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Welcome to the Clinical
Center Grand Rounds,

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a weekly series of educational
lectures for physicians and

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health care professionals
broadcast from the Clinical

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Center at the National
Institutes of Health in

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Bethesda, MD.

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The NIH Clinical Center is the
world's largest hospital totally

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dedicated to investigational
research and leads the global

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effort in training today's
investigators and discovering

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tomorrow's cures.

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Learn more by visiting us online
at http://clinicalcenter.nih.gov

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>>TODAY'S PRESENTATION WHICH 

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IS WHEN HALF IS NOT ENOUGH, STAT

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3 HAPLOINSUFFICIENCY AND FUNGAL

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INFECTION OF THE BRAIN.

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 JOIN ME IN WELCOMING

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TODAY'S PRECEPTORS WHO INCLUDE

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DR. STEVEN HOLLAND, CHIEF OF THE

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IMMUNO PATHOGENESIS SECTION AT

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THE NATIONAL INTUITYS OF ALLERGY

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AND INFECTIOUS DISEASES.

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DR. MICHAIL LIONAKIS, AT THE

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FUNGAL SECTION OF THE NIAID.

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AND DR. AMY HSU, WHO IS A

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BIOLOGIST IN THE IMMUNO

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PATHOGENESIS SECTION OF NIAID

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AND DR. DAVID KLEINER WHO IS

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HEAD OF THE AUTOPSIES SECTION IN

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THE LABORATORY PATHOLOGY CENTER

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FOR CANCER RESEARCH HERE AT THE

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NIH. 

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DR. HOLLAND?

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>>WE'RE GOING TO TALK ABOUT

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HAPLOINSUFFICIENCY AND WE WILL

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GO THROUGH A LITTLE BIT WHAT

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THAT MEANS THROUGHOUT THE COURSE

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OF THE DAY.

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BUT WE'RE TALKING ABOUT

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COCCIDIOMYCOSIS, IT'S AN IRPT

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ACTION AND IT'S TOXIC.

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SO WE'RE TALKING ABOUT A 19

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YEARLY FROM CALIFORNIA WHO

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DEVELOPED COCCIDIOMYCOSIS DURING

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PREGNANCY AND AT THAT POINT

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SHE HAD RESPIRATORY FAILURE,

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RECOVERED AND WAS TREATED WITH

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FLUCONOSALL, AND DELIVERED A

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HEALTHY BABY BOY, A YEAR LATER

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SHE REQUIRED FURTHER TREATMENT

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DUE TO OBSTRUCTION.

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SEVERAL YEARS LATER SHE

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DEVELOPED PROGRESSIVE AND

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DEBILITATING BRAIN AND LUNG

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DISEASE DESPITE TREATMENT WITH

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POSACONAZOLE AND AMPH OTERICIH,

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AND THEN LEDDER WAS LED TO A

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LOBECTOMY.

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SHE WAS HOSPITALIZED AGAIN FROM

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THE SHUNT OBSTRUCTION AND WHEN

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THE SHUNT WAS REMOVED AND

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EXTERNALIZED SHE HAD A FATAL

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INTERCEREBRAL BLEED.

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HER SON WAS UNAVENGHTED IN TERMS

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OF SUSCEPTIBILITY TO

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COCCIDIOMYCOSIS, AT LEAST SO FAR

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AS WE KNEWA THAT POINT.

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AFTER HER DEATH HER MOTHER MADE

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A BOLD AND IMPORTANT AND I THINK

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BRAVE DECISION TO CHOOSE THAT

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HER DAUGHTER'S DEATH NOT BE IN

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VAIN:  AND SHE REACHED OUT TO

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CENTERS IN THE REGION.

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SHE WAS IN CALIFORNIA WHO THEN

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REACHED OUT TO US ASKING IF WE

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COULD DO AN AUTOPSIES IN ORDER

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TO FIGURE OUT WHAT WAS THE

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PROBLEM.

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SO I'M GOING TO STET THE STAGE

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HERE BRIEFLY, I WILL COVER THE

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TOPICS, WHAT IS COCCIDIOMYCOSIS,

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HOW IS IT CONTRACTED, WHERE IS

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IT ENCOUNTERED, HOW DOES IT

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PRESENT CLINICALLY AND WHAT IS

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THE EPIDEMIOLOGY, THE CLINICAL

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EPIDEMIOLOGY OF THIS DISEASE?

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AND THEN WE WILL MOVE TO THE

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ACTION IN WHICH WE WILL PRESENT

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THE AUTOPSIES, THE GENETICS OF

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HER SUSCEPTIBILITY AND THEN WE

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WILL TALK ABOUT FUNGAL

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SUSCEPTIBILITY IN GENERAL.

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SO COCCIDIOMYCOSIS IS CAUSED BY

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THIS ORGANISM CALLED

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COCCIDIDOSIS AND FOR OUR

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PURPOSES WE WILL CONSIDER THEM 1

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AND THE SAME.

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THERE ARE SUBTLE DIFFERENCES

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THAT ARE NOT CLINICALLY

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IMPORTANT NOW.

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IT EXISTED INITIALLY IN THE

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ENVIRONMENT WHERE IT DESICCATES

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AND WHEN IT DESICCATES IT

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DISASSOCIATES INTO THESE SMALL

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THINGS CALLED ARGT ROW

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CANEDUCATIONALLIA AND IN THE

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SETTINGS OF CONSTRUCTION OR WIND

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OR HOUSE BUILDING OR AND SO ON.

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THESE GET INHALED BY HUMANS AND

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MANY OTHER MAMMALS WHERE THEY

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DEVELOP THEN INTO THESE SMALL

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GROWING ORGANISMS CALLED

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SPHEREIOLES THAT RUPTURE INSIDE

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THE BODY AND RELEASE THESE

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THINGS CALLED ENDOSPORES HERE

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THAT CONTINUE TO CYCLE ALONG.

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THIS IS WHAT THEY LOOK LIKE IN

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THE TISSUE.

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THIS IS A SPHEREIOLE THAT YOU

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SEE HERE CHOK FULL OF ENDOSPORES

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AND THIS IS THE SPHEREIOLE

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RUPTURING.

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NOW THIS WAS IDENTIFIED EARLY

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ON, IN THE 1880S BY THIS MAN,

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ALEJANDRO POSADES, AND HE

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IDENTIFIED THIS ORGANISM IN

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CHICKENS, AND THEN IDENTIFIED

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THEM IN HUMANS.

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AND CAME UP AND EVENTUALLY IT

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WAS NAMED COCCIDOIDES, POSADA

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SII, IN HIS HONOR AND YOU'LL

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NOTICE HE ALSO INVENTED THE

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MUSTACHE.

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[LAUGHTER]

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THIS IS MUCH MORE COMMON HERE IN

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THE SOUTHWESTERN UNITED STATES

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THROUGHOUT THE SAN JUAQUIN AND

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RIO GRAND VALLEYS AND IS

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EXTENDING INTO THE UPPER

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NORTHWEST FOR A VARIETY OF

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DEFINITE REASONS I SUSPECT.

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NOW THE EPIDEMIOLOGY OF THIS

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ORGANISM IS IMPORTANT TO

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UNDERSTAND.

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THERE ARE THOUGHT TO BE 150,000

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PEOPLE INFECTED EACH YEAR WITH

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THIS ORGANISM IN THE

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SOUTHWESTERN PART OF THE UNITED

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STATES.

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SO ARIZONA, NEW MEXICO, WEST

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TEXAS, LAS VEGAS, CALIFORNIA,

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ONLY A THIRD OF THOSE PEOPLE

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EVER COME TO MEDICAL ATTENTION,

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AND ONLY A THIRD OF THOSE GET

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DIAGNOSED SO LARGE BURDEN, SMALL

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RECOGNITION, OUT OF THOSE 15,000

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WHO GET DIAGNOSED, SOMEWHERE

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AROUND HALF HAVE WHAT IS CALLED

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A PULMONARY SYNDROME

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CHARACTERIZED AS VALLEY FEVER,

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THAT IS COUGH MALAISE, FEVER,

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AND THEN A SMALL NUMBER GO ON TO

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DEVELOP WHAT WE CALL

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DISSEMINATED COCCIDIOMYCOSIS OR

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DCM.

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AND ALTHOUGH THE RISK GROUP IS

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LARGE, THE MORTALITY ON A TOTAL

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BASIS IS RELATIVELY SMALL.

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BUT IT IS OF COURSE MORE THAN WE

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WOULD LIKE TO SEE.

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OUR EXPERIENCE WITH THIS

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ORGANIZATIONS INFORM AND IT'S

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PROBLEMS STARTED WITH THIS YOUNG

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MAN HERE SEEN AT THE NIH IN A

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REFERRAL FROM JOHN GALGIANI AT

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THE UNIVERSITY OF ARIZONA AND

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THIS WAS A BOY WHO AT 16 HAD

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BEEN A FOOTBALL PLAYER UNTIL HE

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DEVELOPED DISEASE IN HIS SPINE

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FOR WHICH HE REQUIRED

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INSTRUMENTATION, AND THEN YOU

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CAN SEE HERE, EXTENSIVE DISEASE

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IN HIS PELVIS, THESE ARE NOT

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NATURAL BREAKS.

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SO HE CAME TO US WITH

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DISSEMINATED DISSEMINATED

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COCCIDIOMYCOSIS AS WELL AS A

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DISSEMINATED MICROBACTERIAL

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INFECTION AND THAL CASE,

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MICROBACTERIAL M. KANSASII, AND

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HE HAD A DISRUPTION IN THE INTER

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FERON GAMMA RECEPTOR ANDEE HAD

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ABOUT WORKING ON THAT FOR

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SOMETIME.  AND BECAUSE OF WHAT

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WE KNEW ABOUT THAT AND THIS

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PROCESS WE TREATED HIM WITH

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INTERFERON-GAMMA YOU CAN SEE

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THIS WAS BEFORE AND AFTER

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INTERFERON IN ADDITION TO

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ANTIFUNGAL DRUGS.

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THE APPROXIMATE BEFORE PICTURE

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IS WHEN HE WAS ON ANTIFUNGAL

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DRUGS ALONE AND THE AFTER WHEN

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HE WAS ON THE PLUS INTERFERON.

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THAT GOT US INTERESTED IN WHAT

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WERE THE OTHER FACTORS THAT

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MIGHT BE ASSOCIATED WITH

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DISSEMINATED COCCIDIOMYCOSIS AND

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IN A REVIEW OF DISCHARGE RECORDS

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FROM ARIZONA AND SOUTHERN

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CALIFORNIA IN ENDEMIC REGIONS,

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WE IDENTIFIED THAT 1 OF THE

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CRITICAL RISK FACTORS WAS RACE

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AND ETHNICITY AND WHAT YOU SEE

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HERE IS THAT THE RATES OF

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DEVELOPING DISSEMINATED

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COCCIDIOMYCOSIS BASED ON

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HOSPITAL DISCHARGE WERE ALMOST

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10 FOLD HIGHER IN THOSE

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SELF-IDENTIFIED AS BEING OF

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AFRICAN--OF HAVING AN ETHNICITY

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OF AFRICAN ORIGIN AS OPPOSE TO

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ANY OTHER ETHNICITY.

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IN ADDITION, IT'S BEEN WELL

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KNOWN IN THE SOUTHWEST THAT

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PEOPLE WHO ARE RECEIVING TUMOR

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NECROSIS BLOCKERS, ARE AT MUCH

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HIGHER RISK OF DEVELOPING

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DISSEMINATED AND PULMONARY

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COCCIDIOMYCOSIS OVER THE GENERAL

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POPULATION.

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AND THIS TELLS US THAT THAT LIMB

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OF IMMUNITY, SO WE'VE SEEN THAT

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ISHT FERON GAMMA IS IMPORTANT

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NOW TNF IS EXPRNT WE KNOW THERE

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ARE OTHER LIMBS INNATE AND

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ADAPTIVE IMMUNITY THAT ARE

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IMPORTANT.

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SO AS WE LOOK FURTHER INTO THESE

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ISSUES WE SAW THAT THERE WERE

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OTHER RISK GROUPS WE NEEDED TO

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CAPTURE.

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ONE OF THE MOST IMPORTANT AS

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SEEN IN OUR PATIENT TODAY WAS

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PREGNANCY.

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AND YOU CAN SEE HERE THAT A

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LARGE NUMBER OF PEOPLE ARE

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RELATIVELY LARGE NUMBER OF

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PEOPLE DEVELOP DISSEMINATED

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DISEASE IN THE SETTING OF

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PREGNANCY AND SURVIVAL WAS ONLY

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42%.

