

REACHING THE CHILDREN MORE

LIKELY TO DIE ARE THE POOREST IN

THE SETTING.

WE HAD A VERY START ON THINKING

ABOUT THE GLOBAL CONTROL OF ROTO

VIRUS THROUGH THE USE OF

VACCINES.

WE'VE GONE AROUND THE WORLD

SETTING UP SURVEILLANCE TO

DOCUMENT WHETHER ROTO VIRUS IS

IMPORTANT OR NOT.

IN VIETNAM THE MINISTER OF

HEALTH SAID ROTO VIRUS IS NOT A

PROBLEM HERE, WE'VE NEVER SET

IT.

WHEN WE SET UP SURVEALANCE AS

OUR FIRST PILOT PROJECT IN

VIETNAM WITH W.H.O.6,000

CHILDREN WERE SCREENED WITH SIX

HOSPITALS IN FOUR CITIES.

56% OF THEIR STOOL SPECIMENS HAD

ROTO VIRUS AND THE MINISTER OF

HEALTH IMMEDIATELY HAS INVESTED

IN MAKING A ROTO VIRUS VACCINE

FOR VIETNAM ON THEIR OWN, AND

THAT'S IN CLINICAL TRIALS TODAY.

WE'VE ALSO SOOT UP SURVEILLANCE

AROUND THE WORLD THROUGH CDC,

W.H.O. AND -- IN 60 COUNTRIES.

60% OF CHILDREN HAVE ROTO VIRUS

AS IS CALLED THE DIARRHEA.

THE ONLY LOWER INCIDENCE IS IN

AMERICA WHERE THERE'S A GOOD

IMMUNIZATION PROGRAM THAT HAD

JUST BEGUN WHEN THIS WAS DONE.

SO WE REALLY HAVE A GLOBAL

ISSUE.

WELL, WHEN THE VACCINES WERE

THEN TAKEN TO LOW INCOME

COUNTRIES LIKE MO MOLALITY, WE

THOUGHT WE WOULD SEE 90% OR MORE

WITH 49%.

HOW COULD THIS BE?

AND WHEN THE VACCINE, THE ROTO

TECH WAS INTRODUCED IN NICARAGUA

WAS A DISO DONATION OF MERCK, THEY

WENT DOWN AND DID A CASE CONTROL

STUDY TO EVALUATE THE IMPACT OF

THIS VACCINE.

THE FIRST 209 CHILDREN WHO CAME

INTO THE HOSPITAL WITH ROTO

VIRUS, 76% OF THEM HAD BEEN

VACCINATED.

THAT'S NOT SUPPOSED TO HAPPEN.

WE LIKE TO SAY THAT THE CHILDREN

WHO COME IN HAD NOT BEEN

VACCINATED AND THE CONTROLLED

HAD BEEN VACCINATED.

SO WITH THIS DATA YOU COULD SEE

THE EFFICACY OF THIS VACCINE WAS

LESS THAN HALF.

SO WE NOW HAVE A VACCINE THAT WE

SOLD TO THE MINISTER OF HEALTH

AS A VACCINE THAT WAS AS

PROTECTIVE AS THE U.S. AND LATIN

AMERICA, BUT WAS REALLY ONLY

HALF PROTECTED.

HE CAME TO US AND SAID SHOULD WE

BE BUYING THIS VACCINE FOR OUR

POPULATION.

IT ONLY WORKS HALF AS WELL AS WE

THOUGHT.

WELL, WHEN STUDIES HAVE

CONTINUED, WE CAN SEE THAT IN

LITTLE HIGH AND MIDDLE INCOME

COUNTRIES, VACCINE WORKS REALLY

WELL.

90% OR BETTER.

BUT WHEN WE GET THE LOW INCOME

COUNTRY DOWN HERE, THERE'S A

HUGE DISPLAY OF RESULTS FOR

REASONS WE DON'T FULLY

UNDERSTAND.

VARYING FROM ABOUT 10% TO 70%.

WHAT'S GOING ON AND HOW CAN WE

EXPLAIN THIS?

WELL, W.H.O. WAS SO HAPPY WITH

HAVING A VACCINE THAT WAS A

LIFESAVER THAT THEY HAVE

RECOMMENDED THE USE OF THE

VACCINE GLOBALLY ON A VARIETY OF

SCHEDULES.

THERE IS NOW A GLOBAL

RECOMMENDATION.

AT THE SAME TIME WE HAVE A

VACCINE THAT ONLY WORKS HALF AS

WELL AS WE ANTICIPATE.

WHAT'S THE PROBLEM?

WELL WE THINK THAT SOME OF THE

PROBLEM HAS TO DO WITH THE FACT

THAT THIS IS AN ORAL VACCINE AND

BETWEEN THE MOUTH AND THE GUT

WHERE IMMUNIZATION OWE DISURS,

THERE ARE LOTS OF THINGS THAT

CAN LOWER THE TITER OF THE

VACCINE VIRUS.

THIS CAN BE BREAST MILK WHICH

HAS NEUTRALIZATION ACTIVITY AND

CAN NEUTRAL AISLES AND LOWER THE

TITER OF THE VACCINE VIRUS.

OR ISSUES OF THE POOR IMMUNE

RESPONSE OF CHILDREN IN LOW

INCOME SETTINGS.

OR THE INTERFERENCE OF OF THE

MICRO BIOME.

WE'VE LOOKED AT THIS IN A

VARIETY OF SETTINGS AND IT'S

BEEN LOOKED AT BY DICK WARD.

HERE HE LOOKED IN FINNISH

CHILDREN LOOKED IN RESPONDERS

AND NON-RESPONDERS.

THIS IS A TITER OF MATERNAL

APARTMENT BODIES.

THIS IS ANTIBODY THAT PASSES

FROM THE MOTHER TO THE CHILD

DURING PREGNANCY.

AND HE FOUND THAT THOSE CHILDREN

WHO RESPONDED HAD MUCH LOWER

TITER THAN MATERNAL ANTIBODY IN

CHILDREN WHO ARE NOT RESPONDERS.

THAT IS TO SAY IF YOU HAD A HIGH

TITER MATERNAL ANTIBODY, YOU

NEUTRALIZE THE VIRUS AND YOU

DIDN'T RESPOND.

WELL HOW DOES THIS AFFECT US?

WHEN WE LOOKED AT THE MATERNAL

ANTIBODY TITERS FROM A VARIETY

OF LOW INCOME SETTINGS, THESE

TITERS ARE TWOOR THRE TWO OR THREE OR FIVE

TIMES HIGHER THAN THE TITERS IN

THOSE WIN OR THOSE FINNISH.

23 WE WANT THIS CHILD TO START

WITH THE SAME MATERNAL ANTIBODY

TIRLT ATITER AS THE FINNISH CHILD WE

HAVE TO WAIT THE FIRST FEW

MONTHS.

THAT GETS US INTO THE PERIOD OF

INTUSSUSCEPTION.

THIS IS ONE OF THE KEY CAUSES WE

COULD GIVE A BOOSTER DOSE OR WE

COULD RISE THE TITER OF THE

VACCINE BUT WE HAVE TO ADDRESS

THIS IN THE FUTURE.

ANOTHER PROBLEM, HERE YOU SEE

THIS IS BEING BREAST FED AT THE

VERY TIME OF IMMUNIZATION IN

NICARAGUA.

WE'VE DONE STUDIES AND   IF YOU

JUST LOOK AT THIS UPPER

RIGHT-HAND CORNER, THESE ARE THE

NEUTRALIZATION ACTIVITIES

AGAINST THE ROTO RISK VACCINE.

IN THE BREAST MILK OF MOTHERS

FROM IDENTIFY YOU'RE AN INDIA IN THE UNITE
D STATES.

AN AMERICAN MOTHER BREAST MILK

HAS VERY LOW TITER TO THIS SERO

TYPE ONE STRAIN.

AN INDIAN MOTHER HAS A TITER

THAT'S 50 TO 100 FIELD GREATER.

AND THAT'S ENOUGH TO ACTUALLY

NEUTRALIZE THE VIRUS IN A TEST

TUBE AND LOWER THE TITER TWO OR

THREE.

NOW ANOTHER CAUSE OF THE PROBLEM

COULD BE AT THE VERY TIME OF

IMMUNIZATION.

THERE'S A LOT THAT WE COULD DO

AND PROVE THESE VACCINES AND

SOME RESEARCH IS GOING ON BUT

NOT ENOUGH.

WE'VE KNOWN THIS TOWARD ABOUT

EIGHT YEARS NOW AND THE ANSWERS

ARE NOT THERE.

THE OTHER ISSUE IS THAT THERE

ARE OTHER WAYS WE CAN GET AROUND

THIS WITH NEW VASCULAR SEANTZ.

WE'VE WORK -- VACCINES.

WE'VE WORKED IN INDIA THAT GROWS

WELL IN THE PRESENCE OF MATERNAL

ANTIBODIES BUT IS STILL IMMUNE IM--

EMOIMMUNOGENIC.

THAT WILL BE IN CLINICAL TRIALS

IN HALF A DOZEN SITES.

THERE ARE OTHER WAYS TO DEAL

WITH NEW VACCINE APPROACHES.

THESE ARE UNDER DEVELOPMENT AND

STUDY RIGHT NOW.

WELL, WHERE DO WE STAND THEN?

30 COUNTRIES THAT HAVE

INTRODUCED ROTO VIRUS VACCINES

TO DATE.

LOOK AT THIS TERRIBLE PICTURE.

THE PICTURE SHOWS THAT IN THE

U.S. AND LATIN AMERICA WE HAVE

GOOD COVERAGE IN OS TRAIL YOU

YEAH.

-- AUSTRALIA.

HOW ABOUT THOSE COUNTRIES WHERE

THE GREATEST MORTAL TEASE OCCUR.

SUBSAHARA, ASIA.

THERE IS SIX YEARS AFTER THE

VACCINE WAS INTRODUCED.

SO WHAT WILL WE, WHAT CAN WE

EXPECT NEXT?

WELL, THE GLOBAL ALLIANCE FOR

VACCINES AND IMMUNIZATION HAVE

BEEN RAISED, ROTO VIRUS AND

IMMUNOCAUSE CULL VACCINES IN LOW

INCOME COUNTRIES AND ARE

SUBSIDIZING THE PRICE OF THIS AT

15 TO $.30 A DOSE FOR FIVE

YEARS.

WE HOPE IT WILL BE REFUNDING AND

THESE VACCINES WILL START TO GO

INTO GLOBAL USE.

AND WHEN GAFFEY RECEIVED $4.3

BILLION THIS YEAR UNDER NEW

LEADERSHIP, ABOUT 12 COUNTRIES

IN SUB-SAHARAN AFRICA WILL BE

RECEIVING VACCINE OVER THE NEXT

COUPLE YEARS.

WE DON'T KNOW HOW THESE VACCINES

WILL WORK IN THIS SETTING,

WHETHER THEY WILL BE GOOD HARD

PROTECTION AND THEY MIGHT WORK

BETTER THAN WE ANTICIPATE OR

THEY MIGHT WORK LESS WELL FOR

THE REASONS I MENTION.

THERE'S A RESEARCH AGENDA AND AN

EVALUATION AGENDA THAT WILL BE

ABSOLUTELY CRITICAL AS WE MOVE

AHEAD.

AND OF COURSE, THE VACCINES

WHICH ARE VERY EXPENSIVE IN THE

U.S., $200 A CHILD, THAT 15 TO

$20 A CHILD IN THE LATIN AMERICA

AND MIDDLE INCOME COUNTRIES ARE

NOW GOING TO BE OFFERED BY GFK

BY $5 PER CHILD AND LOWER INCOME

COUNTRY.

WE'RE WORKING ON A VACCINE THAT

WOULD BE $2 PER CHILD DEVELOPED

IN COLLABORATION WITH THE

GOVERNMENT OF INDIA.

THERE ARE A BUNCH OF OTHER LIVE

ORAL VACCINES IN THE PIPELINE

AND AT DIFFERENT STAGES SO WE'LL

HAVE TO COME BACK IN A FEW YEARS

AND SEE IF THESE WILL FILL IN

THE GAPS.

INDIAN VACCINE WE'RE VERY

HOPEFUL ABOUT BECAUSE THE IMMUNE

RESPONSE TO THIS VACCINE IN

INDIAN CHILDREN, ONE DOSE IS

COMPARABLE TO EITHER ROTO IN

BACK DERBY OR TWO DOSES GAVE US

90% IMMUNE RESPONSE.