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THIS REMINDS US THAT PREGNANCY

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IS AN INTRINSICALLY SOMEWHAT

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IMMUNOSUPPRESSIVE CONDITION THAT

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CONFERS CERTAIN RISK TO CERTAIN

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INFECTIONS, SO WITH WE PUT ALL

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THAT TOGETHER, NOW SEVERAL YEARS

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AGO, WE COULD ONLY FIND 8 CASES

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OF GENETIC ABNORMALITIES

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00:10:27,800 --> 00:10:29,640
ASSOCIATED WITH THE DISSEMINATED

260
00:10:29,640 --> 00:10:31,960
COCCIDIOMYCOSIS SHOWN HERE, THE

261
00:10:31,960 --> 00:10:34,200
AUTOSOMAL DOMINANT MUTATIONS IN

262
00:10:34,200 --> 00:10:35,080
INTERFERON-GAMMA, RECESSIVE

263
00:10:35,080 --> 00:10:37,080
MUTATIONS IN THE IL12 RECEPTOR

264
00:10:37,080 --> 00:10:39,040
AND SOME GAIN OF FUNCTION

265
00:10:39,040 --> 00:10:40,720
MUTATIONS IN STAT 1.

266
00:10:40,720 --> 00:10:43,920
DESPITE THE FACT THAT THERE WERE

267
00:10:43,920 --> 00:10:46,200
150,000 CASES EACH YEAR.

268
00:10:46,200 --> 00:10:51,760
SO STOP AND THINK, WE HAVE

269
00:10:51,760 --> 00:10:53,640
150,000 INFECTIONS PER YEAR,

270
00:10:53,640 --> 00:10:54,640
ONLY 15,000 GET DIAGNOSED BUT

271
00:10:54,640 --> 00:10:56,280
THERE ARE A THOUSAND

272
00:10:56,280 --> 00:10:57,720
DISSEMINATED CASES PER YEAR,

273
00:10:57,720 --> 00:10:58,480
THERE'S CLEARLY SOMETHING

274
00:10:58,480 --> 00:10:59,640
SPECIAL ABOUT THOSE INDIVIDUALS

275
00:10:59,640 --> 00:11:05,320
AND YET WE'VE ONLY IDENTIFIED 8.

276
00:11:05,320 --> 00:11:07,600
DOES THAT SEEM REASONABLE?

277
00:11:07,600 --> 00:11:07,840
HELL NO.

278
00:11:07,840 --> 00:11:11,880
AND THAT IS WHAT STARTED US TO

279
00:11:11,880 --> 00:11:12,240
WORK ON THIS.

280
00:11:12,240 --> 00:11:13,600
SO WE'RE GOING TO GO AND TALK

281
00:11:13,600 --> 00:11:14,680
ABOUT THE SPECIFICS OF THIS

282
00:11:14,680 --> 00:11:15,880
PATIENT AND OF OTHER THINGS BUT

283
00:11:15,880 --> 00:11:17,640
BEFORE WE MOVE ON, I WANT TO

284
00:11:17,640 --> 00:11:21,760
TAKE 1 MOMENT TO TALK ABOUT WHY

285
00:11:21,760 --> 00:11:24,080
THIS EVENT IS SO IMPORTANT, WHY

286
00:11:24,080 --> 00:11:26,200
THIS KIND OF SECTION OF CPC IS

287
00:11:26,200 --> 00:11:26,960
SO IMPORTANT.

288
00:11:26,960 --> 00:11:30,040
AND I WANT TO POINT OUT THAT THE

289
00:11:30,040 --> 00:11:32,120
ALTRUISM AND THE BRAVERY OF THIS

290
00:11:32,120 --> 00:11:34,600
FAMILY WAS REALLY SPECIAL, THIS

291
00:11:34,600 --> 00:11:36,120
MOTHER REACHED OUT TO FIND A

292
00:11:36,120 --> 00:11:39,760
HOSPITAL THAT WAS WILLING TO DO

293
00:11:39,760 --> 00:11:40,240
AN AUTOPSIES.

294
00:11:40,240 --> 00:11:43,120
THINK ABOUT HOW MANY FAMILY,

295
00:11:43,120 --> 00:11:45,080
DOCTORS DON'T EVEN APPROACH, OH

296
00:11:45,080 --> 00:11:47,160
IT WOULD BE TOO TRAUMATIC, IT'S

297
00:11:47,160 --> 00:11:49,320
TOO HARD TO TALK ABOUT

298
00:11:49,320 --> 00:11:49,800
AUTOPSIES, HELL NO.

299
00:11:49,800 --> 00:11:51,320
IF YOU THINK THE PATIENT WHO

300
00:11:51,320 --> 00:11:53,400
DIED HAD THE MOST SUCCESSFUL

301
00:11:53,400 --> 00:11:56,160
THERAPY POSSIBLE, DON'T ASK.

302
00:11:56,160 --> 00:11:57,960
BUT IF YOU THINK THAT YOU CAN DO

303
00:11:57,960 --> 00:12:01,000
BETTER IF YOU KNOW MORE, THIS IS

304
00:12:01,000 --> 00:12:03,600
WHERE YOU NEED TO BE.

305
00:12:03,600 --> 00:12:05,800
SO IF IT HADN'T BEEN FOR HER

306
00:12:05,800 --> 00:12:07,040
COMMITMENT WE WOULDN'T KNOW

307
00:12:07,040 --> 00:12:07,880
ABOUT THIS.

308
00:12:07,880 --> 00:12:09,400
WE OFTEN, I HEAR PEOPLE SAY ALL

309
00:12:09,400 --> 00:12:11,240
THE TIME, I DON'T NEED TO DO AN

310
00:12:11,240 --> 00:12:12,200
AUTOPSIES I KNOW EVERYTHING

311
00:12:12,200 --> 00:12:13,960
BECAUSE WE HAVE CAT SCANS, WE

312
00:12:13,960 --> 00:12:15,480
HAVE BLOOD WORK.

313
00:12:15,480 --> 00:12:16,680
WRONG, WRONG, WRONG.

314
00:12:16,680 --> 00:12:20,680
I CANNOT EMPHASIZE ENOUGH WHAT A

315
00:12:20,680 --> 00:12:22,320
FELLACIOUS ASSUMPTION THAT IS.

316
00:12:22,320 --> 00:12:23,560
I'VE NEVER BEEN INVOLVED IN

317
00:12:23,560 --> 00:12:26,320
AUTOPSIES WHERE WE DIDN'T LEARN

318
00:12:26,320 --> 00:12:28,360
SOMETHING, NOT ALWAYS THE CAUSE

319
00:12:28,360 --> 00:12:29,680
OF DEATH BUT OFTEN THINGS ABOUT

320
00:12:29,680 --> 00:12:31,080
THE DISEASE, IF YOU DON'T WANT

321
00:12:31,080 --> 00:12:33,640
TO KNOW, DON'T LOOK BUT IF YOU

322
00:12:33,640 --> 00:12:35,600
WANT ANSWERS YOU HAVE TO SEEK

323
00:12:35,600 --> 00:12:37,440
AND IN ORDER TO SEEK, YOU HAVE

324
00:12:37,440 --> 00:12:39,320
TO ASK THESE QUESTIONS AND

325
00:12:39,320 --> 00:12:41,240
THAT'S HOW WE GET THERE THROUGH

326
00:12:41,240 --> 00:12:43,120
THIS KIND OF PROCESS.

327
00:12:43,120 --> 00:12:46,400
SO I'LL TURN IT OVER HERE TO

328
00:12:46,400 --> 00:12:47,120
DR. DAVE KLEINER WHO WILL SHOW

329
00:12:47,120 --> 00:12:53,200
US WHAT WE LEARNED AT AUTOPSY.

330
00:12:53,200 --> 00:12:59,040
>>THANK YOU STEVE FOR THE

331
00:12:59,040 --> 00:13:01,360
VERY KIND--I'M NOTE EVEN SURE

332
00:13:01,360 --> 00:13:02,000
WHAT TO SAY.

333
00:13:02,000 --> 00:13:04,600
YOUR KIND WORDS ABOUT PERFORMING

334
00:13:04,600 --> 00:13:06,280
AUTOPSIES AND WHAT HE SAID IS

335
00:13:06,280 --> 00:13:08,800
QUITE CRITICAL AND THERE IS

336
00:13:08,800 --> 00:13:10,280
ACTUAL DATA TO SUPPORT ALL OF

337
00:13:10,280 --> 00:13:12,640
THOSE POINTS THAT HE MADE.

338
00:13:12,640 --> 00:13:15,360
SO I'M GOING TO GO THROUGH THE

339
00:13:15,360 --> 00:13:16,040
AUTOPSIES FINDINGS, THIS IS

340
00:13:16,040 --> 00:13:18,280
GOING TO BE STRAIGHT PATHOLOGY

341
00:13:18,280 --> 00:13:20,680
AND THEN WE'RE GOING TO--BUT THE

342
00:13:20,680 --> 00:13:22,720
AUTOPSIES WHAT THAT DID WAS

343
00:13:22,720 --> 00:13:25,600
PROVIDE ACCESS TO THE TISSUE AND

344
00:13:25,600 --> 00:13:26,760
AN OPPORTUNITY TO INVESTIGATE

345
00:13:26,760 --> 00:13:29,400
MORE WHAT WAS GOING ON.

346
00:13:29,400 --> 00:13:30,720
SO WITHOUT FURTHER ADO, WE WILL

347
00:13:30,720 --> 00:13:33,360
START IT IN THE LUNGS, 1 OF THE

348
00:13:33,360 --> 00:13:37,760
FIRST OBSERVATIONS THAT WE MADE

349
00:13:37,760 --> 00:13:40,600
AFTER WE SECTIONED THE LUNGS WAS

350
00:13:40,600 --> 00:13:42,320
THAT THERE WAS BRONCHIECTASIS,

351
00:13:42,320 --> 00:13:45,040
IT'S A CONDITION WHERE THE

352
00:13:45,040 --> 00:13:47,240
BRONCH I BECOME DILATED ALL THE

353
00:13:47,240 --> 00:13:48,640
WAIUTE TO THE PLURAL SURFACE AND

354
00:13:48,640 --> 00:13:57,200
YOU CAN SEE HERE IS THE LUMEN OF

355
00:13:57,200 --> 00:14:00,280
THE BRONCHIAS, WHICH IS VERY

356
00:14:00,280 --> 00:14:02,000
FIBROTIC, VERY ATTENUATE UD

357
00:14:02,000 --> 00:14:02,720
EPITHELIUM, ULCERATE INDEED

358
00:14:02,720 --> 00:14:05,200
PLACES AND YOU CAN TELL THIS IS

359
00:14:05,200 --> 00:14:08,160
DILATED BECAUSE IT'S FLAT AND

360
00:14:08,160 --> 00:14:11,680
NORMAL BRONCH I ARE NOT FLAT,

361
00:14:11,680 --> 00:14:15,080
THEY'RE ROUND AND ADJACENT TO

362
00:14:15,080 --> 00:14:19,840
THE BRONCHUS WAS PNEUMONIA THAT

363
00:14:19,840 --> 00:14:21,560
WAS PROBABLY FINAL IN THIS

364
00:14:21,560 --> 00:14:23,280
PATIENT'S LIFE AND FUNGAL.

365
00:14:23,280 --> 00:14:24,600
WE WHEN YOU LOOK IN THE

366
00:14:24,600 --> 00:14:26,440
SURROUNDING TISSUE WE WERE ABLE

367
00:14:26,440 --> 00:14:29,000
TO SEE IN THIS PARTICULAR

368
00:14:29,000 --> 00:14:31,520
SECTION A SMALL FIBROTIC NODULE

369
00:14:31,520 --> 00:14:33,960
AND AROUND THE EDGES OF THE

370
00:14:33,960 --> 00:14:36,800
FIBROTIC NODULE, YOU CAN SEE

371
00:14:36,800 --> 00:14:39,720
GIANT SELLS, THAT HAVE ENGULFED

372
00:14:39,720 --> 00:14:40,880
ORGANISMS, THAT ARE ACTUALLY

373
00:14:40,880 --> 00:14:43,760
FAIRLY RAZE TO SEE ON THE H&
E

374
00:14:43,760 --> 00:14:45,440
WITH THESE LITTLE EMPTY HOLES

375
00:14:45,440 --> 00:14:48,840
BUT WE USE SPECIAL STAINS, IN

376
00:14:48,840 --> 00:14:50,160
THIS CASE A SILVER STAIN TO

377
00:14:50,160 --> 00:14:51,640
HIGHLIGHT THE ORGANISMS AND YOU

378
00:14:51,640 --> 00:14:53,960
CAN SEE THAT THEY'RE VERY NOT

379
00:14:53,960 --> 00:14:55,120
WELL PRESERVED, NOT NEARLY AS

380
00:14:55,120 --> 00:14:59,600
PRETTY AS THE PICTURE STEVE

381
00:14:59,600 --> 00:15:04,320
SHOWED THEY'RE DEFINITELY THE

382
00:15:04,320 --> 00:15:04,920
COCCIDIOMYCOSIS ORGANISMS.

383
00:15:04,920 --> 00:15:06,720
WE LOOKED OF COURSE, A FULL

384
00:15:06,720 --> 00:15:08,480
AUTOPSIES, WE LOOKED EVERYWHERE

385
00:15:08,480 --> 00:15:10,760
WHEN WE SAMPLED THE ADRENAL

386
00:15:10,760 --> 00:15:12,360
GLANDS WE FOUND SMALL WHITE

387
00:15:12,360 --> 00:15:14,240
LESIONS IN THE ADRENAL GLANDINGS

388
00:15:14,240 --> 00:15:16,760
ON BOTH SIDEs AND UNDER

389
00:15:16,760 --> 00:15:18,280
MICROSCOPIC SECTIONS AGAIN A

390
00:15:18,280 --> 00:15:19,400
SMALL FIBROTIC NODULE AND AGAIN

391
00:15:19,400 --> 00:15:20,600
YOU CAN SEE THESE LITTLE HOLES

392
00:15:20,600 --> 00:15:23,360
HERE WHICH ARE THE ORGANISMS AND

393
00:15:23,360 --> 00:15:27,200
OVER HERE I HAVE A P A S STAIN

394
00:15:27,200 --> 00:15:29,440
WHICH HIGHLIGHTS FUNGAL

395
00:15:29,440 --> 00:15:30,880
ORGANISMS BECAUSE OF THE

396
00:15:30,880 --> 00:15:32,920
GLYCOPROTEINS IN THE FUNGAL WALL

397
00:15:32,920 --> 00:15:34,560
AND THEN A SILVER STAIN.

398
00:15:34,560 --> 00:15:35,760
THESE ORGANISMS WERE A LITTLE

399
00:15:35,760 --> 00:15:37,720
BIT BETTER PRESERVED SO YOU CAN

400
00:15:37,720 --> 00:15:43,360
SEE A SPHEREIOLE WITH SOME OF

401
00:15:43,360 --> 00:15:44,920
THESE SMALLER SIS FORMS INSIDE

402
00:15:44,920 --> 00:15:46,200
AND IT LOOKS LIKE IT'S IN THE

403
00:15:46,200 --> 00:15:47,480
PROCESS OF BREAKING OPEN.

404
00:15:47,480 --> 00:15:49,120
THERE WAS A NODULE IN THE LEFT

405
00:15:49,120 --> 00:15:51,200
BREAST AND SO IT WAS ABOUT HALF

406
00:15:51,200 --> 00:15:54,840
A CENTIMETER IN SIZE, FULL OF

407
00:15:54,840 --> 00:15:56,840
NECROTIC MATERIAL, AND A

408
00:15:56,840 --> 00:15:57,840
FIBROTIC CAPSULE AROUND THE EDGE

409
00:15:57,840 --> 00:16:01,760
AND HERE IS ANOTHER 1 OF THESE

410
00:16:01,760 --> 00:16:02,440
SMALL FIBROTIC NODULES.

411
00:16:02,440 --> 00:16:03,880
AGAIN, YOU CAN SEE ORGANISMS

412
00:16:03,880 --> 00:16:05,400
HERE AND THERE WERE ALSO

413
00:16:05,400 --> 00:16:08,600
ORGANISMS OUT IN THE NECROTIC

414
00:16:08,600 --> 00:16:08,880
MATERIAL.

415
00:16:08,880 --> 00:16:10,960
THE UNIQUE THING ABOUT THIS

416
00:16:10,960 --> 00:16:12,400
PARTICULAR SITE WAS NOT ONLY DID

417
00:16:12,400 --> 00:16:17,800
WE FIND THE SPHEREIOLES, BUT WE

418
00:16:17,800 --> 00:16:20,200
ALSO FOUND HEIGHT FULL FORMS OUT

419
00:16:20,200 --> 00:16:21,600
IN THE NECROTIC MATERIAL AROUND,

420
00:16:21,600 --> 00:16:24,640
IN THE CENTER OF THIS ABSCESS.

421
00:16:24,640 --> 00:16:26,200
AND THEN 1 OTHER THING THAT WE

422
00:16:26,200 --> 00:16:29,040
FOUND IN THE BODY CAVITY ITSELF

423
00:16:29,040 --> 00:16:32,640
WAS ALONG THE LEFT VENTRICULAR

424
00:16:32,640 --> 00:16:34,440
ENDOCARDIUM, THERE WAS A SMALL

425
00:16:34,440 --> 00:16:36,000
PATCH OF HEMORRHAGE WE SAMPLED

426
00:16:36,000 --> 00:16:38,280
AND YOU CAN SEE DOWN HERE BELOW

427
00:16:38,280 --> 00:16:43,640
OUR NORMAL MY O CARDIO

428
00:16:43,640 --> 00:16:45,920
SIGHTS,--MY O CARDIO SITES,

429
00:16:45,920 --> 00:16:46,880
THEY'RE NOT NECROTIC BUT ABOVE

430
00:16:46,880 --> 00:16:49,520
THAT WE HAVE AN AREA OF NECROSIS

431
00:16:49,520 --> 00:16:50,840
AND HEMORRHAGE, WE DIDN'T FIND

432
00:16:50,840 --> 00:16:53,920
ORGANISMS HERE BUT I DID SUSPECT

433
00:16:53,920 --> 00:16:55,760
THIS WAS A SITE INFECTED BY

434
00:16:55,760 --> 00:16:56,240
FUNGAL INFECTION.

435
00:16:56,240 --> 00:16:59,200
BUT IN THE BRAIN WHICH WAS OF

436
00:16:59,200 --> 00:17:00,280
COURSE THE PATIENT'S FINAL EVENT

437
00:17:00,280 --> 00:17:03,480
WAS A BRAIN HEMORRHAGE.

438
00:17:03,480 --> 00:17:06,280
WE FOUND INVOLVEMENT OF

439
00:17:06,280 --> 00:17:08,680
SEEREBERALART RYES BY FUNGAL

440
00:17:08,680 --> 00:17:09,440
ORGANISMS CAUSING THIS

441
00:17:09,440 --> 00:17:10,600
VASCULITIS SO YOU CAN SEE THE

442
00:17:10,600 --> 00:17:12,320
WALL OF THE ARTERY HERE AND 1

443
00:17:12,320 --> 00:17:17,240
SIDE INVOLVED BY INFLAMMATION,

444
00:17:17,240 --> 00:17:19,040
WHICH HAS PENETRATED THROUGH THE

445
00:17:19,040 --> 00:17:20,080
MUSCULAR WALL.

446
00:17:20,080 --> 00:17:21,720
YOU CAN SEE THAT THERE ARE

447
00:17:21,720 --> 00:17:24,600
NUTRIFILLS HERE AS WELL AS LOTS

448
00:17:24,600 --> 00:17:26,320
OF LYMPHOCYTES AND AGAIN IF YOU

449
00:17:26,320 --> 00:17:27,640
LOOK CAREFULLY CAN YOU FIND

450
00:17:27,640 --> 00:17:28,680
THESE GIANT SELLS WITH

451
00:17:28,680 --> 00:17:31,280
ORGANIZATIONS INFORMS INSIDE

452
00:17:31,280 --> 00:17:31,800
THEM.

453
00:17:31,800 --> 00:17:34,440
SO HERE'S A LOW POWER SILVER

454
00:17:34,440 --> 00:17:35,600
STAIN OF THAT ARTERY SO YOU

455
00:17:35,600 --> 00:17:36,680
CANEE THERE ARE FUNGAL FORMS IN

456
00:17:36,680 --> 00:17:39,160
THE WALL OF THE ARTERY AS WELL

457
00:17:39,160 --> 00:17:42,800
AS LITTLE GROUPS OF FUNGAL FORMS

458
00:17:42,800 --> 00:17:43,040
OUTSIDE.

459
00:17:43,040 --> 00:17:45,200
AND HERE THEY ARE IN CLOSE UP SO

460
00:17:45,200 --> 00:17:47,280
AGAIN WE HAD THE HIGH FORMS IN

461
00:17:47,280 --> 00:17:52,720
THE WALL AND CAN YOU SEE THEM AT

462
00:17:52,720 --> 00:17:55,480
LOW MAGNIFICATION AND THEN MORE

463
00:17:55,480 --> 00:17:56,760
OF THE TYPICAL SPHOARIOLES AND

464
00:17:56,760 --> 00:17:58,080
YEAST FORMS ELSEWHERE, SO IN

465
00:17:58,080 --> 00:18:00,480
SUMMARY FROM THE AUTOPSIES, WE

466
00:18:00,480 --> 00:18:03,360
CONFIRMED THAT SHE STILL HAD AT

467
00:18:03,360 --> 00:18:05,760
THE TIME OF DEATH

468
00:18:05,760 --> 00:18:07,520
COCCIDIOMYCOSIS INVOLVING THE

469
00:18:07,520 --> 00:18:08,560
BRAIN, LUNGS, ADRENALS AND

470
00:18:08,560 --> 00:18:09,040
BREAST.

471
00:18:09,040 --> 00:18:11,800
WE TOOK CULTURES AT THE TIME

472
00:18:11,800 --> 00:18:13,720
WHICH WERE POSITIVE FOR THE

473
00:18:13,720 --> 00:18:18,160
ORGANISM AND THEN THERE WAS THIS

474
00:18:18,160 --> 00:18:20,840
FOCAL LEFT VENTRICULAR

475
00:18:20,840 --> 00:18:22,600
HEMORRHAGIC ENDOCARDITEIS WHICH

476
00:18:22,600 --> 00:18:24,320
WAS ALSO FUNGAL BUT WE DIDN'T

477
00:18:24,320 --> 00:18:25,720
DEFINE ORGANISMS AND CAUSE OF

478
00:18:25,720 --> 00:18:30,960
DEATH WAS NO SURPRISE,

479
00:18:30,960 --> 00:18:32,520
INTERSEEREBERAL HEMORRHAGE,

480
00:18:32,520 --> 00:18:34,000
UNDERLYING CAUSE OF DEATH

481
00:18:34,000 --> 00:18:34,600
DISSEMINATED COCCIDIOMYCOSIS.

482
00:18:34,600 --> 00:18:36,400
SO I WILL TURN THIS OVER NOW TO

483
00:18:36,400 --> 00:18:42,840
THE NEXT SPEAKER.

484
00:18:42,840 --> 00:18:43,680
>>IT'S NO SURPRISE

485
00:18:43,680 --> 00:18:45,640
I'M GOING TO GIVE IT AWAY THAT

486
00:18:45,640 --> 00:18:47,160
WE ARE DEALING WITH A PATIENT

487
00:18:47,160 --> 00:18:48,440
WITH A STAT 3 MUTATION.

488
00:18:48,440 --> 00:18:50,360
COURTESY OF DR. KLEINER HE ROUGH

489
00:18:50,360 --> 00:18:51,960
ATOM VIEDED ME WITH TISSUE, WE

490
00:18:51,960 --> 00:18:55,360
HAD HEART AND SPLEEN TISSUE,

491
00:18:55,360 --> 00:18:57,000
IOALATED DNA, PERFORMED WHOLE

492
00:18:57,000 --> 00:18:59,080
EXOHM SEQUENCES WHICH IDENTIFIED

493
00:18:59,080 --> 00:19:01,200
A HAPPEN LO STAT VARIANT IN THE

494
00:19:01,200 --> 00:19:01,720
STAT 3.

495
00:19:01,720 --> 00:19:04,960
IT'S IN THE MIDDLE OF THE GENE

496
00:19:04,960 --> 00:19:08,640
EXON 14 OF 24 AND CHANGES TO

497
00:19:08,640 --> 00:19:09,320
STOP CODON.

498
00:19:09,320 --> 00:19:11,960
SO IT'S A PREMATURE TERMINATION,

499
00:19:11,960 --> 00:19:12,760
IT'S NOT NOW IN NATIONAL LIBRARY

500
00:19:12,760 --> 00:19:15,120
OF MEDICINEAD WHICH IS A DAT

501
00:19:15,120 --> 00:19:16,920
BASE OF 40,000 INDIVIDUALS WHICH

502
00:19:16,920 --> 00:19:18,960
HAVE BEEN SEQUENCED AND IT HAS A

503
00:19:18,960 --> 00:19:19,680
CAD SCORE OF 41.