THE CHILD IS ONGOING AND WE

SHOULD HAVE A RESULT?

LESS THAN A YEAR.

AT THAT TIME WE'LL BREAK THE

CODE AND DECIDE WHETHER WE'RE

SMILING OR WHETHER WE HAVE

SOMETHING THAT'S NOT AS

EFFECTIVE AS WE'D LIKE TO SEE.

THE ONLY EXPERIENCE WILL TELL

US.

SO IN SUMMARY, WE'VE SEEN IN THE

U.S., MEXICO, AUSTRALIA,

TREMENDOUS IMPACT OF ROTO VIRUS

VACCINES, THEY REALLY WORK, THEY

REALLY MADE A DIFFERENCE IN OUR

HEALTHCARE.

AND HOSPITALIZATIONS, DOCTOR

VISITS.

IN LOW INCOME COUNTRIES, THE

VACCINES DO WORK BUT THEIR

EFFICACY IS LOWER AND WE'RE

STILL TRYING TO FIGURE OUT WHY.

THE RESEARCH AGENDA IS CLEARLY

IN NEED TO FIGURE THIS OUT AS WE

MOVE AHEAD.

THE ISSUE OF VACCINE FINANCE WE

MADE A CHALLENGE IN THE NEAR

FUTURE.

SO WITH THAT SAID, WE'RE NOT

THERE YET, WE'VE COME A LONG

WAY.

WE STILL HAVE A LONG WAY TO GO.

AND THE GOAL REALLY IS TO

PROTECT ALL CHILDREN AROUND THE

WORLD WITH A SAFE, EFFECTIVE AND

AFFORDABLE ROTO VIRUS VACCINE.

I HAVE TO THANK MY GROUP AT CDC

WHO HAS BEEN RESPONSIBLE FOR

DOING A LOT OF THIS WORK.

-- EPIDEMIOLOGY -- IN THE

LABORATORY.

WE WOULDN'T HAVE GOTTEN AS FAR

AS WE'VE GOTTEN WITHOUT THE

SUPPORT OF BILL GATES BOTH IN

THE SURVEILLANCE, VACCINE

DISOAVMENT AND NOW IN THE

SUPPORT FOR GAVI TO BUY VACCINES

TO PUT IN PLACE.

WE'VE LOOKING FOR CREATIVE

STRATEGY FOR FUTURE FUNDING.

DOESN'T THAT LOOK LIKE A ROTE

ROW I ROY -- ROTARY.

WE'VE NAMED THE FUNDER FOR LIFE

SO THAT'S OUR NEXT HOPE.

WITH THAT I JUST WANT TO STOP

THERE AND THANK YOU FOR YOUR

ATTENTION.

[APPLAUSE]

>> AS CHILDREN GET OLDER AT THE

GET LESS SICK AND NOT

HOSPITALIZED.

I DON'T KNOW IF THIS WILL HOLD

UP IN THE LONG TERM BUT AT LEAST

IT'S A WORKING HYPOTHESES.

>> [INDISCERNIBLE]

>> THE QUESTION IS WHETHER YOU

GET SPREAD FROM THE STOOL OF ONE

CHILD TO ANOTHER.

GREAT QUESTION.

IT CERTAINLY HAPPENS WITH POLIO.

IF YOU IMMUNIZE 70% OF THE

POPULATION, EVERYBODY BECOMES

IMMUNE.

WITH ROTO VIRUS, THE SHEDDING

FOR THE ROTO TECH IT'S HARDLY

SHED AT ALL.

THERE'S SUBSTANTIAL SHEDDING

WITH THE FIRST DOSE BUT NOT THE

SECOND AND THIRD.

SO IF THERE'S HERD IMMUNITY FROM

THE FIRST DOSE, IT MIGHT BE A

SMALL EFFECT BUT I DON'T THINK

WE CAN ACCOUNT FOR WHAT'S

HAPPENED IN THE U.S. BECAUSE OF

THAT SHEDDING.

>> HOW ARE YOU GOING TO ADDRESS

THE INTERFERENCE OF THE MATERNAL

ANTIBODIES IN DEVELOPING

COUNTRIES.

AND IS THAT SAME THAT'S GOING ON

WITH THE ORAL POLIO VACCINE THAT

IT ALSO HAS VERY LOW EFFICACY

RATES?

>> ALL THE LIVE ORAL VACCINES,

ORAL POLIO, ORAL CHOLERA, ORAL

TYPHOID HAVE ALL CAUSED PROBLEMS

IN DEVELOPING COUNTRIES AND THEY

WILL HAVE TO HAVE THEIR

ADMINISTRATION CHANGED.

A COUPLE THINGS FOR MA TERM

ANTIBODIES.

-- MATERNAL ANTIBODIES.

WE COULD GIVE THE VACCINE LATER.

IF WE STARTED AT 14 OR 12 WEEKS,

THE 90 DAY LIMIT FOR THE FIRST

DOSE AND THEN GAVE IT LATER, WE

MIGHT GET MUCH IMPROVED IMMUNE

RESPONSE.

IF WE COULD RAISE THE TITER OF

THE VIRUS, THAT PROBABLY

WOULDN'T BE DONE WITH A

COMMERCIAL PREPARATION BUT MIGHT

BE DONE WITH LOCAL PREPARATION.

OR WE COULD GIVER A BOOSTER DOSE

SAY AT 20 WEEKS TO OVERCOME

THAT.

FOR BREAST FEEDING, WE'D LOVE TO

SEE EXPERIENCE AND SOME

EXPERIMENTS ARE GOING ON NOW IN

PACK STEIPAKISTAN WITHHOLDING BREAST

FEEDING WITH IMMUNIZATION TO SEE

IF WE BET A MUCH BETTER IMMUNE

RESPONSE.

IF WE KNEW WITH THAT SIMPLE

EXPERIMENT WITH A LICENSED

VACCINE, IT WILL CHANGE THE WAY

WE ADMINISTER THE VACCINE TODAY

AND THROUGHOUT THE WORLD.

>> THE HIGH TITER MATERNAL

ANTIBODIES SUGGEST THE WOMEN ARE

BEING CONSTANTLY EXPOSED.

IS IT POSSIBLE TO CLEAN UP THE

WATER SUPPLY AT ALL?

>> WELL ... GIVE ME A CENTURY

AND WE'LL DO IT.

YOU KNOW, HAVING LIVED IN

BANGLADESH, WE USED TO TALK

ABOUT THE FECAL IN THE AIR.

THE FACT THAT YOU HAVE ROTO

VIRUSES ALL OVER, THESE WOMEN

HAVE FIVE OR SIX OR SEVEN KIDS.

THEY HAVE EXTENDED FAMILIES.

THEY'RE EXPOSED TO DIAPERS ALL

THE I'M.

HOW CAN DIAPERS BE INFECTIOUS

FITS BASED ON BREAST FEEDING AND

BREAST MILLERRING.

JOY MILK.

IT'S NOT TREATED AS AN

INFECTIOUS AGENT.

IF WE WERE TO INTRODUCE VACCINE

FOR FIVE OR SEVEN OR TEN YEARS,

WE MIGHT ACTUALLY LOWER THE

AMOUNT OF ROTO VIRUS IN THE

ENVIRONMENT AND LOWER TITERS IN

THOSE WOMEN OVER TIME.

AND THAT'S SOMETHING WE COULD

MONITOR OVER TIME.

BUT I THINK THE DIFFERENCE IN

TITERS IS HUGE.

I MEAN IT'S MUCH BIGGER THAN I

ANTICIPATED.

AND THE COMPANY WOULD SAY WELL

BREAST FEEDING IS NOT A PROBLEM.

BUT WHEN YOU LOOK AT THE TITERS

IN BREAST MILK AND 100 FOLD, 50

FOLD DIFFERENCE IN TITERS AND

THE FACT THAT MOTHERS BREAST

FEED AT THE VERY TIME OF

IMMUNIZATION, IT'S ON THE

BREAST.

YOU GIVE THEM THE VACCINE AND

THEY PUT IT RIGHT ON THERE.

OUR WOMEN IN THE UNITED STATES

DON'T SIT AROUND BREAST FEEDING

THE WAY THEY DO IN OTHER

SETTINGS.

I THINK THERE'S A LOT THAT CAN

BE DONE WITH THAT.

>> ALL RIGHT, THANK YOU ROGER.

THERE WILL BE TIME FOR MORE

QUESTIONS AND DISCUSSIONS AFTER

MARK'S TALK.

YOU MIGHT WONDER HOW DO YOU GET

DIARRHEA FROM A VIRUS OR FOR

THAT MATTER FROM CHOLERA OR MANY

OTHER THINGS.

THE END RESULT IS THE SAME BUT

HOW DO YOU GET THERE.

SO MARK, YOU'RE GOING TO TELL US

HOW WE GET THERE.

>> YES, HOW WE GET THERE.

I'M SO GLAD TO BE HERE TO TELL

YOU A LITTLE BIT ABOUT SOME OF

THINGS WE THINK ABOUT.

SO ABOUT 120 DIFFERENT DYE RARYL

DISEASES -- DIARRHEAL DISEASES,

DISEASES THAT HAVE DIARRHEAL AS

A MAJOR COMPONENT.

IF YOU WERE PLOTTING HOW THE A

WAY TO DEAL WITH THAT TO

UNDERSTAND THE PATHOPHYSIOLOGY

OR IN FACT THE THERAPY, CAN'T

GET 120 VACCINES PROBABLY, BUT

IT'S LUCKY THAT THE NUMBER OF

MECHANISMS IS QUITE LIMITED SO

THAT'S WHAT I'M GOING TO TALK TO

YOU ABOUT TODAY.

SO THE GOAL OF MY TALK IS TO

EXPLAIN DIARRHEA AS

ABNORMALITIES IN WATER AND

ELECTROLYTE TRANSPORTS.

I'LL FIRST START BY REVIEWING A

LITTLE BIT ABOUT WHAT'S KNOWN

ABOUT NORMAL WATER IN

ELECTROLYTE TRANSPORTS BY THE

GUT.

THEN HELP USE EXAMPLES TO LET

YOU UNDERSTAND DIARRHEAL

DISEASES AS ABNORMALITIES IN

WATER AND ELECTROLYTE TRANSPORT.

AND THEN TO UNDERSTAND BOTH ORS

AND DRUG THERAPY AS WAYS TO

CORRECT THE ABNORMALITIES IN

WATER AND ELECTROLYTE

TRANSPORTS.

SO THIS WILL BE A

PATHOPHYSIOLOGY TALK.

LET ME START BY TELLING YOU THE

OVERALL BURDEN OF DIARRHEAL

DISEASES IN THE UNITED STATES.

THERE ARE ACUTE DIARRHEAL

DISEASES THAT ROGER WAS TALKING

ABOUT WITH ROTO VIRUS BEING A

CRITICAL ONE.

AND A CHRONIC DIARRHEAL

DECEMBER, THOUGH THA DISEASEAND THOSE THAT
 DON'T GO AWAY.

THEY OCCUR IN THE UNITED STATES

BUT NOT AS FREQUENTLY AS

DEVELOPING CASE.

THERE ARE ABOUT 200 CASES OF

DIARRHEAL CASES IN THE UNITED

STATES PER YEAR.

A THIRDOR FOOD BORNE AND TWO

THIRDS ARE NOT.

ACROSS THE MEDICAL SYSTEM COSTS

ABOUT SO THREE MILLION CASES.

NOTICE THE AMOUNT OF MONEY

THAT -- THIS IS NOT GOING TO

FLY, SORRY.

SO THE COST OF THESE CHRONIC

DIARRHEAL DISEASES ARE ALSO $3

BILLION.

EVEN THOUGH THERE ARE MANY FEWER

CASES.

AND THAT'S BECAUSE ONE OF THE

MAJOR CAUSES OF CHRONIC DIARRHEA

IN THE UNITED STATES ARE SHORT

GUT SUN DRONE.

SOME HAVE HAD THEIR BOWEL

RESECTED AND KEPT ALIVE THROUGH

VERY EXPENSIVE THERAPY.

NOW ROGER TOLD YOU THAT ONLY

ABOUT 60 PEOPLE IN THE UNITED

STATES, CHILDREN DIE OF DIARRHEA

FROM ROTO VIRUS.