504
00:19:19,680 --> 00:19:24,160
THAT PUTS IT IN THE TOP .01% OF

505
00:19:24,160 --> 00:19:26,440
DAMAGING VARIANTS POSSIBLE IN

506
00:19:26,440 --> 00:19:27,040
THE GENOME.

507
00:19:27,040 --> 00:19:30,120
STAT 3 IS A GENE AS IS

508
00:19:30,120 --> 00:19:30,760
CONSTRAINED AGAINST MUTATIONS.

509
00:19:30,760 --> 00:19:33,840
WE KNOW WHAT THE MUTATION RATE

510
00:19:33,840 --> 00:19:35,240
IS ACROSS THE HUMAN GENOME AND

511
00:19:35,240 --> 00:19:37,920
SO GIVEN THE SIZE OF A GENE, WE

512
00:19:37,920 --> 00:19:40,280
CAN CALCULATE WHAT WOULD BE THE

513
00:19:40,280 --> 00:19:42,720
EXPECTED NUMBER OF MUTATIONS

514
00:19:42,720 --> 00:19:44,800
THAT OCCUR, NUMBER OF VARIANTS

515
00:19:44,800 --> 00:19:46,040
THAT OCCUR JUST BY CHANCE AND

516
00:19:46,040 --> 00:19:49,000
YOU CAN BEND THOSE BY FUNCTION

517
00:19:49,000 --> 00:19:50,280
WHETHER THEY'RE SYNONYMOUS SO

518
00:19:50,280 --> 00:19:52,840
THEY DON'T CHANGE THE IMMUNO

519
00:19:52,840 --> 00:19:54,800
ACID, IN THIS SENSE IT DOES

520
00:19:54,800 --> 00:19:57,840
CHANGE THE AMINO ACID WHICH

521
00:19:57,840 --> 00:19:59,360
WOULD BE A SPLICE MUTATION.

522
00:19:59,360 --> 00:20:01,800
AND YOU CAN SEE THAT THE

523
00:20:01,800 --> 00:20:04,000
SYNONYMOUS CHANGES, THE NUMBER

524
00:20:04,000 --> 00:20:05,280
OBSERVED OVER THIS 140,000 ARE

525
00:20:05,280 --> 00:20:07,720
INDIVIDUALS IS EXACTLY WHAT YOU

526
00:20:07,720 --> 00:20:08,480
WOULD EXPECT.

527
00:20:08,480 --> 00:20:10,480
BY CORN TRAOF THE THE MISSENSE

528
00:20:10,480 --> 00:20:12,240
CHANGES ARE ONLY A THIRD WHAT

529
00:20:12,240 --> 00:20:13,520
YOU WOULD EXPECT INDICATE

530
00:20:13,520 --> 00:20:16,040
NOTHING NORMAL HEALTHY PEOPLE,

531
00:20:16,040 --> 00:20:17,760
MISSENSE CHANGES IN STAT 3

532
00:20:17,760 --> 00:20:19,400
AREN'T USUALLY COMPATIBLE WITH

533
00:20:19,400 --> 00:20:20,280
THAT NORMAL HEALTHY PHENOTYPE

534
00:20:20,280 --> 00:20:24,000
AND EVEN MORE STRIKING IS LOSS

535
00:20:24,000 --> 00:20:25,040
OF FUNCTION MUTATIONS, THERE'S

536
00:20:25,040 --> 00:20:27,280
ONLY 1 PRESENT IN NOMAD.

537
00:20:27,280 --> 00:20:28,360
SO 2%.

538
00:20:28,360 --> 00:20:30,680
IN FACT, STAT 3 IS 1 OF THE MOST

539
00:20:30,680 --> 00:20:34,440
CONSTRAINED GENES IN THE GENOME

540
00:20:34,440 --> 00:20:35,080
AGAINST MUTATIONS.

541
00:20:35,080 --> 00:20:37,440
SO WHAT IS STAT 3 ON DO, IT'S A

542
00:20:37,440 --> 00:20:39,880
MEMBER OF THE STAT FAMILY OF

543
00:20:39,880 --> 00:20:40,960
TRANSCRIPTION FACTORS WHICH

544
00:20:40,960 --> 00:20:42,600
STANDS FOR SIGNAL TRANSDUCTION,

545
00:20:42,600 --> 00:20:44,800
AND ACTIVATOR OF TRANSCRIPTION.

546
00:20:44,800 --> 00:20:45,760
UPON EXTRA CELLULAR CYTOKINES

547
00:20:45,760 --> 00:20:48,240
SUCH AS THOSE LISTED ABOVE, IN

548
00:20:48,240 --> 00:20:50,560
THE BIND TO THE COGNATE

549
00:20:50,560 --> 00:20:51,600
RECEPTORS, THOSE KINASES WHICH

550
00:20:51,600 --> 00:20:55,280
ARE BOUND TO THE RECEPTORS KROS

551
00:20:55,280 --> 00:20:56,480
PHOSPHORYLATE AND PHOSPHORYLATE

552
00:20:56,480 --> 00:20:57,640
THE RECEPTOR WHICH PROVIDES A

553
00:20:57,640 --> 00:20:59,720
DOCK BEING SITE FOR THE STAT

554
00:20:59,720 --> 00:21:01,160
MOLECULE TO BIND.

555
00:21:01,160 --> 00:21:03,200
AT THAT POINT THE JAGS WILL

556
00:21:03,200 --> 00:21:04,160
PHOSPHORYLATE THE STATS, THEY

557
00:21:04,160 --> 00:21:06,360
WILL DECOUPLE FROM THE RECEPTOR,

558
00:21:06,360 --> 00:21:08,200
FORM HETEROGENEOUS OR O OR

559
00:21:08,200 --> 00:21:09,280
HOMODIMERS WITH OTHER STAT

560
00:21:09,280 --> 00:21:11,120
MOLECULES AND THAT DISCIPLINARY

561
00:21:11,120 --> 00:21:12,600
MERRIC STAT 3 MOLECULE IN THIS

562
00:21:12,600 --> 00:21:16,160
CASE, STAT 3 WILL TRANSLOCATE TO

563
00:21:16,160 --> 00:21:17,440
THE NUCLEUS, BIND RECOGNITION

564
00:21:17,440 --> 00:21:20,280
SITES ON THE DNA AND DRIVE

565
00:21:20,280 --> 00:21:24,400
TRANSCRIPTION OF TARGET GENES.

566
00:21:24,400 --> 00:21:25,520
SO EACH HEALTHY INDIVIDUAL

567
00:21:25,520 --> 00:21:27,520
SHOULD HAVE 2 COPIES, IT'S AN

568
00:21:27,520 --> 00:21:29,280
AUTOSOMAL GENE, SO HAVE YOU 2

569
00:21:29,280 --> 00:21:31,480
COPIES OF WILD-TYPE STAT 3, BOTH

570
00:21:31,480 --> 00:21:32,800
OF WHICH CAN PROVIDE TRANSCRIPT,

571
00:21:32,800 --> 00:21:34,440
BOTH OF WHICH CAN PROVIDE

572
00:21:34,440 --> 00:21:38,120
PROTEIN AND EACH OF WHICH LEADS

573
00:21:38,120 --> 00:21:38,640
TO NORMAL PHYSIOLOGY.

574
00:21:38,640 --> 00:21:41,320
IN THE CASE OF DOMINANT NEGATIVE

575
00:21:41,320 --> 00:21:43,400
MUTATIONS WHICH WERE THE FIRST

576
00:21:43,400 --> 00:21:49,240
MUTATIONS IDENTIFIED IN STAT 3,

577
00:21:49,240 --> 00:21:52,040
THESE LEAD TO WILD-TYPE IN BLUE,

578
00:21:52,040 --> 00:21:53,880
1 MUTANT ALLELE SHOWN IN ORANGE

579
00:21:53,880 --> 00:21:55,680
OR PINK DEPENDING ON YOUR EYES,

580
00:21:55,680 --> 00:21:57,640
AND THAT MEANS THAT 50% OF THE

581
00:21:57,640 --> 00:21:59,160
TRANSCRIPT MADE AND THE 50% OF

582
00:21:59,160 --> 00:22:02,920
THE PROTEIN MATED ARE GOING TO

583
00:22:02,920 --> 00:22:03,440
CONTAIN A MUTATION.

584
00:22:03,440 --> 00:22:05,520
SO AS I MENTIONED DOMINANT

585
00:22:05,520 --> 00:22:09,160
NEGATIVE STAT 3 MUTATIONS CAUSE

586
00:22:09,160 --> 00:22:11,120
AUTOSOMAL DOMINANT HYPER IGE

587
00:22:11,120 --> 00:22:12,080
SYNDROME, USING IL6 AS AN

588
00:22:12,080 --> 00:22:13,960
EXAMPLE, CAN YOU SEE THE STAT

589
00:22:13,960 --> 00:22:16,040
MOLECULES BINDING TO THE

590
00:22:16,040 --> 00:22:16,680
RECEPTOR AFTER CYTOKINE BINDING

591
00:22:16,680 --> 00:22:19,160
AND IT CAN BE A WILD-TYPE STAT 3

592
00:22:19,160 --> 00:22:20,560
MOLECULE OR A MUSEUM STANT STAT

593
00:22:20,560 --> 00:22:22,320
3 MOLECULE BUT WHEN THE DIMERS

594
00:22:22,320 --> 00:22:24,200
FORM, 3 OUT OF 4 OF THOSE DIMERS

595
00:22:24,200 --> 00:22:26,200
WILL CONTAIN A MUTATION AND

596
00:22:26,200 --> 00:22:27,840
WHILE THEY CAN TRANSLOCATE TO

597
00:22:27,840 --> 00:22:30,440
THE NUCLEUS, THAT MEANS 3 OUT OF

598
00:22:30,440 --> 00:22:35,640
THE 4 TIMES IT BYPASSEDS TO THE

599
00:22:35,640 --> 00:22:36,720
TRANSCRIPTION PROMOTER, TO THE

600
00:22:36,720 --> 00:22:39,080
PROMOTER SITE, YOU WILL HAVE

601
00:22:39,080 --> 00:22:41,920
ABNORMAL OR DECREASED

602
00:22:41,920 --> 00:22:42,480
TRANSCRIPTION.

603
00:22:42,480 --> 00:22:44,520
IN THE CASE OF THE PATIENT WE'RE

604
00:22:44,520 --> 00:22:46,200
DISCUSSING TODAY, WE HAVE AN

605
00:22:46,200 --> 00:22:48,160
EARLY STOP CODON AND THAT MEANS

606
00:22:48,160 --> 00:22:51,240
WE HAVE TRANSCRIPT AND PROTEIN

607
00:22:51,240 --> 00:22:53,400
PRENT FROM THE ALLELE, AND MANY

608
00:22:53,400 --> 00:22:55,080
GENES THAT WOULD BE FINE BUT I

609
00:22:55,080 --> 00:22:56,800
WILL SHOW YOU TODAY THAT IT'S

610
00:22:56,800 --> 00:22:57,160
NOT.

611
00:22:57,160 --> 00:22:59,240
IN THE CASES OF

612
00:22:59,240 --> 00:23:00,520
HAPLOINSUFFICIENCY, COMPARING IT

613
00:23:00,520 --> 00:23:02,400
TO THE AUTOSOMAL DOMINANT LOSS

614
00:23:02,400 --> 00:23:03,800
OF FUNCTION MUTATIONS, WE HAVE

615
00:23:03,800 --> 00:23:05,840
AN ISSUE OF QUANTITY, NOT

616
00:23:05,840 --> 00:23:06,200
QUALITY.

617
00:23:06,200 --> 00:23:07,680
EVERYTHING MADE IS WILD-TYPE,

618
00:23:07,680 --> 00:23:11,440
THERE'S JUST NOT ENOUGH OF IT.

619
00:23:11,440 --> 00:23:13,160
SO THAT'S WHAT YOU WOULD PREDICT

620
00:23:13,160 --> 00:23:15,080
FROM WHAT WE KNOW HERE'S HOW WE

621
00:23:15,080 --> 00:23:15,520
CAN PROVE IT.

622
00:23:15,520 --> 00:23:18,360
WE DIDN'T HAVE A LOT OF SAMPLE

623
00:23:18,360 --> 00:23:20,880
AVAILABLE FROM THIS PATIENT, SHE

624
00:23:20,880 --> 00:23:22,160
WAS DECEASED.

625
00:23:22,160 --> 00:23:27,120
WE GOT SAMPLE FOR DNA BUT NOT

626
00:23:27,120 --> 00:23:28,440
FOR PROTEIN. 

627
00:23:28,440 --> 00:23:29,600
OR TRANSCRIPT.

628
00:23:29,600 --> 00:23:31,440
FORTUNATELY, THERE WAS ANOTHER

629
00:23:31,440 --> 00:23:34,760
PATIENT FROM DR. LIONAKIS'S LAB

630
00:23:34,760 --> 00:23:37,000
WHO HAD THE SAME MUTATION AND A

631
00:23:37,000 --> 00:23:38,360
50 YEAR HISTORY OF

632
00:23:38,360 --> 00:23:38,760
[INDISCERNIBLE].

633
00:23:38,760 --> 00:23:41,640
SO HERE YOU'RE LOOKING AT CDNA

634
00:23:41,640 --> 00:23:43,840
FROM PBMCs FROM A PATIENT WITH

635
00:23:43,840 --> 00:23:44,600
A MISSENSE CHANGE.

636
00:23:44,600 --> 00:23:45,920
THIS DOESN'T EFFECT THE RNA AND

637
00:23:45,920 --> 00:23:48,520
YOU CAN SEE HERE THE CDNA

638
00:23:48,520 --> 00:23:51,120
SHOWING 2 PEEKS, THE WILD-TYPE

639
00:23:51,120 --> 00:23:53,720
IN BLACK, MUTANT IN GREEN AND

640
00:23:53,720 --> 00:23:55,280
THEY'RE BOTH EXPRESSED ROUGHLY

641
00:23:55,280 --> 00:23:55,520
EQUALLY.

642
00:23:55,520 --> 00:24:00,000
BY CONTRAST THE PATIENT WITH THE

643
00:24:00,000 --> 00:24:02,320
R24/23 STOP SHOWS WILD-TYPE

644
00:24:02,320 --> 00:24:02,640
SEQUENCE HERE.

645
00:24:02,640 --> 00:24:05,200
NOW WE CAN STABILIZE THAT

646
00:24:05,200 --> 00:24:07,480
TRANSCRIPT USING PROTEIN

647
00:24:07,480 --> 00:24:09,680
SYNTHESIS INHIBITOR, THIS HAS

648
00:24:09,680 --> 00:24:10,480
TRANSLATION AND INHIBITS

649
00:24:10,480 --> 00:24:12,040
NONSENSE MEDIATED TO K WHICH IS

650
00:24:12,040 --> 00:24:12,960
A PROOF READING MECHANISM AND

651
00:24:12,960 --> 00:24:14,880
WHEN YOU DO THAT THERE'S NO

652
00:24:14,880 --> 00:24:17,760
DIFFERENCE IN THE MISSENSE OF

653
00:24:17,760 --> 00:24:20,160
THE PATIENT HOWEVER IN THIS CASE

654
00:24:20,160 --> 00:24:24,080
OF THE R423 STOP, NOW WE RESCUED

655
00:24:24,080 --> 00:24:26,480
THE MUTANT ALLELE SHOWN IN RED

656
00:24:26,480 --> 00:24:27,840
PROVING THIS UNDERGOES NONSENSE

657
00:24:27,840 --> 00:24:29,280
MEDIATED K AND NO TRANSCRIPT

658
00:24:29,280 --> 00:24:30,760
FROM THE MUTANT ALLELE FROM THE

659
00:24:30,760 --> 00:24:31,160
PATIENT.

660
00:24:31,160 --> 00:24:33,760
BUT DOES THAT EFFECT PROTEIN?

661
00:24:33,760 --> 00:24:35,600
WE RAN WESTERN BLOTS, YOU

662
00:24:35,600 --> 00:24:38,160
CLEARLY SEE BY EYE COMPARED TO A

663
00:24:38,160 --> 00:24:39,880
HEALTHY CONTROL OR AGAIN THE

664
00:24:39,880 --> 00:24:41,080
MISSENSED PATIENT, CAN YOU

665
00:24:41,080 --> 00:24:42,400
CLEARLY SEE REDUCED LEVELS OF

666
00:24:42,400 --> 00:24:48,160
STAT 3 COMPARED TO BETA ACTIN

667
00:24:48,160 --> 00:24:49,680
AND USING [INDISCERNIBLE] WE CAN

668
00:24:49,680 --> 00:24:50,600
QUANTIFY THIS SHOWING THERE'S

669
00:24:50,600 --> 00:24:53,040
LESS AND IF WE USE THE HEALTHY

670
00:24:53,040 --> 00:24:54,280
CONTROL SAMPLES AS 1 AND

671
00:24:54,280 --> 00:24:55,480
NORMALIZE TO THAT, CAN YOU

672
00:24:55,480 --> 00:24:58,320
QUANTIFY THIS AT ABOUT 35-40%

673
00:24:58,320 --> 00:25:03,120
THE TOTAL LEVEL OF STAT 3, IN

674
00:25:03,120 --> 00:25:04,120
THESE PATIENTS.

675
00:25:04,120 --> 00:25:05,760
BUT AGAIN, IT'S A TRANSCRIPTION

676
00:25:05,760 --> 00:25:07,360
FACTOR, SO THE JOB OF A

677
00:25:07,360 --> 00:25:09,200
TRANSCRIPTION FACTOR IS TO

678
00:25:09,200 --> 00:25:09,800
ACTIVATE TRANSCRIPTION.

679
00:25:09,800 --> 00:25:12,000
SO DOES THIS IMPACT THE TARGET

680
00:25:12,000 --> 00:25:13,640
SEQUENCING OR THE TARGET SIGNALS

681
00:25:13,640 --> 00:25:16,720
IT NEEDS TO DO.

682
00:25:16,720 --> 00:25:17,760
USING IL-21, WHICH SIGNALS

683
00:25:17,760 --> 00:25:23,440
THROUGH STAT 3 AND LOOKING AT

684
00:25:23,440 --> 00:25:24,960
SOCS3 TRANSCRIPT, THESE ARE

685
00:25:24,960 --> 00:25:28,880
T-CELLS FROM A PAPER THAT WAS

686
00:25:28,880 --> 00:25:30,600
RECENTLY PUBLISHED, THIS IS 4

687
00:25:30,600 --> 00:25:32,440
HEALTHY CONTROLS WITH 4 PATIENTS

688
00:25:32,440 --> 00:25:34,680
WITH AUTOSOME AT IGE AND YOU SEE

689
00:25:34,680 --> 00:25:35,960
THE DECREASED LEVEL OF

690
00:25:35,960 --> 00:25:36,360
TRANSCRIPT.

691
00:25:36,360 --> 00:25:37,680
SO THESE PEOPLE WERE THINKING

692
00:25:37,680 --> 00:25:39,880
THAT SINCE BONE MARROW

693
00:25:39,880 --> 00:25:41,280
TRANSPLANTATION CARRIES LOTS OF

694
00:25:41,280 --> 00:25:43,400
RISKS FOR IT, FOR IMMUNE

695
00:25:43,400 --> 00:25:45,280
DEFICIENCIES, MAYBE THEY COULD

696
00:25:45,280 --> 00:25:47,440
SIMPLY SILENCE THE MUTANT ALLELE

697
00:25:47,440 --> 00:25:48,600
AND WITH THAT RESTORE SIGNALING

698
00:25:48,600 --> 00:25:51,240
BECAUSE NOW YOU WILL HAVE

699
00:25:51,240 --> 00:25:53,800
SIGNALING THROUGH THE WILD-TYPE

700
00:25:53,800 --> 00:25:56,640
AND WHEN THEY DID THAT USING

701
00:25:56,640 --> 00:25:58,600
THIS PATIENT, SO THOU THEY

702
00:25:58,600 --> 00:26:01,160
SILENCED THE MUTANT ALLELE, THEY

703
00:26:01,160 --> 00:26:02,280
HAVE EXPRESSION FROM THE

704
00:26:02,280 --> 00:26:05,120
WILD-TYPE ALLELE AND YET THAT IS

705
00:26:05,120 --> 00:26:07,560
INSUFFICIENT TO RESTORE SOCS 3

706
00:26:07,560 --> 00:26:08,280
TRANSCRIPT LEVELS SHOWING THAT

707
00:26:08,280 --> 00:26:09,920
HALF IS NOT ENOUGH.

708
00:26:09,920 --> 00:26:11,560
SO IN ADDITION TO THE PATIENT

709
00:26:11,560 --> 00:26:13,040
WE'RE DISCUSSING HERE TODAY

710
00:26:13,040 --> 00:26:15,840
SHOWN BY THE RED ARROW, THE

711
00:26:15,840 --> 00:26:16,640
INITIALLY PUBLISHED PAPER IS

712
00:26:16,640 --> 00:26:20,800
SHOWN ON TOP THIS, IS A PATIENT

713
00:26:20,800 --> 00:26:25,000
WITH INVASIVE ASPER GEELOSEIS,

714
00:26:25,000 --> 00:26:28,760
REPORTED BY LIANOKIS'S LAB, AND

715
00:26:28,760 --> 00:26:29,440
ALSO HAPLOINSUFFICIENCY 3 WITH

716
00:26:29,440 --> 00:26:32,880
THAT PATIENT, THERE WAS ANOTHER

717
00:26:32,880 --> 00:26:34,400
PATIENT WITH COCCI MENINGITIS,

718
00:26:34,400 --> 00:26:38,320
AS WELL AS NEW PATIENT WITH CNS

719
00:26:38,320 --> 00:26:41,480
ASPERGILLOSIS, A PATIENT WITH

720
00:26:41,480 --> 00:26:47,360
CRYPTO MENINGITIS AND CMC FROM

721
00:26:47,360 --> 00:26:48,160
DR. ROSENZWEIG'S LAB.

722
00:26:48,160 --> 00:26:49,320
SO THIS IS MISSENSE AND

723
00:26:49,320 --> 00:26:50,000
NONSENSE, THIS COMES FROM THE

724
00:26:50,000 --> 00:26:51,040
NATIONAL LIBRARY OF MEDICINEAD

725
00:26:51,040 --> 00:26:52,200
DATA SET.

726
00:26:52,200 --> 00:26:57,720
WE  DEMONSTRATED THESE BY THE

727
00:26:57,720 --> 00:26:59,240
DATA THAT LEADS TO DECREASED

728
00:26:59,240 --> 00:27:02,040
STAT 3 PROTEIN LEVELS AS SEEN IN

729
00:27:02,040 --> 00:27:03,680
WESTERNS AND DIMINISH DOWN

730
00:27:03,680 --> 00:27:05,520
STREAM TARGET TRANSCRIPTS AND

731
00:27:05,520 --> 00:27:07,520
REALLY IMPORTANTLY THAT WHILE

732
00:27:07,520 --> 00:27:08,480
STAT 3 HAPLOINSUFFICIENCY TEND

733
00:27:08,480 --> 00:27:10,520
TO APPEAR TO HAVE NORMAL

734
00:27:10,520 --> 00:27:12,560
IMMUNITY, THIS WOMAN HAD NO

735
00:27:12,560 --> 00:27:14,680
SIGNS OF BEING SICK UNTIL SHE

736
00:27:14,680 --> 00:27:16,840
WAS CONFRONTED WITH THIS FUNGAL

737
00:27:16,840 --> 00:27:17,320
INFECTION.

738
00:27:17,320 --> 00:27:19,280
AND YET INVASIVE FUNGAL

739
00:27:19,280 --> 00:27:20,440
INFECTIONS ARE A COMMON THEME.

740
00:27:20,440 --> 00:27:23,080
AND THIS IS A SCHEMATIC SHOWING

741
00:27:23,080 --> 00:27:24,680
THE DEGREE OF STAT 3 SIGNALING,

742
00:27:24,680 --> 00:27:26,800
SO IF HAVE YOU A HOMOZYGOUS

743
00:27:26,800 --> 00:27:29,720
KNOCK OUT LIKE IN MICE THAT'S

744
00:27:29,720 --> 00:27:31,240
EMBRYONIC LETHAL, STAT 3 HYPER

745
00:27:31,240 --> 00:27:33,920
IGE SYNDROME CALLED BY AUTOSOMAL

746
00:27:33,920 --> 00:27:38,480
DOMINANT STAT 3 MUTATION SYSTEM

747
00:27:38,480 --> 00:27:40,080
MULTISYSTEMIC SYNDROMIC DISEASE

748
00:27:40,080 --> 00:27:44,920
AND HERE ARE  3 HAPLOs, THAT

749
00:27:44,920 --> 00:27:45,960
HAVE THE FUNGAL INFECTION.

750
00:27:45,960 --> 00:27:50,880
AND WITH THAT I WILL PASS IT TO

751
00:27:50,880 --> 00:27:54,640
DR. LIANOKIS TO PUT THIS FUNGAL

752
00:27:54,640 --> 00:27:59,240
INFECTION IN GENERAL.