BUT IS THAT WHO DIES IN THE

UNITED STATES FROM DIARRHEA.

SO I DON'T KNOW THE ANSWER BUT

THERE'S THIS REALLY IMPORTANT

EPIDEMIOLOGICAL STUDY THAT WAS

PUBLISHED A LOT OF YEARS AGO

NOW.

1992.

THAT TOOK A HUGE DATA BASE OF

HOSPITALIZED PATIENTS AND SAID

WHO GETS SUBMITTED TO THE

HOSPITAL.

NO SURPRISE KIDS GET ADMITTED.

WHO DIES, NO SURPRISE.

IT'S THE VERY AGE THAT DIE IN

HOSPITALS.

WHEN THEY DID THE SAME THAT IS

FOR DIARRHEAL DISEASES A SHOCK

IS IT'S A YOUNG WHO ARE GETTING

ADMITTED AND THE OLD WHO ARE

DYING.

BUT THE DEATH RATE AND THE AGE

POPULATION ADMITTED TO HOSPITAL

WAS VERY LARGE.

IT WAS 3% OF PEOPLE OVER 80.

SO THAT 85% OF THE DEATHS FROM

DIARRHEA WERE THE AGE

POPULATION.

EVEN THOUGH IT WAS A VERY SMALL

NUMBER OF PEOPLE WHO WERE BEING

ADMITTED.

NOW PLEASE REMEMBER THAT A LOT

OF PEOPLE WHO ARE IN NURSING

HOMES, WE'RE GOING TO HAVE A LOT

MORE PEOPLE IN NURSING HOMES

THAT DON'T MAKE IT TO THE

HOSPITAL.

SO THE QUESTION I THINK NEEDS

ADDRESSING IN THE UNITED STATES

IS FROM DIARRHEA NOW A PROBLEM

OF THE AGING AND AGE POPULATION.

IT USED TO BE WE GAVE A NAME TO

PNEUMONIA.

IT WAS AN OLD MAN, AN OLD

PERSON'S FRIEND, RIGHT.

REALLY OLD PEOPLE WOULD DIE OF

PNEUMONIAS.

I THINK THAT QUESTION NOW NEEDS

TO BE RAISED ABOUT DIARRHEAL

DISEASES.

IT COULD VERY WELL BE THAT A

HUGE NUMBER OF PEOPLE ARE DYING

FROM DIARRHEAL DISEASES IN

NURSING HOMES.

>> SO LET'S TALK ABOUT THE

PATHOPHYSIOLOGY OF DIARRHEA.

THROUGHS A DEFINITION.

DIARRHEAL DISEASES ARE DISEASES

IN WHICH THERE'S AN INCREASE

LOSS OF WATER IN THE STOOL EACH

DAY.

NORMAL PEOPLE, PEOPLE WHO FEEL

THAT THEIR DOWELS ARE NORMAL ON

AN AMERICAN OR BRITISH DIET LOSE

APPROXIMATELY 130MILS OF WATER

IN THEIR STOOL PERDAY.

THERE'S 130 MILLS.

I'M GOING TO BE COUGHING DURING

THIS TALK SO I GOT MYSELF A COME

OF WATER.

THIS IS A FULL CUP IS THI 240 SO 130

IS HALF A CUP OF WATER PER DAY.

THAT'S NORMAL STOOL LOST.

WHEN PEOPLE PUT OUT 200MILS A

DAY ARE COMPLAINING TO THE

PHYSICIAN, DO SOMETHING ABOUT

THIS TERRIBLE CONDITION THAT I

HAVE.

NOW, I'D LIKE TO PUT INTO

PERSPECTIVE THAT 130 MILLS.

I CALL THIS A WATER BALANCE.

IT SHOWS YOU HOW MUCH WATER GOES

INTO THE GI TRACT AND HOW MUCH

WATER LEAVES THE GI TRACT.

SO EVERY DAY THE GI TRACT DEALS

WITH NINE LITERS OF WATER.

THE MINORITY IS WHAT YOU DRINK.

WE'RE ALL DRINK ABOUT TWO

LITERS.

SOME PEOPLE ARE MORE THURSDAY

FEE, SOME PEOPLE LESS THIRSTY

BUT BASICALLY THE MINORITY OF

THE FLUID, THE WATER THE GUT HAS

TO DEAL WITH EACH DAY IS WHAT

YOU CONSUME EXOGENOUSLY.

BUT THE MAJORITY IS WHAT YOU

SECRET AS FASECRETE AS FAR AS THE DIGESTIV
E

PROCESS.

THIS OVERALL PROCESS IS

SUFFICIENT.

NINE LITERS IS PUT IN, YOU

ABSORB 8.8 OR 8.87 WORKING AT

98% EFFICIENCY.

NOW IN TERMS OF UNDERSTANDING

THE PATHOPHYSIOLOGY OF DIARRHEA,

THIS SLIDE REALLY HAS AN

IMPORTANT MESSAGE.

IT SAYS WE HAVE ABSORB 8.8

LITERS AND WE SECRETE ONE LITER

OF WATER.

SO THE GUT IS BOTH ABSORBING AND

SECRETING WATER EACH DAY.

THE ABSORPTIVE PROCESSES ARE

PREDOMINANT BUT THERE IS

SECRETION GOING ON UNDER NORMAL

CONDITIONS.

SO WHAT HAPPENS IN DIARRHEA?

OKAY.

SO THAT'S GOING TO BE A MESSAGE

I'M GOING TO GIVE YOU.

NOW WHEN WE TALK ABOUT HOW THE

GUT ABSORBS WATER, THE INTESTINE

IS AN EPITHELIAL CELLS LIKE A

LUNG OR KIDNEY OR ANY EPITHELIAL

CELL WHEN MEANS THAT WATER

TRANSPORT OCCURS PASSIVELY DOWN

ELECTROCHEMICAL GRADIENTS

GENERATED BY ACTIVE TRANSPORT

USUALLY OF ELECTROLYTES THAT CAN

BE OF SIMPLE NON-ELECTROLYTES

LIKE SUGARS AND AMINO ACIDS.

THIS IS AN OLD STUDY FROM A RAT

WHICH WATER TRANSPORT IS

CORRELATED WITH ELECTROLYTE

TRANSPORT.

THERE'S A LINEAR RELATIONSHIP

WHEN THERE'S NO WATER TRANSPORT

THERE'S NO ELECTROLYTE

TRANSPORT.

TO UNDERSTAND DIARRHEAL DISEASES

YOU NEED TO UNDERSTAND HOW DO

ELECTROLYTES GET TRANSPORTED BY

THE GUT.

NOW, THERE ARE SEPARATE CELLS

THAT DO THE ABSORPTION AND

SECRETION THAT I MENTIONED.

THE CELLS THAT DO ABSORPTION ARE

ON THE VILLUS OF THE SMALL

INTESTINE AND THE SURFACE OF THE

COLON AND THE ABSORPT FIFTH

PROCESSES ARE THE SODIUM

ABSORPTIVE PROCESSES.

-- IT'S AN AN AN ION ORBIT SORPTIVE

PROCESS.

THIS IS THE WAIVE THE

ELECTROLYTE TRANSPORT OCCURS.

THESE EPITHELIAL CELLS ARE

POLARIZED, WHICH MEANS THAT

FUNCTIONALLY THEIR PLASMA

MEMBRANE IS -- WE HAVE PHASING

LUMEN OF THE GUT, THE APICAL

MEMBRANE AND A PART FACING THE

BASAL LATERAL MEMBRANE.

THE ENERGY IS IN THE SODIUM PUMP

THE SAME SODIUM PUMP IN EVERY MA

MALE ANNUAL SIST -- MA MALE

ANNUAL SYSTEM.

IT MAKES A CHEMICAL GRADIENT

MOVING SODIUM INTO THE CELL FROM

ALL DIRECTIONS.

HOWEVER THE ONLY PLACE THAT THIS

CELL HAS SODIUM TRANSPORTERS ARE

IN THE APICAL MEMBRANE.

THERE ARE TWO CLASSES OF SODIUM

TRANSPORTERS.

THEY'RE THE ONES THAT WHEN

SODIUM MOVES CHARGED, CALLED

ELECTROGENIC AND THERE ARE ONES

WHEN SOMETHING MOVES ALONG WITH

THE SODIUM SO THERE'S NO NET

MOVEMENT OF CHARGE.

THE ELECTROGENICS OCCUR AFTER

EATING.

THEY ARE THE LINKING OF SODIUM

INTO THE SODIUM GREAT YENT OF

END PRODUCTS OF DIGESTION AND

AMINO ACIDS.

THIS OCCURRED IN THE POST

PRANDIAL STATE.

IT'S CALLED NEUTRAL SODIUM

CHLORIDE ABSORPTION.

IT'S TWO TRANSPORT PROTEINS THAT

ARE LINKED.

IF SODIUM EXCHANGING NH3C AND

CHLORIDE BICARBONATE EXCHANGER

MEMBER OF THE -- SOMETHING

CALLED DRA OR PAT ONE.

AND THESE TWO PROCESSES ARE

CLOSELY LINKED PRESUMABLY BY

ELECTROCHEMICAL GRADIENTS BUT

THEY ARE ACTUALLY PHYSICALLY

LINKED TOBACCO AS WELL.

NOW, THIS APICAL MEMBRANE

PROTEIN PROCESSES DON'T OCCUR IN

EVERY PART OF THE GUT.

NOT ALL OCCUR?

PARTS OF THE GUT.

I LIST THE ONES THAT ARE IN

SPECIFIC LOCATION.

9 END PRODUCTS OF DIGESTION, THE

SODIUM LINKED GLUCOSE, THEY ARE

PRETTY MUCH THE UPPER HALF OF

THE SMALL VALVE, THE JEJUNUM.

THEY'RE NOT IN THE ILIUM OR THE

COLON.

ABSORPTION IS IN THE ILIUM AND

COLON BUT DEFINITELY PRESENT AND

SODIUM CHANNELS, THE FAMOUS

EPITHELIAL CHANNELS IS IN THE

COLON.

YOU HAVE DIFFERENT TRANSPORTERS

IN DIFFERENT LOCATIONS.

NOW IT'S BEEN NOT FOR A LONG

TIME THAT THE ELECTROGENIC

TRANSPORTERS EXPLAIN SODIUM

ABSORPTION AFTER EATING AND THE

ELECTRONEUTRAL PROCESS OCCURRED

PARTICULARLY IN BETWEEN MEALS.

BUT THAT ACTUALLY IS NOT TRUE.

IN A STUDY THAT I DID WITH JERRY

TURNER FROM CHICAGO IN A POST

DOC SUPPORTED BY THE FOGERTY, WE

FOUND THAT GLUCOSE, WHICH GETS

TAKEN A UP THROUGH THE SO ANNUAL

GLUCOSE TRANSPORTER ONE, IS NOT

ONLY A TRANSPORT PROTEIN BUT

IT'S A SIGNAL TRANSDUCER.

WHENEVER GLUCOSE LINKS TO SGLT1

IT HAS TRANSDUCTION.

VERY INTERESTING IT TURNS ON P38

ALL OF THEM ARE LINKED TO THAT

FOR MAP KINASE.

TURNS ON TO AN APICAL PROTEIN.

INVOLVES PHOSPHO-- MAIN PROTEIN

CALLED NERF2 AND CAUSES NHG3

INSIDE THE CELL TO 2R56IC TO THE

APICAL MEMBRANE.

IT MEANS EVERY TIME YOU HAVE

GLUCOSE OR AWE PHENO ACIDS AND

HAVE UP TAKE OF THAT PROCESS,

YOU TURN ON DISMAL TRANSDUCTION

THAT MOVES NHA3 TO THE MEMBRANE.

THERE'S LEAKING OF THE TWO

CLASSES OF TRANSPORT PROTEINS.

IN FACT NAC3 AND -- TURNS OUT TO

BE THE MAJOR WAY YOU ABSORB

SODIUM IN THE GI TRACT AND THE

KIDNEY FOR THAT MATTER AS WELL.

NOW IN A COLON THERE'S ONE OTHER

SODIUM-LINKED NEUTRAL TRANSPORT

PROCESS THAT I'VE GOT TO TELL

YOU ABOUT BECAUSE OF THE

ADVANCES IN ORAL REHYDRATION

SOLUTION.

IN THE COLON THERE IS THE

NEUTRAL SODIUM PROCESS I TALKED

ABOUT THAT ARE LINKED TO DRA.