753
00:27:59,240 --> 00:28:00,160
>>THANKS, AMY, SO WHAT I
WILL

754
00:28:00,160 --> 00:28:03,200
TRY TO DO IN THE LAST 15 MINUTES

755
00:28:03,200 --> 00:28:06,920
OF THIS GRAND ROUND SYSTEM TRY

756
00:28:06,920 --> 00:28:08,680
TO DISCUSS WHY DO THESE

757
00:28:08,680 --> 00:28:11,480
INDIVIDUALS THAT LACK PROPER

758
00:28:11,480 --> 00:28:16,240
STAT 3 SIGNALING DEVELOP FUNGAL

759
00:28:16,240 --> 00:28:17,360
DISEASE.

760
00:28:17,360 --> 00:28:19,760
SO THE INFECTIONS THAT AMY

761
00:28:19,760 --> 00:28:20,840
SUMMARIZED IN THE SLIDE EARLIER

762
00:28:20,840 --> 00:28:23,480
THAT WE'VE SEEN IN THE CONTEXT

763
00:28:23,480 --> 00:28:25,560
OF THE NOW 2 GENETIC SIN DROMS

764
00:28:25,560 --> 00:28:28,240
FOR LOSS OF FUNCTION OF STAT 3.

765
00:28:28,240 --> 00:28:31,560
THE AUTOSOMAL DOMINANT HYPER IG

766
00:28:31,560 --> 00:28:32,480
SYNDROME, HYMARY INSUFFICIENCY

767
00:28:32,480 --> 00:28:34,240
THAT STEVE HOLLAND AND ALEX

768
00:28:34,240 --> 00:28:34,880
[INDISCERNIBLE] HAVE ENROLLED

769
00:28:34,880 --> 00:28:36,600
AND SEEN THROUGH THE DECADES

770
00:28:36,600 --> 00:28:38,240
MULTIPLE PATIENTS HERE AT THE

771
00:28:38,240 --> 00:28:40,400
NIH. 

772
00:28:40,400 --> 00:28:43,880
AS WELL AS THE MORE RECENT

773
00:28:43,880 --> 00:28:44,600
DISCOVERY OF STAT 3

774
00:28:44,600 --> 00:28:45,600
HAPLOINSUFFICIENCY ARE LISTED

775
00:28:45,600 --> 00:28:46,080
HERE.

776
00:28:46,080 --> 00:28:49,120
THERE ARE MULTIPLE FUNGAL

777
00:28:49,120 --> 00:28:51,360
PATHOGENS THAT RELY ON DIFFERENT

778
00:28:51,360 --> 00:28:52,920
IMMUNE HOST DEFENSE REQUIREMENTS

779
00:28:52,920 --> 00:28:56,120
FOR PROTECTION. 

780
00:28:56,120 --> 00:28:57,120
MOLD INFECS PRIMARILY

781
00:28:57,120 --> 00:28:58,760
ASPERGILLOSIS, SO 2 PATIENTS

782
00:28:58,760 --> 00:29:00,760
BOTH OF WHICH HAD CNS DISEASE

783
00:29:00,760 --> 00:29:04,280
AND 1 HAD VERY MILD PULMONARY

784
00:29:04,280 --> 00:29:06,120
DISEASE SO VERY UNUSUAL FOR WHAT

785
00:29:06,120 --> 00:29:08,360
WE THINK OF FOR ASPERGILLOSIS,

786
00:29:08,360 --> 00:29:12,240
WHICH IS A TYPICALLY INHALED

787
00:29:12,240 --> 00:29:13,920
PATHOGEN, SO BOTH

788
00:29:13,920 --> 00:29:15,000
COCCIDIOMYCOSIS AND

789
00:29:15,000 --> 00:29:16,320
HISTOPLACENTAS MOZIS FALL UNDER

790
00:29:16,320 --> 00:29:23,640
THIS CATEGORY AS WELL AS

791
00:29:23,640 --> 00:29:24,920
MUCOCUTANIOUS FUNGAL INFECTIONS

792
00:29:24,920 --> 00:29:29,680
AS WELL AS DERMA TIARAS FIELD

793
00:29:29,680 --> 00:29:31,880
FUNCTIONSITOSEIS, SO IN THE

794
00:29:31,880 --> 00:29:33,760
INTEREST OF TIME AND WHY WE DO

795
00:29:33,760 --> 00:29:34,880
UNDERSTAND WHY IT HAPPENS SO

796
00:29:34,880 --> 00:29:39,200
STAT 3 IS A IMPORTANT REGULATOR

797
00:29:39,200 --> 00:29:40,840
OF UPREGULATING T-CELL THROUGH

798
00:29:40,840 --> 00:29:42,400
GAMMA T UPREGULATION, SO IN BOTH

799
00:29:42,400 --> 00:29:43,680
OF THOSE SETTINGS, WE THINK WE

800
00:29:43,680 --> 00:29:47,080
HAVE AN UNDERSTANDING WHY THESE

801
00:29:47,080 --> 00:29:47,680
INFECTIONS HAPPEN.

802
00:29:47,680 --> 00:29:50,200
I WILL SPEND MOST OF OUR TIME

803
00:29:50,200 --> 00:29:50,880
DISCUSSING THE FIRST 2 WHERE

804
00:29:50,880 --> 00:29:53,280
IT'S A BIT MORE UNCLEAR.

805
00:29:53,280 --> 00:29:57,080
SO WHAT I WILL DO IS VERY

806
00:29:57,080 --> 00:29:59,840
BRIEFLY DISCUSS HOW WE ALL

807
00:29:59,840 --> 00:30:00,520
DESPITE EXPOSURE, DEFEND

808
00:30:00,520 --> 00:30:03,160
OURSELVES AGAINST THESE

809
00:30:03,160 --> 00:30:04,360
INFECTIONS, THESE ARE

810
00:30:04,360 --> 00:30:05,080
OPPORTUNISTIC INFECTIONS AND TRY

811
00:30:05,080 --> 00:30:07,440
TO PUT THAT IN CONTEXT IN

812
00:30:07,440 --> 00:30:09,560
REGARDS TO WHAT WE KNOW OR WANT

813
00:30:09,560 --> 00:30:11,000
TO KNOW ABOUT STAT 3.

814
00:30:11,000 --> 00:30:13,840
SO ASKER GILLIS IS A UBIQUITOUS

815
00:30:13,840 --> 00:30:14,080
MOLD.

816
00:30:14,080 --> 00:30:16,440
WE RIGHT NOW INHALE SOME SPORES

817
00:30:16,440 --> 00:30:18,880
IN THIS WONDERFUL ROOM.

818
00:30:18,880 --> 00:30:21,680
AND DESPITE THAT WE DON'T GET

819
00:30:21,680 --> 00:30:23,160
ASPERGILLOSIS AND THAT IS

820
00:30:23,160 --> 00:30:25,680
BECAUSE WE HAVE VERY, VERY

821
00:30:25,680 --> 00:30:26,280
IMPORTANT INNATE IMMUNE

822
00:30:26,280 --> 00:30:28,760
RESPONSES IN OUR LUNGS.

823
00:30:28,760 --> 00:30:30,000
PRIMARILY NUTRIFILLS AND

824
00:30:30,000 --> 00:30:30,800
MONOCYTES MACROPHAGES THAT DON'T

825
00:30:30,800 --> 00:30:34,520
ALLOW US TO GET IN TROUBLE

826
00:30:34,520 --> 00:30:35,800
BECAUSE THOSE INHALE

827
00:30:35,800 --> 00:30:38,160
CONEDUCATIONALLIA AND THE EARLY

828
00:30:38,160 --> 00:30:42,120
TERMS OF THAT FOR HYPH ACE GET

829
00:30:42,120 --> 00:30:44,200
DESTROYED SO MANY OF YOU HAVE

830
00:30:44,200 --> 00:30:48,720
SEEN ASKER GILLOSEIS IS THE

831
00:30:48,720 --> 00:30:52,400
SETTING OF PROLONGED CHEMO

832
00:30:52,400 --> 00:30:54,600
THERAPY OR BUT NOT NORMAL

833
00:30:54,600 --> 00:30:55,960
PATIENTS OF FUNCTIONS OR NUMBERS

834
00:30:55,960 --> 00:30:57,200
OF NUTRIFILL.

835
00:30:57,200 --> 00:31:01,000
NOW, HOW DO THOSE NUTRIFILLS DO

836
00:31:01,000 --> 00:31:03,520
THEIR TRICK?

837
00:31:03,520 --> 00:31:04,520
ANOTHER PRIMARY INSUFFICIENCY

838
00:31:04,520 --> 00:31:07,000
ALSO FOLLOWED THROUGH BY

839
00:31:07,000 --> 00:31:10,840
DRS. CALIN, AND MOLLIC AND

840
00:31:10,840 --> 00:31:12,320
STEVE'S GROUP, DISEASE HAVE

841
00:31:12,320 --> 00:31:13,840
GIVEN US AN IMPORTANT INSIGHT

842
00:31:13,840 --> 00:31:14,280
INTO THAT.

843
00:31:14,280 --> 00:31:15,960
SO WHAT YOU SEE HERE IS THE FAIG

844
00:31:15,960 --> 00:31:18,400
O STUDIES  FAG

845
00:31:18,400 --> 00:31:24,360
O STUDIES -

846
00:31:24,360 --> 00:31:25,280
-PHAGE O STUDIES OF MULTIPLE

847
00:31:25,280 --> 00:31:27,200
ENDOCRINE PRODUCE THE SUPEROXIDE

848
00:31:27,200 --> 00:31:31,560
AND THROUGH NOT VERY CLEAR

849
00:31:31,560 --> 00:31:32,200
MECHANISMS INTRACELLULARLY ASPER

850
00:31:32,200 --> 00:31:33,920
GILLIS CAN GET CONTROL.

851
00:31:33,920 --> 00:31:36,480
SO MUTATIONS IN MANY OF THESE

852
00:31:36,480 --> 00:31:38,920
SUBUNITS CAUSE THESE PROTOTYPIC

853
00:31:38,920 --> 00:31:41,320
4 ASPER GILL ISOTOPE, DEDEFENSE,

854
00:31:41,320 --> 00:31:43,960
AND 40% OF THOSE PATIENTS OVER

855
00:31:43,960 --> 00:31:47,640
THE COURSE OF THEIR LIFETIME

856
00:31:47,640 --> 00:31:48,440
WILL DEVELOP ASPERGILLOSIS

857
00:31:48,440 --> 00:31:50,080
INDICATE THANKSGIVING AXIS IS

858
00:31:50,080 --> 00:31:52,200
ABSOLUTELY CRITICAL FOR OUR

859
00:31:52,200 --> 00:31:54,480
NUTRIFILLS TO DEFEND AGAINST

860
00:31:54,480 --> 00:31:55,240
ASPER GILLIS.

861
00:31:55,240 --> 00:31:58,840
IT ALSO TELLS US THAT 60% OF

862
00:31:58,840 --> 00:32:00,320
PATIENTS DESPITE CONSTANT

863
00:32:00,320 --> 00:32:02,080
EXPOSURE DON'T GET ASPER GILL

864
00:32:02,080 --> 00:32:04,080
ONOSEIS, MEANING THEY'RE ALSO

865
00:32:04,080 --> 00:32:04,960
DEPENDENT MECHANISMS THAT ARE

866
00:32:04,960 --> 00:32:05,720
CRITICAL HERE.

867
00:32:05,720 --> 00:32:09,320
THOSE ARE LESS CLEAR.

868
00:32:09,320 --> 00:32:13,800
NOW, WHEN WE TALK ABOUT THE

869
00:32:13,800 --> 00:32:15,720
SYNDROME OF AUTOSOMAL DOMINANT

870
00:32:15,720 --> 00:32:17,240
HYPER IG SYNDROME, WORK FROM

871
00:32:17,240 --> 00:32:19,080
STEVE'S LAB HERE PUBLISHED ABOUT

872
00:32:19,080 --> 00:32:21,840
A DECADE AGO, LOOKEDDA THE

873
00:32:21,840 --> 00:32:25,400
SUSCEPTIBILITY OF THESE PATIENTS

874
00:32:25,400 --> 00:32:26,240
TO INVASIVE PULMONARY

875
00:32:26,240 --> 00:32:28,240
ASPERGILLOSIS AND AS CAN YOU

876
00:32:28,240 --> 00:32:30,600
APPRECIATE HERE UP TO 25-30% OF

877
00:32:30,600 --> 00:32:32,880
THE THESE PATIENTS CAN DEVELOP

878
00:32:32,880 --> 00:32:34,640
ASKER GILLOSEIS, HOWEVER AS YOU

879
00:32:34,640 --> 00:32:35,840
NOTEOT ASTERISK, ALL OF THOSE

880
00:32:35,840 --> 00:32:38,120
CASES DEVELOPED IN PATIENTS WHO

881
00:32:38,120 --> 00:32:40,760
ALREADY HAVE STRUCTURAL LUNG

882
00:32:40,760 --> 00:32:44,200
DISEASE, THIS SYNDROME CAUSES

883
00:32:44,200 --> 00:32:47,200
TISSUE REMODELING DEFECTS, WHICH

884
00:32:47,200 --> 00:32:48,040
THAT LEAD TO NATIONAL LIBRARY OF

885
00:32:48,040 --> 00:32:53,600
MEDICINEAT O SILLS AND LEADS TO

886
00:32:53,600 --> 00:32:55,440
BRONCH YECTOSEIS, AND THE WHY IT

887
00:32:55,440 --> 00:32:58,760
LEADS TO THE AUTODOMINANT HYPER

888
00:32:58,760 --> 00:32:59,960
IG SYNDROME IS HAPPENING IS NOT

889
00:32:59,960 --> 00:33:04,640
BECAUSE THE PATIENTS HAVE AN

890
00:33:04,640 --> 00:33:06,040
IMMUNE DEFECT BUT THEY STRUCTURE

891
00:33:06,040 --> 00:33:08,680
OF LUNG THAT MIGHT LEAD TO THAT.

892
00:33:08,680 --> 00:33:10,320
THESE PATIENTS HAVE BEEN TESTED

893
00:33:10,320 --> 00:33:11,600
FOROXIDATIVE BURSTS AND THEY ARE

894
00:33:11,600 --> 00:33:11,920
QUITE NORMAL.

895
00:33:11,920 --> 00:33:15,320
NOW THIS IS THE INDEX PATIENT

896
00:33:15,320 --> 00:33:16,520
THAT AMY MENTIONED EARLIER.

897
00:33:16,520 --> 00:33:19,200
IN IS AN UNFORTUNATE GENTLEMEN

898
00:33:19,200 --> 00:33:21,880
WHO WAS FINE UNTIL HIS 30S,

899
00:33:21,880 --> 00:33:25,200
UNTIL HE WASN'T FINE SO HE

900
00:33:25,200 --> 00:33:26,720
DEVELOPED SIGNUEICITIS, IT WAS

901
00:33:26,720 --> 00:33:30,240
THOUGHT BACTERIAL BUT IT WAS

902
00:33:30,240 --> 00:33:33,040
ASPER GILLIS, DESPITE THE

903
00:33:33,040 --> 00:33:34,200
MULTIANTIFUNGAL DRUGS HE WAS

904
00:33:34,200 --> 00:33:36,960
PLACED ON, HE DEVELOPED SINUS

905
00:33:36,960 --> 00:33:38,920
ORBITAL BRAIN DISEASE WHICH WAS

906
00:33:38,920 --> 00:33:41,120
FIGHTAL REQUIRED HIS ORBIT TO BE

907
00:33:41,120 --> 00:33:43,000
REMOVED SURGICALLY AND DESPITE

908
00:33:43,000 --> 00:33:44,680
THAT SECONDARY TO THE INFECTION.

909
00:33:44,680 --> 00:33:46,600
THIS PATIENT DID NOT HAVE

910
00:33:46,600 --> 00:33:48,280
PULMONARY DISEASE AND CERTAINLY

911
00:33:48,280 --> 00:33:52,160
DID NOT HAVE PULMONARY

912
00:33:52,160 --> 00:33:53,320
STRUCTURAL LUNG DISEASE,

913
00:33:53,320 --> 00:33:54,920
THEREFORE MADE US THINK AS THE

914
00:33:54,920 --> 00:33:57,760
SECOND PATIENT WE'VE SEEN HERE

915
00:33:57,760 --> 00:33:59,840
WHICH I'M NOT SHOWING DUE TO THE

916
00:33:59,840 --> 00:34:01,920
INTEREST OF TIME YOU DON'T NEED

917
00:34:01,920 --> 00:34:03,800
STAT 3 INSUFFICIENT TO GET ASKER

918
00:34:03,800 --> 00:34:04,360
GILLOSEIS.

919
00:34:04,360 --> 00:34:05,800
THIS IS THE PATHOLOGY OF THAT

920
00:34:05,800 --> 00:34:06,400
INDIVIDUAL PATIENT.

921
00:34:06,400 --> 00:34:07,400
IT'S SIMILAR TO THE OTHER

922
00:34:07,400 --> 00:34:10,760
PATIENT AS WELL WITH STAT 3

923
00:34:10,760 --> 00:34:11,240
HAPLOINSUFFICIENCY AND

924
00:34:11,240 --> 00:34:13,440
ASPERGILLOSIS AND WHAT YOU SEE

925
00:34:13,440 --> 00:34:15,360
IS NECROSIS AND GRANULA TIS

926
00:34:15,360 --> 00:34:17,320
RESPONSE WITHOUT THE PRESENCE OF

927
00:34:17,320 --> 00:34:19,640
THOSE NUTRIFILLS THAT ARE

928
00:34:19,640 --> 00:34:22,160
CRITICALLY IMPORTANT. 

929
00:34:22,160 --> 00:34:24,000
INDICATING THAT PERHAPS WHETHER

930
00:34:24,000 --> 00:34:24,960
ACCUMULATION OR RECRUITMENT OF

931
00:34:24,960 --> 00:34:27,120
CELLS OR THEIR PRESENCE AND

932
00:34:27,120 --> 00:34:28,040
TISSUE MIGHT NOT BE SUFFICIENT

933
00:34:28,040 --> 00:34:29,800
TO CONTROL THE DISEASE.

934
00:34:29,800 --> 00:34:31,800
SO WE DON'T QUITE UNDERSTAND HOW

935
00:34:31,800 --> 00:34:33,560
NUTRIFILLS IN THIS CONTEXT ARE

936
00:34:33,560 --> 00:34:34,640
IMPAIR BUD IT DOES RAISE

937
00:34:34,640 --> 00:34:35,360
IMPORTANT QUESTIONS ABOUT WHAT

938
00:34:35,360 --> 00:34:38,840
WE NEED TO LOOK TO RETHINK OF

939
00:34:38,840 --> 00:34:41,840
HOW MOLD DISEASE MIGHT HAPPEN IN

940
00:34:41,840 --> 00:34:43,320
STATES OF STAT 3 DEFENSE.

941
00:34:43,320 --> 00:34:47,080
NOW THE PATIENT WE DISCUSSED

942
00:34:47,080 --> 00:34:48,360
TODAY HAD DISSEMINATED

943
00:34:48,360 --> 00:34:49,000
COCCIDIOMYCOSIS, OTHER PATIENTS

944
00:34:49,000 --> 00:34:50,320
WITH ON THE STUDIES OF MULTIPLE

945
00:34:50,320 --> 00:34:52,520
ENDOCRINAL DOMINANT HYPER IG

946
00:34:52,520 --> 00:34:54,480
SYNDROME AND STAT 3

947
00:34:54,480 --> 00:34:56,280
HAPLOINSUFFICIENCY CAN DEVELOP

948
00:34:56,280 --> 00:34:58,080
HISTOPLASMOSIS, THE FREQUENCY OF

949
00:34:58,080 --> 00:34:59,920
THOSE AS WHAT WE DISCUSS ABOUT

950
00:34:59,920 --> 00:35:01,440
ASPER GILLIS IS A BIT LESS

951
00:35:01,440 --> 00:35:02,840
CLEAR, A LOT OF PATIENTS IN

952
00:35:02,840 --> 00:35:04,520
ORDER TO GET THESE PATIENTS NEED

953
00:35:04,520 --> 00:35:06,920
TO GO TO ENDEMIC AREA, SO IT'S

954
00:35:06,920 --> 00:35:08,600
NOT LIKE ASPER GILLIS WHERE IT'S

955
00:35:08,600 --> 00:35:09,560
EVERYWHERE, AND A LOT OF

956
00:35:09,560 --> 00:35:11,200
PATIENTS ARE PUT ON EABT FUNGAL

957
00:35:11,200 --> 00:35:13,160
DRUGS BECAUSE THEY HAVE MUCOSAL

958
00:35:13,160 --> 00:35:15,320
[INDISCERNIBLE] THEY MIGHT HAVE

959
00:35:15,320 --> 00:35:16,600
MOLD SUSCEPTIBILITY SO THAT

960
00:35:16,600 --> 00:35:18,240
PROBABLY PROTECTS A LOT OF THEM

961
00:35:18,240 --> 00:35:19,520
FROM DEVELOPING INFECTIONS SO

962
00:35:19,520 --> 00:35:21,080
IT'S UNCLEAR HOW FREQUENT THAT

963
00:35:21,080 --> 00:35:23,400
MIGHT BE IN AUTOSOMAL DOMINANT

964
00:35:23,400 --> 00:35:24,600
HYPER ID SYNDROME BUT THERE ARE

965
00:35:24,600 --> 00:35:27,560
SEVERAL CASES THAT HAVE NOW BEEN

966
00:35:27,560 --> 00:35:27,840
REPORTED.

967
00:35:27,840 --> 00:35:31,040
NOW IN THIS SET OF INFECTIONS

968
00:35:31,040 --> 00:35:32,600
NUTRIFILLS ARE NOT CRITICAL FOR

969
00:35:32,600 --> 00:35:34,160
DEFENSE, AND NEWT ROUGH ATOM

970
00:35:34,160 --> 00:35:37,480
PENIC PATIENTS DON'T DEVELOP

971
00:35:37,480 --> 00:35:39,640
HISTOPLASMOSIS OR COXOSEIS, THE

972
00:35:39,640 --> 00:35:40,840
CLASSIC GROUP OF IMMUNO

973
00:35:40,840 --> 00:35:42,040
COMPROMISED PATIENTS THAT WE ALL

974
00:35:42,040 --> 00:35:45,560
LEARN THROUGH THE DECADES THAT

975
00:35:45,560 --> 00:35:46,200
CAUSE THE--PROMOTE

976
00:35:46,200 --> 00:35:48,080
SUSCEPTIBILITY AND HIV/AIDS SO

977
00:35:48,080 --> 00:35:53,520
DECREASE IN CD4 T-CELLS IS NOT

978
00:35:53,520 --> 00:35:54,440
GOOD.

979
00:35:54,440 --> 00:35:57,760
LETUZMAB WHICH CAN DEPOLICE THE

980
00:35:57,760 --> 00:36:00,200
CD4 T-CELLS CAN DESTROY THESE,

981
00:36:00,200 --> 00:36:04,720
IT'S ACTUALLY THE T-CELLS THAT

982
00:36:04,720 --> 00:36:05,320
PRODUCE INTERFERON-GAMMA

983
00:36:05,320 --> 00:36:08,080
NATURALLY THAT ACT ON THE

984
00:36:08,080 --> 00:36:09,040
RECEPTOR MACROPHAGES ACTIVATE

985
00:36:09,040 --> 00:36:11,400
JACK STAT SIGNALING THAT DRIVE

986
00:36:11,400 --> 00:36:13,480
MACROACTIVATION IN THE CROSS

987
00:36:13,480 --> 00:36:16,800
TALK TO HANDLE YEAST CELLS

988
00:36:16,800 --> 00:36:21,960
WHETHER IT'S HISTOPLASMA AND

989
00:36:21,960 --> 00:36:22,840
COCCIDIOMYCOSIS

990
00:36:22,840 --> 00:36:23,320
INTERRACELLULARLY OR

991
00:36:23,320 --> 00:36:24,040
ENDOSPHEREIOLES THAT BROKE OUT

992
00:36:24,040 --> 00:36:27,440
EARLY OR EXTRA CELLULARILY.

993
00:36:27,440 --> 00:36:29,040
SO YOU HEARD STEVE SAY THAT

994
00:36:29,040 --> 00:36:30,600
THROUGH THE YEAR THERE HAVE BEEN

995
00:36:30,600 --> 00:36:32,040
CLOSE TO 8 PATIENTS THAT HAVE

996
00:36:32,040 --> 00:36:33,440
BEEN IDENTIFY AS A PROOF OF

997
00:36:33,440 --> 00:36:35,720
CONCEPT THEY JUST TOLD THAT YOU

998
00:36:35,720 --> 00:36:37,680
THIS ACCESS IS CRITICAL FOR HOST

999
00:36:37,680 --> 00:36:39,240
DEFENSE AGAINST THE FUNGI BUT

1000
00:36:39,240 --> 00:36:39,800
ONLY 8 PATIENTS.