BUT THERE'S A OPERATE PROCESS IN

WHICH NAT2 OR 3, TWO SEPARATE

SODIUM HYDRASE, CHANGES --

HYDROXYL EXCHANGE AND THAT IS

ALSO A NEUTRAL TRANSPORT

PROCESS.

AND YOU'LL HEAR ABOUT HOW

IMPORTANT IT IS A LITTLE LATER.

NOW THE UPPER PART OF THE GI

TRACT AND THE LOWER PART OF THE

GI TRACT HAVE BASICALLY

DIFFERENT FUNCTIONS.

THE UPPER PART, THE SMALL

INTESTINE DOES MOST OF THE

SODIUM ABSORPTION.

IT'S ON LOW EFFICIENCY BUT HIGH

VOLUME SYSTEM.

THE DISTAL PART OF THE VALVE,

THE COLON IS VERY EFFICIENT BUT

DOESN'T DO MUCH TRANSPORT.

AND THAT'S THE ORGANIZATION OF

THE KIDNEY AS WELLS THE

INTESTINE SO YOU GET A LOT OF

ABSORPTION APPROXIMATELY WITH

LOW EFFICIENCY AND WHATEVER'S

LEFT GETS SUCKED UP BY THE

DISTAL MECHANISMS.

IN THE SECRETORY CELL IS THE

SAME, THE ABSORPTIVE CELL I TOLD

YOU ABOUT IS PRETTY MUCH UNIQUE

TO THE GI TRACT.

IF YOU WENT TO A KIDNEY OR BRAIN

OR LUNG, IT WOULDN'T BE EXACTLY

THE SAME SODIUM ABSORBING CELL.

IN CONTRAST, THE SECRETORY CELL

IS EXACTLY THE SAME SECRETORY

CELL THAT'S PRESENT IN THE LUNG

TARGET OF CYSTIC FIBROSIS IN THE

KIDNEY, IN THE CORACOID PLEXUS.

IT WAS FIGURED OUT IN 1979 WHICH

IS PRETTY AMAZING AND IS THE

SAME POLARIZED DISTRIBUTION.

SODIUM PUMP IS IN THE BASAL

LATTER MEMBRANE.

INSIDE THAT PUMP IS A CORTICOID

TRANSPORTER.

THIS CELL ACCUMULATES COURTOIDS

ABOVE THE POTENTIAL AND UNDER

BASAL CONDITIONS IT'S FILLED

WITH CHLORIDE.

THERE'S IN THE EIGHTH OF A MM-MM

BRAIN A SERIES -- MEMBRANE A

SERIES OF CHLORIDE CHANNELS BET

KNOWN CFTR.

BUT ALSO CALCIUM ACTIVATED

CHLORIDE CHANNELS MEMBERS OF THE

ANNUITY JEAN FAMILY HAS BEEN

STUDIED IN THE LAST TWO OR THREE

YEARS CALLED A -- 1618 AGING

FAMILY.

THIS SECRETIVE CELL IS A COME

PARETO IN CERTAIN TYPES OF

DIARRHEAL DISEASES BUT NOT IN A

HUGE NUMBER OF DIARRHEAL

DISEASES.

SO I'M GOING TO COME BACK TO

THAT AND HOPE YOU'LL GET THE

POINT.

BUT CHLORIDE SECRETION OR AN ION

SECRETION OCCURS IN SOME OF OUR

WORSE DIARRHEAL DISEASES BUT NOT

IN THE MOST COMMON DIARRHEAL

DISEASES.

I'LL TELL YOU ABOUT THAT IN A

SECOND.

NOW, THE IN ADDITION TO CHLORIDE

SECRETION THERE'S BICARBONATE

SECRETION AND THAT'S VERY

IMPORTANT IN SEVERE DIARRHEAL

DISEASES.

IT'S THE SAME CELL PRESUMABLY

IT'S DOING CHLORIDE SECRETION

BUT LINKED TO CFTR IS A CHLORIDE

BICARBONATE EXCHANGE, A MEMBER

OF THE SAME GENE FAMILY THAT'S

INVOLVED IN SODIUM AND CHLORIDE

ABSORPTION, WHEN CHLORIDE

SECRETION OCCURS THAT CREATES A

NEXT TO THE APICAL MEMBRANE,

THERE'S A CONCENTRATION GRADIENT

FOR CLIE CHLORIDE WHICH DRIVES -- AND

IN THE BASO LATERAL MEMBRANE

IT'S TAKEN UP BY A MEMBER OF THE

SOC4 BY SODIUM BICARBONATE

TRANSPORTER OR SODIUM DEPENDENT

BICARBONATE EXCHANGE PROTEIN.

NOW, I'VE SAID THAT UNDER SOME

CONDITIONS THE ABSORPTIVE

PROCESSES WAY EXCEED THE

SECRETIVE PROCESSES.

HOWEVER, WHEN YOU EAT, THE

OPPOSITE HAPPENS.

THE ABSORPTIVE PROCESSES GET

INHIBITED AND THE SECRETORY

PROCESSES GET STIMULATED.

PRESUMABLY THE PURPOSE OF THIS

IS TO LET WATER SLUSH INTO THE

GUT AND PRESIDENT THE DIGESTIVE

ENZYMES ACROSS THE ABSORBING

SURFACE SO YOU GET MORE

EFFICIENT DIGESTION AND THEN

ABSORPTION.

LATER IN DIGESTION, YOU REVERSE

THAT PROCESS.

SO PRESUMABLY SO EVERY TIME YOU

EAT YOU DON'T GET DEHYDRATED.

THAT'S KIND OF THE SERIES OF

EVENTS.

WHAT EXBELLIGERENC EXPLAINS THAT.

IT EXPLAINS THE BALANCE OF

SECRETION IN THE POST PRAN PRANDIAL STATE.

EVER TIME YOU EAT OR PUT A FOOD

SUSTONS INTO THE NERVE THESE

CELLS FIRE OFF, REGULATE EACH

OTHER AND CHANGE THE ABSORPTIVE

PROCESS AND THE SECRETIVE

PROCESS.

THAT'S NORMAL DIGESTION.

NOW THE PATHOPHYSIOLOGY OF

DIARRHEAL DISEASES WAS FRS

UNDERSTOOD IN THE -- FIRST

UNDERSTOOD IN THE 60'S BY --

THOSE OF YOU WHO ARE MEDICAL

STUDENTS, YOU WOULD BE USING

PHYSIOLOGY TEXTBOOKS OR GI

TEXTBOOKS.

HE'S THE ONE WHO WROTE THE FIRST

MAJOR GI TEXTBOOK.

HE UNDERSTOOD HOW TO MEASURE

WATER AND ELECTROLYTE TRANSPORT

WHILE USING A NON-ABSORBABLE

MARKETER.

HE WILL TAKE AN INTESTINE AND

PROFUSE IT WITH A NON-ABSORBAL

MARKETER TO REACH A STEADY STATE

AND THEN COULD RELATE THE

CONCENTRATION CHANGES TO THE

RATES OF TRANSPORT.

SO IF YOU HAVE THE SAME AMOUNT

MOVING, SAME AMOUNT OF YOUR

NON-ABSORBABLE MARKETER MOVING

THROUGH AN INTESTINAL LOOP, IF

YOU THEN MODIFY, LET THE PERSON

THINK ABOUT EATING OR GIVE HIM A

HORMONE OR DRUG.

IF YOU GET AN INCREASE IN

CONCENTRATION THAT WILL INDICATE

YOU'RE GETTING ABSORPTION AND IF

YOU GOT DILUTION OF YOUR MARKER

YOU WOULD BE INDICATING THE

SECRETION.

THE OBSERVATION YOU MADE IN THE

GUT, YOU'RE IN AN ABSORPTIVE

STATE, BUT EVERY DIARRHEAL

DISEASE YOU STUDIED SOME PART OF

THE GUT WAS CONVERTED FROM AN

ABSORPTIVE INTO A SECRETORY

ORGAN.

THE CONCEPT WAS IF YOU PRODUCED

MORE FLUID IN A LOOP THAT CAME

OUT AND YOU PROFUSED WITH, THAT

IS TO PRODUCE DIARRHEA IF LFSZ

ENOUGH OF THIS SECRETION TO

OVERWHELM THE ABSORPTIVE PROCESS

DOWN STREAM.

AND YOU MIGHT GUESS OF COURSE

THAT WHEN HE DID THESE STEEFTSDZ

YOU REALIZE THAT -- STUDIES YOU

REALIZE THAT COLONIC DISEASES

NEEDED LOT CHANGES OF TRANSPORT

THAN THE SMALL INTESTINAL

DISEASES.

YOU HAD A LOT OF STUFF DOWN

STREAM LIKE THE COLON TO

COMPENSATE.

SO COLONIC DISEASES NEAT NEED

RELATIVELY SMALL CHANGE.

ALSO WORKED OUT THE CONCEPT OF

SECRETE GOGS.

EVERY CAUSE WHEN PUT INTO AN

ANIMAL MODELED CONVERTED THE GUT

FROM AN ABSORPTIVE TO SECRETORY.

THIS INCLUDED BACTERIAL OR VIRAL

TALKENS, MORE MOANS OR LARKSIVES

AND EXAMPLES OF THESE YOU CAN

SEE SOME OF YOUR FAVORITE

DISEASES ALL OF THESE WOULD CON

VERT THE GUT FROM ABSORPTIVE

INTO A SECRETORY ORGAN.

I'LL CONCENTRATE ON CHOLERA AND

ROTO VIRUS WHICH ARE THE TWO

HUGE REALLY IMPORTANT DIARRHEAL

DISEASES.

SO TELLING YOU THAT THE

PATHOPHYSIOLOGY OF DIARRHEA

MEANS THAT SOME PART OF THE

GOVERNMENT IS CONVERTED FROM AN

ABSORPTIVE INTO A SECRETIVE

DOESN'T TELL YOU ANYTHING ABOUT

MECHANISMS.

IN FACT, IT DOESN'T.

SO YOU INVENTORY HAVE TO SAY HOW

CAN THE GUT BE CONVERTED FROM AN

ABSORPTIVE INTO A SECRETORY

ORGAN.

ROUGHLY FOR PEOPLE TO THAT

STUDIED DIARRHEA, THE NUMBER OF

MECHANISMS ARE VERY FEW.

A LOT OF DISEASES, 120 DISEASES,

VERY FEW MECHANISMS.

SO HERE THEY ARE LISTED.

YOU CAN CONVERT THE GUT FROM

ABSORPTION INTO A SECRETORY BY

INHIBITING ABSORPTION OR BY

TURNING ON ACTIVE AN ION

SECRETION.

SORE YOU CAN INCREASE LUMINAL

ODDODDSOSMOLARITY.

IT PRODUCES DIARRHEA IN THE

COLON AND INCREASING STICKER

HYDROSTATIC PRESSURE.

 IT IS STIMULATION OF ACT TIFER

STILL LATION.

THERE ARE MANY CLASSIFICATIONS

OF DIARRHEAL DISEASES.

AND WHERE ALL THE SEVERE

DIARRHEAL DISEASES CHOLERA AND

ROTO VIRUS, WE NOW REALIZE

THAT -- GENERALLIC DIARRHEA AND

INFLAMMATORY DIARRHEAL DISEASES

ARE BASICALLY DIFFERENT IN THEIR

MECHANISMS.

END ROENT ROW TALK GENIC -- SUCH AS

FLUMITFLAMMITY -- WE'LL TALK ABOUT

WHAT DRUGS SHOULD BE DEVELOPED

FOR TREATING DIARRHEAL DISEASES.

I'LL GIVE YOU AN EXAMPLE OF

DIARRHEAL DISEASES SECRETORY AND

FLAMMITY DIARRHEAL DISEASES.

CHOLERA, CAMP DISEASE OR E COLI

WHICH IS THE -- OR -- QUHS A

CALCIUM AN EL INDICATE ELEVATED CALCIUM

DISEASE AND -- E COLI -- NHE3OR

PRIMARILY INHIBITED.

THE AN ION EXCHANGED ARE LINKED,

THEY ARE ALSO EXAMPLES OF

MULTIPLE DIARRHEAL DISEASES IN

WHICH THAT PROCESS IS INHIBITED.

SO WE'LL SHOW YOU THIS PICTURE

AND I'M NOW GOING TO TELL YOU

ABOUT THE PATHOPHYSIOLOGY OF TWO

DIARRHEAL DISEASES.

I'LL TALK ABOUT CHOLERA THE MOST

SEVERE DIARRHEAL DISEASE AND

I'LL TALK ABOUT THE ROTO VIRUS

THAT ROGER SPOKE ABOUT BUT I'LL

GO MORE PEC MECHANICALLY HOW MECHANIC MECH
ANISTICALLY

OCCURRED.

THE MOST WELL-KNOWN OF WHICH IS

TO RELEASE INTO THE LUMINA OF

GUT A BACK FERAL PROTEIN CALLED

CHOLERA TOXIN.

NOW, THE VOLUME OF CHOLERA

DIARRHEA CAN BE PRODIGIOUS.

IT CAN BE A LITER PER HOUR WHICH

IS 24 LITERS PER 24 HOURS WHICH

IS FIVE FILES YOUR INTRAVASCULAR

VOLUME PERDAY AND IT'S A THREE

DAY ILLNESS.

SO IF YOU'RE LOSING THREE TIMES

YOUR INTRA VASCULAR VIRUS IT'S

NO SURPRISE UNLESS YOU HYDRATE

THESE PATIENTS, MANY TIMES

THEY'RE GOING TO DIE.

THE BACTERIAL LOAD THAT PRODUCES

CHOLERA THE IS FECAL

CONTAMINATION.

IS IT BACTERIA THAT DO IT?

THEY YOU ACTUALLY NEED A MILLION

CHOLERA TOXIN BACTERIA TO

PRODUCE CHOLERA.

EVEN IF YOU GET EXPOSED TO A

MILLION CHOLERA ONLY 10% OF THE

PEOPLE WILL GET ANY DIE RAW.

ABOUT 10% ONLY 10% OF THOSE WILL

GET THAT TYPE OF DIARRHEA.

SO IT TELLS YOU THAT THERE'S A

LOT OF FEEDBACK MECHANISMS AND A

LOT OF CONTROLS.

BUT WHEN YOU DO GET THIS KIND OF

DIARRHEA, YOU BETTER DO

SOMETHING ABOUT IT.

AND THE WAY THIS IS TREATED IN

DEVELOPING COUNTRIES CURRENTLY,

IS TO KEEP PEOPLE ALIVE BY

MEASURING THE STOOL OUTPUT WHICH

YOU DO WITH A VERY LOW TECH

PIECE OF EQUIPMENT CALLED A

CHOLERA CAUGH COULD THE COT AND THE ATTEND
ANCE

CAN COME BY AND MEASURE THEIR

VOLUMES.

IF THEY CAN GET THE VOLUME BACK

INTO PEOPLE NO MATTER HOW THEY

GET IT INTO PEOPLE THEY'LL STAY

ALIVE AND IF THEY DON'T, THEY

MAY NOT MAKE IT.

NOW IS CHOLERA SOMETHING THAT

OCCURS IN THE WESTERN

HEMISPHERE?

SO I WAS AMAZED THIS WEEKEND IN

THE "NEW YORK TIMES" AND LAST

WEEKEND IN THE "NEW YORK TIMES,"

BOTH WEEKS THEY HAD ARTICLES

ABOUT CHOLERA POINTING OUT THAT

LAST YEAR THERE WERE THREE TO

FIVE MILLION CASES OF CHOLERA IN

THE WORLD.

THERE WERE 10 ON T 0-120 DEATHS OF

CHOLERA IN THE ADULT POPULATION.

IN HAITI, THE LAST TWO YEARS

THERE WERE EPIDEMICS FOLLOWING

THE EARTHQUAKE.

AND THE NEW RAINY SEASON IS

ABOUT TO BEGIN, MAYBE IT BEGAN

ALREADY BUT IT'S ABOUT TO BEGIN

AND EVERYONE IS EXPECTING A

THIRD WAVE OF CHOLERA.

ALL THE LESSONS OF PUBLIC HEALTH

THAT HAVE BEEN FIGURED OUT TO

LOWER THE DEATH RATE OF CHOLERA

TO LESS THAN 15%, WORKED IN

HEIGHTY IN THHAITI IN THE FIRST YEAR.

SOME OF THE INITIALS HITS OF

CHOLERA HAD MORTALITY RATES AS

HIGH AS 25%.

THIS IS STILL A VERY IMPORTANT

PUBLIC HEALTH PROBLEM IN THE

WORLD.

SO WHAT CAUSES CHOLERA.

HOW DOES THIS CHOLERA PRODUCE

DIARRHEA.

LET ME TELL YOU ABOUT THAT.

THE CHOLERA IS REALLY GARYD TO

PRODUCTION OF DIARRHEA.

THERE'S A STAGE THAT HA INFECTED

CHOLERA AND HAS A PAT NO

PATHOJAWNESSITY WHICH ARE THREE

OR FOUR TAWRKSENS.

THERE IS A CHOLERA ANTI-TOXIN ON

THE RIGHT AND SOMETHING

CALLED -- TOXIN.

THERE IS AN ACCESSORY CHOLERA

ANTHRO TOXIN AND A FOURTH ONE

THAT LOOKS LIKE ANN THRO AN ANTHRO TOXIN.

THIS IS TWO PICTURES OF IT.

 YOU CAN SEE THE STRUCTURE HERE

WITH FIVE SUBUNITS SURROUNDING

THE CENTRAL A SUBUNIT.

YOU CAN SEE THE A SUBUNIT LINKED

BY THE BINDING SUBUNITS.

CALL RAW TOXIN GETS TAKEN OH --

CHOLERA TOXIN GETS TAKEN UP --

AND MOST CELLS ARE CAPABLE OF

BEING INFECTED WITH CHOLERA

TOXIN.

THE RECEPTOR IS IN THE MEMBRANE.

IT'S ACTUALLY NOT PROFUSELY

PRESENT IN THE APICAL MEMBRANE.

IT'S PRESENT IN LIPID -- SMALL

COLLECTION OF CHOLESTEROL AND

SINGLE LIPIDS.

IT GETS TAKEN UP INTO THIS GM1

IN THE LIPID -- IT'S NOT

DEPENDENT ON -- IT'S A LIPID

BASED ONE, A SUBGROUP CALLED THE

GEEK PATHWAY WHICH IS A CDC

BASED -- PROCESS.

THE TOXIN IS TAKEN UP INTO THE

EARLY END S SOSOMES.

THERE'S A PATHWAY CALLED THE

RETROGRADE PATHWAY.

YOU MAKE PROTEINS IN THE ER AND

THEN EXPLOIT IT AND MOST

PROCESSES GO THAT WAY.

HOWEVER CHOLERA TOXIN AND --

TOXIN MOVE FROM THE EARLY

ENDOSOMES INTO THE TRANSGOLGI

AND THEN BACK TO THE END PLASM

RETICULUM.

THE ENTIRE TOXIN IS PRESENT AND

IT'S PROVED BY PDI AND THEN THE

SUBUNIT OR THE A SUBUNIT ACTIVE

SUBUNIT GOES OUT THERE A

TRANSPORT PROTEIN REALLY --

WHICH IS A TRANSPORTER GETS INTO

THE CYTOSOL AND ACTIVATES -- IN

THE INTESTINAL CELLS FOUND ON

THE LATERAL MEMBRANE OF THE

ANTHRO CYTES.

WHAT HAPPENS ONCE THE SUBUNITS

IS FLOATING AROUND.

CALL RAW TOXIN A SUBJEUNT

CARRIES OUT AN ND ENZYMATIC

SUBSTANCES -- CHOLERA TOXIN A

ONE SUBUNIT IS AN ENZYME AND

BEEN WORKED ON BY THE PEOPLE AT

NIH.

THEY FIXATE ON PART OF THE ADENO

SIGH CALCULATION AN CASE -- IT HAS AN -- A

BINDING SITE ON THE OUTSIDE ON

THE BASO LATERAL MEMBRANE AND

TWO COMPONENTS ON THE INSIDE.

ONE IS THE CATALYTIC SUBUNIT AND

THEN IT HAS A SERIES OF

NUCLEOTIDE BINDING PROTEINS.

CHOLERA TOXIN DOES IS -- G SUBS

ACTIVATING THAT WAY AND IT'S AN

ENZYMATIC ACTIVATION.

THERE'S PANCREATIC CHOLERA IN

WHICH THERE'S A NON-BETA TUMOR

THAT MAKES BIP AND BECOMES VERY

HIGH IN BLOOD LEVELS, BINDS TO

THE OUT SIDE AND GIVES THE SAME

DIARRHEAL DISEASE.

SAME HUGE VOLUME CAN BE A LEADER

FOR PATIENTS WITH PANCREATIC

CHOLERA.

SO WHEN IT'S ACTIVATED AS IT

DOES IN THIS DISEASE THE INTES

INTESTINAL CELLS -- GIVING YOU

AN ACTIVE CA CATALYTIC SUBUNIT AND

IT PHOSPHORYLATES THE

SUBSTRATES.

FROM THIS DESCRIPTION, YOU WOULD

THINK THAT THE CELLS IN WHICH

CHOLERA TOXIN IS ACTIVATING THE

SIGH CLAVES GO WILD.

THERE ARE MANY PEOPLE HERE

STUDYING AND THEY ARE TURNED ON

OR OFF -- YOU CAN THINK THE CELL

IS MADLY REGULATED.

IN FACT NOT THAT MANY DIFFERENT

PROCESSES OCCUR IN THE

INTESTINAL CELLS.

IN THE INTESTINAL -- CELL, WHAT

HAPPENS WHEN YOU ELEVATE CYCLIC

AMP WITH CHOLERA YOU INHIBITED

THE SODIUM CHLORIDE -- YOU DON'T

INHIBIT THE SODIUM POTASSIUM

ATPASE YOU DON'T ALTER THE

CHEMICAL GRADIENT OR THE

ELECTROGENIC TRANSPORTERS OR THE

SODIUM GLUCOSE TRANSPORTERS.

THESE ARE THE BASIS AND I'LL

TELL YOU ABOUT ORAL REHYDRATION

SOLUTION.

NOWIS THERE A LIMITED ACTIVITY,

LIMITED -- IN THE INTESTINES.

WHY IS IT NOT THAT THE CELL IS

TOTALLY GOING WELL.

ATE TURNS OUT THAT KINASES, THE

LOCATION OF THE KINASE, PKA TYPE

2 IS HELD PREDOMINANTLY IN THE

SODIUM ABSORPTIVE CELLS CLOSE TO

NAT3.

THIS IS A NAT3 EXISTS AS A

COMPLEX IN THE APICAL MEMBRANE

AND IT IS LINKED BY THESE NEVER

PROTEINS -- REGULATORY FAMILY

PROTEINS WHICH ARE MULTIPPD

DOMINION PROTEINS LINKED TO THE

SKELETON ESRIN -- BINDS PKA.

SO IT INCREASES PKA WHICH IS

FOUND VERY CLOSE TO NAG3 AND

THE -- THAT SEEMS TO BE THE

MAJOR THING THAT HAPPENS IN THE

SODIUM ABSORPTIVE CELLS.

A LOT OF OTHER THINGS HAPPEN

THAT ARE NOT NEARLY TO THE

QUANTITATIVE EXTENT OF

INHIBITION OF NAH3.

THIS SHOWS YOU THERE ARE FAMILY

OF PROTEINS MADE UP OF MULTIPD3

PROTEINS.

THE TWO THAT REGULATE NAG3 IS

PART OF THE CYCLIC A AND P

EFFECT ARE THE ONES THAT'S

LINKED TO THE CYTOSKELETON

THROUGH THE ESRIN BINDING

DOMAIN.

WHAT HAPPENS IN THE SECRETITY

CELLS.

THEY HAVE A SERIES OF TRANSPORT

CHANGES.

SODIUM PUMP'S NOT AFFECTED.

YOU OPEN CFTR IN THE APICAL

MEMBRANE.

YOU OPEN AN APICAL MEMBRANE

POTASSIUM CHANNEL FROM THE --

MA1.

YOU OPEN A BASAL LATERAL

POTASSIUM CHANNEL AND YOU MOVE

THE SODIUM POTASSIUM CHLORIDE

TRANSPORTERS SOME OF WHICH ARE

TO THE BASAL LATERAL MEMBRANE

LEADING TO CHLORIDE SECRETION.

IT PREDOMINANTLY OCCURS THROUGH

CFTR BUT WE NOW KNOW PKA HAS TWO

MESSENGERS, PROTEIN KINASE A&E

PACK AND IT TURNS OUT THAT

CYCLIC A AND P, INTESTINAL CELLS

ALSO ACTS THROUGH E PACK, E PACK

ACTIVATES IT AND SO YOU HAVE A

CONTRIBUTION OF CALCIUM

ACTIVATED CHLORIDE CHANNELS AND

CHLORIDE SECRETION AS WELL.

NOW IF SOMEONE ASKS YOU ON A

TEST AS WE DO TO OUR MEDICAL

STUDENTS WHAT IONS ARE ABNORMAL

IN SEVERE CHOLERA.

YOU'RE HEARING ABOUT SODIUM

ABSORPTION BEING DECREASED AND

YOU'RE HEARING ABOUT CHLORIDE

SECRETION BEING INCREASED.

IT MIGHT BE YOU WOULD GUESS

ABNORMAL SODIUM AND CHLORIDE.

BUT THE ANSWER IS POTASSIUM AND

BICARBONATE.

HOW CAN THAT BE.

IT'S THROUGH THE APICAL MEMBRANE

POTASSIUM CHANNELS.

AND CARBONATE LOSS OWE KUR OCCURS THIS

WAY.

WHEN YOU HAVE CHLORIDE SECRETION

THROUGH CFTR THIS EXTRA

CHLORIDE -- SO YOU HAVE

TREMENDOUS BICARBONATE SECRETION

TO AN APICAL MEMBRANE

BICARBONATE EXCHANGE.

IN ADDITION WHEN YOU LOWER

INTRACELLULAR CHLORIDE IT LOOKS

AS IF YOU CHANGE THE

PERMEABILITY IN CFTR.

THERE'S PLENTY OF CHLORIDE

MOSTLY A CHLORIDE PERMEABLE

CHANNEL AND IT BECOMES A

BICARBONATE DEPENDENT CHANNEL.

NOW, THERE'S A SECOND TOXIN THAT

CHOLERA MAKES CALLED -- WHAT

THIS TOXIN DOES IS TO CHANGE THE

PERMANENT ANNUALITY.

AS YOU -- PERMEABILITY.

IT CAN BE JUDGED HOW MANY

STRANDS YOU HAVE OF THE APICAL

MEMBRANE EPITHELIAL CELLS AND

YOU CAN SEE THIS IS NORMAL AND

THIS IS AFTER THE -- SO THE

PERMEABILITY OF THIS CELL IS NOW

VERY MUCH INCREASED.

IF YOU HAVE CHLORIDE SECRETION

OR BICARBONATE SECRETION

CREATING A GRADIENT, THEN WATER

WILL FOLLOW DOWN THAT GRADIENT

AND WILL DRAG WITH IT WHATEVER

IS DISSOLVED IN THE WATER WHICH

IS OTHER ELECTROLYTES.

BY SOLVE AND DRAG, IT

EXAGGERATES THE FLUID

ELECTROLYTE LOSS IN THE

SECRETORY PROCESS.

NOW CHOLERA IS TRULY A MASSIVE

DIARRHEAL DISEASE SO WHAT,

PLAINS SUCH MASSIVE DIARRHEA.

I TALKED TO YOU ABOUT TWO

INTROTOXINS HOWEVER THERE'S MORE

THAN THAT.

50% OF THE VOLUME LOSS OF

DIARRHEA IS NEUTRAL, IS

NEUTRALLY MEDIATED.

HOW CAN THAT BE IN THERE ARE

ENDOCRINE CELLS IN THE GUT THAT

THERE APICAL MEMBRANE FACING THE

LUMEN.

THEY POSSESS GM1 IN THEIR APICAL

MEMBRANE.

IT CAUSES RELEASE OF SEROTONIN.

SEROTONIN THEN EFFECTS THE NERVE

AND TURNS ON THE INTERENTERIC

NERVOUS -- AND ALSO RELEASES

INTESTINAL PROSTAGLANDINS.

HOW DO WE KNOW THIS, THE

BEAUTIFUL WORK -- IN GOTTENBERG

IN THE 1980'S DID THESE KINDS OF

STUDIES IN CATS, IN WHICH HE

MADE A CHOLERA TOXIN MODEL ON A

CAT.

HERE'S THE NORMAL ABSORPTIVE

CHOLERA AND YOU GET INTESTINAL

SECRETION.

AND NOTICE IF YOU GET -- YOU

CAUSE ABOUT A 50% PRE DEDUCTION

IN THE FLUID LOSS.

THIS CONCEPT THAT THROUGHS

NEURAL INVOLVEMENT NOT ONLY FOR

CHOLERA BUT ALSO FOR ROTO VIRUS

FOR INSTANCE.

ALL THE JOY HAVE 50% EFFECT TO

NEURAL ACTIVATION.

SO THAT'S WHY YOU ARE GET SUCH

SEVERE DIARRHEA FROM CHOLERA.

WHAT ABOUT ROTO VIRUS.

I WANT TO TALK TO YOU ABOUT

TRYING TO PREVENT ROTO VIRUS.

IF YOU DON'T GET THE DISEASE IS

BETTER DEALING TO DEAL WITNESS.

50% OF KIDS WHO ARE VACCINATED

ARE STILL GETTING DIARRHEAL

DISEASE.

SO I DON'T KNOW WHAT THE NUMBER

ON THOUSANDS PEOPLE DYING B.P.

IT'S PRETT -- BUTIT'S PRETTY SIGNIFICANT.

YOU INHIBIT THE ABSORPTIVE

PROCESS.

YOU DO SO INHIBITING NHE3 AS

WELL AS SGL1.

THERE'S A BIG EFFECT TO INHIBIT

SODIUM ABSORPTION.

YOU INTERIM STATE THE ENTERIC

NERVOUS SYSTEM.

IT PRODUCES DIARY YEAH BECAUSE

IT MAKES A TOXIN --

INTRACELLULAR TOXIN.

IT'S A COMBINATION OF MUCOSAL

DAMAGE, THE NSP4 INCREASE

INTRACELLULAR CALCIUM TO INHIBIT

NAH3 AND INDUCE SOME SECRETION.

AND THIS STIMULATION OF

SECRETION IS REALLY PRETTY

POORLY DEFINED.

WE DON'T EVEN KNOW WHICH

CHANNELS ARE ACTIVATED AT THIS

TIME.

IN OUR LABORATORY WE JUST

RECENTLY FOUND THAT NH3 IS

INHIBITED.

THIS JUST SHOWS YOU A PICTURE OF

SOMEONE WITH ROTO VIRAL

DIARRHEAL WHICH LOOKS SOMEWHAT

LIKE CELIAC DISEASE BUT IS

PRETTY PATCHY.

ORAL REHYDRATION SOLUTION WORKS

REALLY WELL IN THESE KIDS.

JUST BECAUSE THEY HAVE SOME HIPS

LOGIC DAMAGE DO NOT PREVENT

PEOPLE FROM TREATING THESE WITH

ORAL REHYDRATION SOLUTION.

IN THE LAST PART OF MY TALK I

WOULD LIKE TO TELL YOU THE BASIC

SCIENCE THAT HAS LED TO THE

DEVELOPMENT OVERALL OF

REHYDRATION SOLUTION.

NOW, WHEN IT ASKS FOR US TO PUT

SEVERAL REFERENCES INTO OUR

HANDOUTS.

AND IF THERE'S ONLY ONE THAT

YOU'RE GOING TO READ, THIS WOULD

BE THE ONE THAT I WOULD SUGGEST

THAT YOU READ.

IT'S A HISTORY OF ORAL

REHYDRATION SOLUTION.

THE CONCEPT NOW OF ORAL

REHYDRATION SOLUTION IS

EXCEPTIONALLY SIMPLE.

I'VE ALREADY TOLD IT TO YOU.

THE SEVERE DIARRHEAL DISEASES

LEAVE THE SODIUM SUBSTRATE

MECHANISMS IN TACT.

THE GREAT YENT AN GRADIENT AND THE PUMP US
ED

TO HYDRATE PEOPLE.

THE DIFFICULTY FOR PEOPLE, THE

BASIC SCIENTISTS WHO WERE

UNDERSTANDING AND DISCOVERING

THE SODIUM-LINKED GLUCOSE

TRANSPORT PROCESS.

AND THE CLINICIANS WHO ARE

TRYING TO SAVE PEOPLE'S LIVES BY

HYDRATING THEM BY IV'S OR ORAL

REHYDRATION SOLUTIONS COULDN'T

GET, COULDN'T SPEAK TO EACH

OTHER WELL ENOUGH TO UNDERSTAND

WHAT THE OTHER PERSON'S, OTHER

PEOPLE WERE DOING.

SO TRANSLATIONAL MEDICINE AND I

PRESUME IT'S MOSTLY A PH.D.

CROWD HERE, WE'RE ALL INTERESTED

IN DOING TRANSLATION EITHER FROM

A CLINICAL PERSPECTIVE OR FROM A

BASIC SCIENCE PERSPECTIVE.

FROM READING THIS ARTICLE IT'S

GOING TO SHOW YOU THAT IT'S

REALLY IMPORTANT TO DO IT BUT IT

ISN'T THAT EASY TO GET IT DONE.

AND INTERACTING WITH YOUR

COUNTERPART, IF YOU'RE A

CLINICIAN WITH A BASIC SCIENTIST

OR VICE VERSA REALLY SHOULD BE

AN IMPORTANT PART OF WHAT YOU

TRY TO DO AS YOU MOVE YOUR

TRANSLATIONAL RESEARCH FORWARD.

THIS IS THE ARTICLE THAT I WOULD

READ, IT'S REALLY FASCINATING

READING.

THE CONCEPT OF ORS IS VERY

SIMPLE IN CHOLERA OR YOU HAVE

INHIBITION OF THIS NEUTRAL

SODIUM PROCESS THE PUMP THE RAID

YENT AND THE ELECTROGENICS ARE

PERFECTLY IN TACT.

SO THE CONCEPT IS IF YOU HAVE A

NORMAL PERSON'S PIECE OF BOWEL

AND YOU PROFUSE IT AT A CERTAIN

RATE WITH JUST SALINE THERE'S

ABSORPTION GOING ON.

IF YOU ADD GLUCOSE OR AMINO

ACIDS YOU INCREASED ABSORPTION

BY A CERTAINMENT.

THIS IS A CARTOON WHICH I SAID

PICK THREE MILLS A MINUTE THAT

YOU INCREASE BY ADDING GLUCOSE.

IN CHOLERA YOU START IN A

SECRETORY STATE WHEN YOU'RE JUST

PROFUSING WITH SALINE.

IF YOU ADD GLUCOSE IT'S

PERFECTLY IN TACT.

YOU GOT THE SAME INCREASE OF

THREE MILLS PER MINUTE AND YOU

CAN DECREASE YOUR NET SECRETORY

STATE TO AN ABSORPTIVE STATE.

IN SPITE OF NOT AFFECTING THE

SECRETORY CHANGES OR THE

INHIBITION OF -- YOU CAN STILL

HYDRATE THE PATIENT BY USING THE

IN TACT ABSORPTIVE PROCESSES

THAT ARE NOT AFFECTED IN THESE

DIARRHEAL DISEASES.

THAT IS THE CONCEPT OF ORAL

REHYDRATION.

THE WORLD HEALTH ORGANIZATION

FOR YEARS WAS PUSHING THIS

PARTICULAR SOLUTION THAT WORKED

IN ADULTS AND CHILDREN.

SOLUTIONS THAT HAD 50-90 MILL

MOLAR AND CONVERTED TO

GLUCOSE -- PEPTIDES.

ANY OF THOSE WOULD WORK JUST

FINE.

NOW, THIS BECAME VERY POPULAR

AND YOU COULD WALK INTO A

TYPICAL DRUG STORE AND YOU COULD

BUY -- SOLD RIGHT OFF THE

SHELVES HAVING EXACTLY THE WORLD

HEALTH ORGANIZATION SOLUTION.

NOW IN THE INTRODUCTION HE SAID

WHY DON'T WE JUST DRINK GATORADE

OR FOOTBALL PLAYERS DO BUT WHEN

YOU LOOK AT THE IONS IN GATORADE

YOU NOTICE THE SODIUM IS TOO

LOW, THE POTASSIUM THE TOO LOW

AND IONS IS TOO LOW.

THERE'S A LOT OF SUGAR BUT NOT

ENOUGH OF THE ANY IONS TO MEEK

UP IMPORTANT SEVERE ELECTROLIED

LOSS YOU GET IN BAD DEVELOP.

THIS IS DEVELOPED FOR WHEN YOU

SEE IT ON THE SIDELINES MAKING

UP FOR ELECTROLYTE LOSS IN SWEAT

NOT IN DIARRHEAL DISEASE.

IT'S GOOD IF YOU'RE NOT TOO

SICK, ANYTHING'S GOOD WITH RICE

THROWN IN BUT FOR SEVERE

DIARRHEAL DISEASES YOU NEED

POTASSIUM, SODIUM AND ANIONS TO

COMPENSATE FOR THE LOSS.

MORE RECENTLY THERE HAVE BEEN

THREE ADVANCES IN ORAL

REHYDRATION SOLUTION THAT YOU

NEED TO HEAR ABOUT.

FIRST IN THE EARLY 2000'S IT WAS

RECOGNIZED THAT HYPO OSMOTIC

SOLUTIONS WORKED BETTER.

WHY?

IF YOU HAVE THE LUMINAL

OSMOLARITY IN THE BLOOD YOU NOW

HAVE AN OSMOTIC DRIVING FORCE

ACROSS.

IN THE USE US USE -- AND GLUCOSE ABSORPTIO
N

ARE PASSIVE.

BY LOWERING THE OSMOLARITY YOU

EXAGGERATE THAT EFFECT.

ALL ORAL REHYDRATION SOLUTIONS

SPOIRTD BY THE W.H.O. NOW ARE

HYPO O OSMOTIC.

NOW SPEA ZINC IS AN INTERESTING

STORY.

IF YOU ADD ZINC IT WILL

ACCELERATE THE RAPIDITY OF

REHYDRATION.

THESE WHAT IT SEEMS TO BE.

WHY THAT'S TRUE, NOBODY'S

INVESTED TO FIND OUT.

THE SCIENTISTS NOT BEEN DONE WHY

ZINC HELPS.

IS IT IMMUNOLOGIC OR TRANSPORT.

SANK STIMULATES NHE3 AND BLOCKS

CHLORIDE CRETION BY BLOCKING

POTASSIUM CHANNELS PUBLISHED IN

THE NEW YORK ACADEMY OF

SCIENCES.

IT'S NOT A STUDY DEFINITIVE YET

SO ZINC IS USED AND RECOMMENDED

BY W.H.O., NOT UNDERSTOOD WHY.

SECOND ADVANCE IS TO USE RICE.

RICE IS PRESENT IN ALL THE MAJOR

COUNTRIES.

IT NEEDS ORAL REHYDRATION

SOLUTION IN DEVELOPING COUNTRIES

AND IT PROVIDES -- GETS BROKEN

DOWN TO GLUCOSE AND PROTEIN GETS

BROKEN DOWN TO PEPTIDES.

THAT'S AN ADVANCED COMPARED TO

MORE STANDARD ORS.

NOW I THINK A VERY BIG BREAK

THROUGH IS THE CONCEPT OF

RESISTANCE STARCH.

THIS IS ANOTHER AREA THAT THE

GATES ARE SUPPORTING AND FIGURED

OUT BY HENRY FENDER.

THE CONCEPT IS THE CONVENTIONAL

ORS WORKS BY STIMULATION OF

SODIUM, GLUE COAST OR AMINO AWE

KIDS.

REMEMBER THE SODIUM AMINO AWE

KIDS ARE ONLY JEJUNUMMAL AND NOT

IN THE COLON AT ALL.

SO ORS IS LARGELY A JEJUNUMMAL

WORKING MECHANISM.

RESISTANCRESISTANCE STARCH CAN ADD

COLONIC SODIUM ABSORPTION TO

CONVENTIONAL ORS.

THE IDEA IS YOU TAKE THE STARCH

AND IT'S NOT BROKEN DOWN BECAUSE

IT'S RESISTENT -- IT ENTERS THE

COLON WHERE IT'S BROKEN DOWN BY

BACTERIA TO SHORT CHANGE FATTY

ACIDS STIMULATE COLONIC NEUTRAL

SODIUM ABSORPTION ADDING COLONIC

ABSORPTION TO EFFECTS OF

CONVENTIONAL ORS.

IT'S ADDING COLONIC ABSORPTION

WHICH IS ANOTHER UP TO FIVE

LITERS PER DAY.

AND YOU WILL REMEMBER THIS

NEUTRAL SODIUM ABSORPTIVE

PROCESS IS HG2 OR 36789 LINKED

TO CHLORIDE BICARBONATE, CHANGE.

IN THE LONE YOU HAVE THIS

ADDITIONAL ONE.

NHE2 OR 36789 WITH FATTY ACID

HYDROXYL EXCHANGE.

THIS SEVERE CALL RON YOU WILL

INHIBIT NHE3 IN THE GUT

INCLUDING THE COLON BUT YOU

DON'T INHIBIT 2 SO YOU HAVE A --

THERE'S DIS THIS WORK, RIGHT,

IT'S A NICE IDEA.

HERE'S A STUDY THAT WAS

PUBLISHED IN 2008 ACROSS ONE OF

THE IN WHICH CONVENTIONAL HYPO

OSMOTIC CAUSED PATIENTS WITH

CHOLERA AND SEVERE DIARRHEA TO

RESOLVE THEIR DIARRHEA BY 60

HOURS AND THE RESOLUTION OF ALL

OF THEM OCCURRED BY 35 HOURS

WHEN THEY ADDED THE RESISTANCE

STARCH.

THIS IS THE SECOND MAIN STUDY

WHICH SHOWED THAT YOU COULD

SHORTEN DIARRHEA AND DECREASE

THE OVERALL VOLUME OF DIARRHEA

BY USING THIS RESISTANCE STARCH.

NOW, THE LAST POINT I WOULD LIKE

TO TALK ABOUT IS DRUG THERAPY.

NOW, IF YOU HAVE ORS, YOU NEED

DRUG THERAPY.

TREMENDOUS DECREASE IN MORTALITY

OF DIARRHEA THAT HAS OCCURRED

OVER THE LAST 20 YEARS HAS

CORRELATED WITH THE USE OF ORS

WITH 12 MILLION PEOPLE KIDS

DYING OF DIARRHEA IN DEVELOPING

COUNTRIES ARE DOWN TO 1.2

MILLION.

IT'S STILL UNCONSCIONABLE THAT

THERE ARE SO MANY CHILDREN DYING

BUT IT'S 10% OF WHAT IT USED TO

BE.

AND THIS CORRELATES DIRECTLY

WITH USE OF ORS.

SO PEOPLE COULD TELL YOU SUCH AS

PEOPLE WITH THE WORLD HEALTH

ORGANIZATION THE ONLY NEED WE

NEED IS TO GET ORS USED IN LARGE

NUMBERS.

IT PACKS AROUND 65% IN

DEVELOPING COUNTRIES FOR

DIARRHEA.

AND IS NOW FALLEN TO ABOUT 32%

OF CASES WITH SEVERE DIARRHEA.

THERE ARE MULTIPLE REASONS,

ROGER CAN PROBABLY GO INTO THEM

A LOT BETTER THAN I CAN BUT

THINGS LIKE THERE WAS BIG

PUBLICITY ADVERTISING CAMPAIGN

WITH MARKETEDLY INCREASED USE.

PEOPLE REQUIRE MORE JOB, PEOPLE

WORKOUT SIDE THE HOMES A LOT

MORE.

PEOPLE DON'T HAVE THIS 36 HOURS

OR 48 HOURS TO SIT THERE WITH

OUR KIDS FORCING THEM TO DRINK

THE ORS.

THERE ARE LOTS OF REASONS BUT

THE BOTTOM LINE IS ORS COULD

SAVE ALL THE LIVES IF EVERYBODY

TOOK IT BUT I DON'T THINK IT'S

GOING TO HAPPEN.

IT SEEMS TO ME THESE DEVELOPING

COUNTRY MODERNIZES THERE'S

PROBABLY GOING TO BE EVEN LESS

TIME TO USE ORS.

SO DRUG THERAPY HAS A ROLE.

CURRENTLY THERE ARE NO EFFECTIVE

AND SAFE DRUGS THAT HAVE REALLY

BEEN IDENTIFIED.

BUT WE UNDERSTAND THE DRUG

TARGETS VERY WELL.

WE KNOW THAT BY STIMULATING NHE3

OR DOWN REGULATED ADENOMA OR E

NAC OR BLOCKED -- OR

ACTIVATED -- CHANNELS WE CAN

PROBABLY MIKE A BIG DIFFERENCE.

IT SEEMS TO ME THAT THIS IS AN

AREA THAT NEEDS SOME INVESTMENT.

AND LUCKILY, BOTH THE HEAD OF

THE NIH AND THE NCI HAVE COME

OUT STRONGLY SAYING THEY THINK

IT'S PRETTY SAD THAT WE'RE

SPENDING A LOT OF MONEY ON TB,

MA LAWYER YEAH AND HIV AND NOT

SUFFICIENT MONEY ON PULMONARY

DEATHS AND WHEN DIARRHEAL DEATHS

IN DOLING COUNTRIES.

IT LOOKS AS IF TIME IS RIGHT TO

TRY TO DEVELOP DRUGS FOR

TREATING DIARRHEA.

WE UNDERSTAND THE PHYSIOLOGY AND

WE JUST NOW HAVE TO DO IT.

I'LL STOP AT THIS POINTED AND IF

THERE ARE ANY QUESTIONS I WILL

BE GLAD TO ANSWER THEM.

THANK YOU.

[APPLAUSE]

>> DO WE HAVE SOME QUESTION OR

COMMENTS ON THIS ELEGANT

PRESENTATION OF ELECTROLYTE

BALANCE AND INTESTINE.

SO WHY DOES JUST, WHAT HAPPENS

TO THE CHOLERA?

I MEAN WHY DO PEOPLE GET BETTER

IF YOU JUST HIGH DRAIFT THE HYDRATE THEM I
F

THEY'VE BEEN INFECTED AND MAKING

THIS TOXIN.

>> IN SOME WAYS INTESTINAL CELLS

IN MAN TURN OVER EVERY 72 HOURS

SO TYPICALLY WHAT HAPPENS IS THE

DISEASE IS THREE DAYS AND WHEN

THE CELLS TURN OVER AND THE CALL

RAW IS NO LONGER BOUND TO THE

SURFACE THEN YOU GET BETTER.

>> SO WHY DOESN'T THAT HAPPEN

WHEN YOU HAVE ROTO VIRUS OR CDIF

OR SOME OTHER THINGS?

>> ROTO VIRUS PROBABLY DOES, YOU

SAW THE DAMAGE THAT'S OCCURRED.

SO TO GENERATED THE CELLS AGAIN,

TO OVERCOME THE DAMAGE IS NOT AS

QUICK AS JUST NORMAL TURNOVERS.

SO THAT'S PART ONE.

A LOT OF PEOPLE WHO GET ROTO

VIRUS CONTINUE WITH DIARRHEA BUT

IT'S LACTASE DEFICIENCY DIARRHEA

SO THAT CAN GO ON FOR SIX WEEKS.

YOU GET A HISTOLOGIC CHANGE.

SEE THE CELLS ARE A DIFFERENT

STORY UNFORTUNATELY.

WITH A DON'T HAVE ANY WAYS OF

STOPPING THAT VERY WELL SO WE

DON'T EVEN UNDERSTAND THE

PATHOPHYSIOLOGY OF THAT VERY

WELL.

THERE ARE STILL BATTLES OVER THE

B TOXIN OR A TALKSEN IS THE

IMPORTANT ONE SO WE NEED MANY

MORE STUDIES OF THAT.

>> I THINK THE OBSERVATION IS IF

YOU'RE ELDERLY AND GO INTO A

NURSING HOME OR A HOSPITAL, YOU

MAY ABOUT A ASKING FOR MORE

TROUBLE.

IN FACT AFTERNOON YOU ARE THAN

WHAT ACTUALLY HAPPENED.

>> EPIDEMIOLOGY IS SO IMPORTANT.

THIS IS AN AREA THAT SEEMS TO

HAVE BEEN IGNORED AFTER THIS

INITIAL STUDY AND IT'S TRUE THAT

A VERY LARGE NUMBER OF PEOPLE

ELDERLY ARE DYING FROM DIARRHEA

THEN THE COUNTRY WOULD THEN HAVE

TO FACE IT AND DECIDE HOW

IMPORTANT WAS IT TO DEAL WITH

BUT THEY NEED TO UNDERSTAND IT

BEFORE THEY DECIDE WHETHER

THEY'RE GOING TO DEAL WITH IT OR

NOT.

IT SEEMS TO ME IT'S VERY

SURPRISING THAT STUDY HADN'T

BEEN FOLLOWED UP.

>>

>> IN THE UNITED STATES THERE

ARE SEVERAL THOUSAND ADULTS WHO

DIE OF DIARRHEA.

I TALKED ABOUT ROTO VIRUS OF

YOUNG CHILDREN UNDER FIVE BUT

THERE ARE SEVERAL THOUSANDS

BETWEEN FIVE AND 10 FOR THEM A

DRUG WOULD BE INCREDIBLY

IMPORTANT AS A TRAPMENT.

SO MY QUESTION -- AS A

TREATMENT.

SO MY QUESTION FOR YOU IS WHEN

YOU TRAVEL AND GET DIARRHEA,

WHAT DO YOU DO?

VERY PRACTICAL QUESTION.

>> I DEFINITELY CARRY IMMODE

ANNUAL WITH ME AND -- AN AMOUNT

BODY THAT SHORTENS THE ACUTE

DIARRHEAL DISEASE AND SOMETHING

THAT STOPS IT FOR MILD DIARRHEA.

LUCKILY I HAVE NOT HAD SEVERE

CHOLERA DIARRHEA YET.

ACTUALLY FOR TRAVEL, NU NONE OF US

WANT TO V THE RULE IS YOU TELL

YOUR PATIENTS IF YOU FEEL YOUR

TRAVEL IS SO IMPORTANT YOU CAN'T

HAVE DIE RAY AWE THEN YOU CAN DO

THIS.

WE DON'T WANT MASSIVE USE OF

ANTIBODY TO DEVELOP RESISTANCE.

IF YOU SPEND THE MONEY TO

TRAVEL, TRAVEL IS CRITICAL.

NOBODY -- SOME PEOPLE DO WHAT I

DO.

>> ROGER, YOUAR YOU TRAVEL A BIT.

WHAT DO YOU DO.

>> NEVER GET DIARRHEA.

I'M IMMUNE.

I THINK IMMOD IMODIUM.

I HEARD IT WASN'T GOOD FOR YOU.

IT COULD MAKE THE DIARRHEA

WORSE.

IN FACT.

THERE'S SO MUCH OF THE WATERY

DIARRHEA IT'S SUPPOSED TO HAVE

NOT ABSORBIVE COMPONENT AS WELL

AS AN EFFECT ON THE INTARYK ENTERIC SYSTEM
.

>> IN DEVELOPING COUNTRIES THE

WAYS THE MOTHERS USED IT THEY

BASICALLY GAVE IT, WHEN IT

CONTINUED THEY GAVE MORE AND

MORE.

THERE'S A SIGNIFICANT MORTALITY

FROM IMODIUM.

WHATEVER DRUG WE DEVELOP IT'S

GOT TO BE REALLY SAFE BECAUSE

IT'S NOT GOING TO BE USED THE

WAY IT'S SUPPOSED TO BE USED.

IT'S GOING TO BE POURED INTO

PEOPLE.

>> WITH THE PHYSIOLOGIC

MECHANISMS WORKED OUT SO WELL

FOR CHOLERA FOR EXAMPLE.

IT'S BEEN DIFFICULT TO DEVELOP

VACCINE IT'S BEEN AROUND FOR A

LONG TIME.

THEY HAVE INACTIVATED VACCINES,

ALL KINDS OF APPROACHES.

BUT STILL YOU GO TO CHOLERA

COUNTRIES AND YOU DON'T TAKE A

VACCINE OR DO YOU OR WHAT'S THE

PROBLEM, WHAT'S THE IMMUNITY

ISSUES WITH K5U8 RA CHOLERA THAT'S SO

UNIQUE.

>> YOU CAN CORRECT ME BUT THERE

IS A VACCINE AND IT'S CURRENTLY

BEING USED IN HAITI FINALLY AND

THE RATIONALE FOR NOT GIVING IT

TO US, TRAVELING IS BECAUSE MOST

PEOPLE BY BEING CAREFUL EVEN IF

YOU'RE GOING TO DEVELOPED

COUNTRY YOU'RE NOT GOING TO GET

CHOLERA YOU BOIL YOUR WATER WE

KNOW HOW TO WATCH OUT FOR IT.

WE KNOW THEOF THE -- HAITI IT TALKS

ABOUT HOW PUBLIC HEALTH DIDN'T

WORK THERE.

MAYBE NOW THEY'RE STARTING TO

USE IT THREE YEARS INTO THE

EPIDEMIC.

ROGER, DO YOU WANT TO COMMENT ON

IT.

>> I THINK THE VACCINE WORKS,

THE VACCINE NOW KILLED WHOLE

CELL VACCINE WORKS VERY WELL.

THE TWO COMPANIES THAT MAKE IT,

IT'S QUITE CHEAP.

AND SO THE SUPPLY IS LIMITED.

SO IT'S JUST BEING STARTED IN

HAITI BUT THERE'S NOT AN

ADEQUATE SUPPLY TO IMMUNIZE THE

HAITIAN POPULATION WHICH IS

SMALL.

>> I'VE GOT A QUESTION ABOUT

LIKE SAY YOU'RE IN A VILLAGE IN

END YEAH ANINDIA AND THEY HAVE CHOLERA SO

THEY HYDRATE THEIR PATIENT WITH

WATER.

IF YOU WERE A NORMAL PERSON

LIVING TODAY AND DID NOT HAVE

CHOLERA AND YOU DRANK AS MUCH

WATER TO REPLACE LOSING A LITER

PER HOUR YOU WOULD VERY QUICKLY

DEVELOP ELECTROLYTE IMBALANCE

AND YOU WOULD DIE FROM THAT AS

SOME COLLEGE KIDS DID RECENTLY

ABOUT A YEAR AND-A-HALF AGO.

HOW DOES IT WORK FOR THOSE

PEOPLE.

DO THEY REALLY DIE OF THE DE

HYDRATION OR --

>> THEY DON'T DRINK WATER.

THEY'RE NOT GOING TO DRINK

WATER.

THE MOTHERS, THERE'S THAT

COMMUNICATION NETWORK.

SO THE NUTS ALL KNOW WELL MOST

OF THEM KNOW THAT WHAT YOU DO IS

YOU ARE SUPPOSED TO HAVE AN

ELECTROLYTE SOLUTION AND THEY

ARE AVAILABLE IN LITTLE STORES

ON THE STREETS.

THERE ARE OPEN SHOPS AND LOOKS

LIKE LITTLE SECTIONS.

>> THEY HAVE IT AVAILABLE TO

THEM.

>> IT'S VERY CHEAPER TO GET

HYDRATION SOLUTION.

>> WHY DO PEOPLE DIE FROM IT.

IT'S NOT THAT HARD TO DRINK A

SOLUTION.

>> IT'S THE ONES THAT DON'T PAY

ATTENTION TO IT.

>> THEY HAVE SOME KIND OF

GOVERNMENTAL ENFORCEMENT OF LIKE

THE POLICE THAT WILL GIVE YOU A

TICKET IF YOU'RE SPEEDING YOU

HAVE TO GO CHECK ON THESE

PEOPLE.

THAT DOESN'T SEEM TO BE TOO

DIFFICULT.

>> YOU THINK IT WOULD BE

STRAIGHTFORWARD BUT IF YOU VISIT

INDIA, YOU'LL SEE THERE'S A LOT

OF PEOPLE THAT JUST DON'T LOOK

LIKE THEY'RE PART OF WHAT YOU

CONSIDER KIND OF MODERN

EXISTENCE.

>> OKAY, THANK YOU.

>> I HATE TO CHANGE THE FOCUS OF

AN EXCELLENT TALK ABOUT

ELECTROLYTES AND DIARRHEA.

BUT DO EITHER OF YOU HAVE ANY

COMMENTS ABOUT THE USE OF

PROBIOTICS AND DIARRHEA?

>>

>> I'VE GOT A FEW COMMENTS ABOUT

IT.

SO IF YOU GO TO A HEALTH FOOD

STORE AND BUY A PROBIOTIC TODAY

AND GO TOMORROW, YOU MAY NOT

FIND THAT THE SAME PRODUCT HAS

THE SAME BACTERIA IN THE SAME

CONCENTRATION.

CONSEQUENTLY, THE STUDIES THAT

HAVE BEEN DONE HAVE BEEN VERY

CONTROLLED.

YOU BUY THIS BACTERIA.

AND I LOORKZ AS IF AN ACUTE

DIARRHEA PROBIOTICS PROBABLY DO

SEEM TO SHORTEN THE DURATION OF

ACUTE DIARRHEA.

THERE ARE A LOT OF OTHER

DISEASES.

WE'RE TRYING IT, WITH A DON'T

REALLY NOW.

IS IT GOOD FOR INFLAMMATORY

BOWEL DISEASE NOT SO CERTAIN.

WHEN IT'S GOING TO BE USED BY

THE PUBLIC WHAT YOU'RE TALKING

ABOUT BECAUSE YOU CAN BUY THESE

THINGS ACROSS IN ANY HEALTH FOOD

STORE.

I DON'T KNOW HOW IT'S GOING TO

WORK BECAUSE I DON'T KNOW IF THE

PRODUCTS ARE CAREFULLY

CONTROLLED.

THE GOVERNMENT'S BEEN VERY

CAREFUL AND NOT CONTROLLING

THESE PRODUCTS.

AND CONSEQUENTLY I DON'T KNOW IF

THEY'RE GOING TO BE, HOW

EFFECTIVE IT WILL BE.

FOR ACUTE DIARRHEA IT LOOKS

PRETTY GOOD SO FAR.

>> A LOT OF THE INTEREST IN THE

HUMAN MICRO BIOME WHICH ARE THE

NORMAL FLORA AW FLORA THAT ARE

LOST, RECONNIZING THE GUT WITH A

PROBIOTIC.

I WOULD SAY THAT THERE ARE LOTS

OF OPPORTUNITIES FOR PRO

BIOTICS, THE CLINICAL TRIALS FOR

ROUTINE USE IN DIARRHEA HAVE YET

TO BE DONE AND WE DON'T REALLY

UNDERSTAND ENOUGH ABOUT THE

MICRO BIOME TO KNOW ABOUT HOW TO

REPLACE RIGHT NOW.

>> I HAVE A RELATED QUESTION.

YOU POINTED OUT THAT THE --

ABSORPTION IN THE COLON REALLY

RESPHOARRESTORED COLONIC PROCESS

FOLLOWING DIARRHEA.

THOSE ARE MADE BY BACTERIA.

BY THE TIME WE GET TO THOSE

PATIENTS, THEIR NORMAL BACTERIAL

FLORA IS GONE BECAUSE THEY HAVE

DIARRHEA SO IS THERE A PRODUCT

IN THE MARKET THAT WOULD BE

DEVELOPED.

>> THAT WAS THE INITIAL CONCERN,

RIGHT, THIS WHOLE CONCEPT OF THE

RESISTENT STARCH IS PREDICATED

ON THE FACT THERE ARE ENOUGH

AROUND YOIPPED DESPITE OF THE

SEVERE DIE ARE REA AWE THERE ARE

SHORT CHAIN FATTY AWE KIDS

PRODUCED THERE.

THOSE NUMBERS ARE SUFFICIENT TO

DRIVE THIS SYSTEM.

EVEN THOUGH YOU THINK YOU'RE

WASHING THINGS OUT THOSE BUGS

ARE PRETTY CLEVER ABOUT STAYING

AROUND.

>> LISTEN, THANK YOU.

[APPLAUSE]

>> FOR THOSE WHO ARE NOT

INTIMATELY FAMILIAR WITH ION

TRANSPORT IN THE INTESTINE, AWE

OF THE POWER -- ALL OF THE POWER

POINTS MARK SHOWED ON THE

WEBSITE SO YOU CAN REFRESH YOUR

MEMORY AND STUDY A BIT MORE

CAREFULLY.

SO NEXT WEEK IS AUTISM SO WE'LL