1001
00:36:39,800 --> 00:36:41,760
AND OUR PATIENT DID NOT HAVE

1002
00:36:41,760 --> 00:36:45,880
MUTATIONS IN THE

1003
00:36:45,880 --> 00:36:47,320
INTERFERON-GAMMA IL12AXIS.

1004
00:36:47,320 --> 00:36:49,160
SO IN SEARCH OF MORE THAN 6 OR 8

1005
00:36:49,160 --> 00:36:51,360
PATIENTS OUT OF THE THOUSANDS

1006
00:36:51,360 --> 00:36:53,520
PER YEAR, THAT DEVELOP

1007
00:36:53,520 --> 00:36:54,480
DISSEMINATED DISEASE, STEVE'S

1008
00:36:54,480 --> 00:36:56,080
GROUP PUBLISHED THIS ELEGANT

1009
00:36:56,080 --> 00:36:59,400
PAPER JUST A FEW MONTHS AGO,

1010
00:36:59,400 --> 00:37:00,840
THEY DID WHOLE EXOHM SEQUENCES

1011
00:37:00,840 --> 00:37:03,320
IN PATIENT WHO IS HAD

1012
00:37:03,320 --> 00:37:04,400
DISSEMINATED MYCOSIS AND

1013
00:37:04,400 --> 00:37:05,800
VERIFIED THOSE FINDINGS IN AN

1014
00:37:05,800 --> 00:37:06,880
INDEPENDENT COHORT OF PATIENT

1015
00:37:06,880 --> 00:37:09,760
WHO IS HAD DISSEMINATED

1016
00:37:09,760 --> 00:37:10,720
COCCIDIOMYCOSIS MYCOSIS AND IN

1017
00:37:10,720 --> 00:37:12,240
THIS CASE, THEY DIDN'T ONLY

1018
00:37:12,240 --> 00:37:14,120
FOCUS ON RARE DELETERIOUS

1019
00:37:14,120 --> 00:37:14,960
MUTATIONS LIKE THE 1S WE JUDGE

1020
00:37:14,960 --> 00:37:16,160
UOF THE DISCUSSED IN THE

1021
00:37:16,160 --> 00:37:18,360
PREVIOUS SLIDE BUT ALSO MORE

1022
00:37:18,360 --> 00:37:19,720
COMMON POPULATION VARIANCE, THAT

1023
00:37:19,720 --> 00:37:20,960
IS VARIANTS THAT MIGHT BE THERE

1024
00:37:20,960 --> 00:37:23,200
AND IN THE SETTING OF THE PROPER

1025
00:37:23,200 --> 00:37:27,040
EXPOSURE AND A VIRULENT FUNGUS,

1026
00:37:27,040 --> 00:37:28,120
COCCIDIOMYCOSIS, IT CAN ACTUALLY

1027
00:37:28,120 --> 00:37:31,880
CAUSE MORE SEVERE DISEASE.

1028
00:37:31,880 --> 00:37:36,280
AND INDEED, NOT THROUGH THE

1029
00:37:36,280 --> 00:37:38,400
INTERFERON-GAMMA 12 ACCESS BUT

1030
00:37:38,400 --> 00:37:40,880
THROUGH A FUNGAL PATHWAY OF

1031
00:37:40,880 --> 00:37:43,640
RECOGNITION THAT IS A PROLIFICT

1032
00:37:43,640 --> 00:37:46,800
DETECTEDIN 1 THAT RECOGNIZES

1033
00:37:46,800 --> 00:37:49,120
[INDISCERNIBLE], THAT THE

1034
00:37:49,120 --> 00:37:53,120
PLC GAMMA 2 AND 2 IMPORTANT

1035
00:37:53,120 --> 00:37:56,760
MOLECULES CALLED DUOX1 AND

1036
00:37:56,760 --> 00:38:02,000
DUOXAC1, ALL COMERS ENROLLED

1037
00:38:02,000 --> 00:38:04,640
PROSPECTIVELY WITHOUT BIAS, THAT

1038
00:38:04,640 --> 00:38:06,360
HAD MUTATIONS IN THE GENES.

1039
00:38:06,360 --> 00:38:08,520
SO GOING FROM 8 PATIENTS TO NOW

1040
00:38:08,520 --> 00:38:11,960
BEING ABLE TO UNDERSTAND 50% OF

1041
00:38:11,960 --> 00:38:13,920
THE WIDE DISSEMINATED

1042
00:38:13,920 --> 00:38:14,680
DISSEMINATED COCCIDIOMYCOSIS

1043
00:38:14,680 --> 00:38:14,920
HAPPENS.

1044
00:38:14,920 --> 00:38:18,680
NOW AGAIN OUR PATIENT DID DIDN'T

1045
00:38:18,680 --> 00:38:21,520
HAVE MUTATIONS IN THOSE GENES.

1046
00:38:21,520 --> 00:38:22,520
HOWEVER 1 POSSIBILITY WE'RE

1047
00:38:22,520 --> 00:38:23,800
CONSIDERING IS BECAUSE IN DATA

1048
00:38:23,800 --> 00:38:25,080
I'M NOT SHOWING HERE FOR THE

1049
00:38:25,080 --> 00:38:27,800
INTEREST OF TIME AMY AND STEVE

1050
00:38:27,800 --> 00:38:29,400
HAVE SHOWN THAT THOSE 2

1051
00:38:29,400 --> 00:38:32,560
MOLECULES HERE DEPEND ON STAT 3

1052
00:38:32,560 --> 00:38:34,160
FOR TRANSCRIPTION, IT IS

1053
00:38:34,160 --> 00:38:37,320
POSSIBLE THAT PERHAPS STAT 3

1054
00:38:37,320 --> 00:38:38,720
DEFICIENCY STATES IMPAIR THIS

1055
00:38:38,720 --> 00:38:41,680
ACCESS THAT LEADS TO EPITHELIAL

1056
00:38:41,680 --> 00:38:44,680
PARASITE PRODUCTION THAT MIGHT

1057
00:38:44,680 --> 00:38:46,240
HELP CONTROL COCCIDIOMYCOSIS.

1058
00:38:46,240 --> 00:38:50,360
AND IN FACT, DUOX1 MICE ARE

1059
00:38:50,360 --> 00:38:52,320
HIGHLY SUSCEPTIBLE, SO 1

1060
00:38:52,320 --> 00:38:54,240
POSSIBILITY THAT COULD PERHAPS

1061
00:38:54,240 --> 00:38:58,320
STAT 3 IS THROUGH THESE RECENT

1062
00:38:58,320 --> 00:38:58,880
DISCOVERY.

1063
00:38:58,880 --> 00:39:02,640
ANOTHER POSSIBILITY IS THAT, AS

1064
00:39:02,640 --> 00:39:03,640
I MENTIONED, LYMPHOCYTE

1065
00:39:03,640 --> 00:39:05,920
MACROPHAGE CROSS TALK AND

1066
00:39:05,920 --> 00:39:06,760
ULTIMATELY MACROPHAGE IS

1067
00:39:06,760 --> 00:39:08,560
IMPORTANT FOR CONTROLLING THESE

1068
00:39:08,560 --> 00:39:10,640
FUNGI, SO, 1 OTHER POSSIBILITY

1069
00:39:10,640 --> 00:39:14,640
IS THAT INDEPENDENT OF DUOX1 OR

1070
00:39:14,640 --> 00:39:18,400
IN CONCERT WITH DUOX1 IMPACTS,

1071
00:39:18,400 --> 00:39:19,560
PERHAPS ACTIVATION OF

1072
00:39:19,560 --> 00:39:21,080
MACROPHAGES THROUGH IL6 OR OTHER

1073
00:39:21,080 --> 00:39:24,400
CYTOKINES THAT DO RELY ON STAT 3

1074
00:39:24,400 --> 00:39:25,480
SIGNALING MIGHT BE SUBOPTIMAL

1075
00:39:25,480 --> 00:39:27,240
AND THAT'S NOTHING THAT HAS NOT

1076
00:39:27,240 --> 00:39:28,680
BEEN EXAMINED BEFORE.

1077
00:39:28,680 --> 00:39:30,480
IERVETION L6 INHIBITORS HAVE

1078
00:39:30,480 --> 00:39:32,560
BEEN REPORTED AS TNF INHIBITORS

1079
00:39:32,560 --> 00:39:35,440
AS YOU HEARD EARLIER TO START

1080
00:39:35,440 --> 00:39:37,040
THIS, THIS IS PLAUSIBLE,

1081
00:39:37,040 --> 00:39:38,160
TESTABLE AND SOMETHING THAT IS

1082
00:39:38,160 --> 00:39:40,080
IMPORTANT TO DO.

1083
00:39:40,080 --> 00:39:45,480
SO, WHERE ARE WE GOING FROM

1084
00:39:45,480 --> 00:39:45,680
HERE?

1085
00:39:45,680 --> 00:39:49,560
AMY IS HERE TO DO RNA SEQUENCING

1086
00:39:49,560 --> 00:39:51,360
OF BOTH STAT 3

1087
00:39:51,360 --> 00:39:52,480
HAPLOINSUFFICIENCY AND AUTOSOMAL

1088
00:39:52,480 --> 00:39:56,200
DOMINANT HYPER IG SYNDROME HUMAN

1089
00:39:56,200 --> 00:39:56,520
LEUKOCYTES.

1090
00:39:56,520 --> 00:39:58,520
FOLLOWING STIMULATION WITH

1091
00:39:58,520 --> 00:40:00,120
FUNGAL PATHOGENS AND/OR CERTAIN

1092
00:40:00,120 --> 00:40:01,920
STAT 3 ASSOCIATED CYTOKINES.

1093
00:40:01,920 --> 00:40:05,080
SO WHICH OF THOSE ARE IMPAIRED?

1094
00:40:05,080 --> 00:40:06,400
WHICH PATHWAYS ARE

1095
00:40:06,400 --> 00:40:08,000
DIFFERENTIALLY IMPAIRED WHEN YOU

1096
00:40:08,000 --> 00:40:10,800
ARE MISSING 50% VERSUS 75-80% OF

1097
00:40:10,800 --> 00:40:12,840
THE STAT 3 SIGNALING?

1098
00:40:12,840 --> 00:40:14,760
AS I ALLUDED EARLIER, I THINK WE

1099
00:40:14,760 --> 00:40:17,920
NEED TO REVISIT WHETHER THERE

1100
00:40:17,920 --> 00:40:20,400
MIGHT BE SUBTLE ASPER GILLIS

1101
00:40:20,400 --> 00:40:21,640
DEFECTS IN NUTRIFILLS FROM STAT

1102
00:40:21,640 --> 00:40:23,520
3 PATIENTS THAT PERHAPS IN THE

1103
00:40:23,520 --> 00:40:25,080
SETTING OF AUTOSOMAL DOMINANT

1104
00:40:25,080 --> 00:40:27,480
HYPER IG SYNDROME WHERE THE

1105
00:40:27,480 --> 00:40:29,640
RESTRUCTURAL LUNG DISEASE, THEN

1106
00:40:29,640 --> 00:40:31,080
THEY ADDED EFFECT CAN MAGNIFY

1107
00:40:31,080 --> 00:40:32,760
THE PROBLEM AND YOU END UP WITH

1108
00:40:32,760 --> 00:40:34,320
30% OF PATIENTS GETTING ASKER

1109
00:40:34,320 --> 00:40:36,800
GILLIS OR IN THE CONTEXT OF STAT

1110
00:40:36,800 --> 00:40:37,960
3 HAPLOINSUFFICIENCY, WITHOUT

1111
00:40:37,960 --> 00:40:39,160
THE STRUCTURAL LUNG DISEASE,

1112
00:40:39,160 --> 00:40:42,360
DEPENDING ON THE EXPOSURE OF THE

1113
00:40:42,360 --> 00:40:44,040
PATIENT MIGHT SUFFICE AS WELL TO

1114
00:40:44,040 --> 00:40:44,600
DO THAT.

1115
00:40:44,600 --> 00:40:47,400
DURING SOME OF THESE THINGS WILL

1116
00:40:47,400 --> 00:40:50,480
REQUIRE MOUSE WORK WHERE STAT 3

1117
00:40:50,480 --> 00:40:51,680
HAPPEN LO INSUFFICIENT MICE CAN

1118
00:40:51,680 --> 00:40:53,840
BE COMPARED WITH HYPER IG MICE,

1119
00:40:53,840 --> 00:40:55,720
AND ULTIMATELY TRY TO UNDERSTAND

1120
00:40:55,720 --> 00:40:57,880
BETTER THIS DISEASE, BOTH FROM

1121
00:40:57,880 --> 00:41:00,760
THE CONTEXT OF COCCIDIOMYCOSIS

1122
00:41:00,760 --> 00:41:02,600
BUT ALSO ASPERGILLOSIS, THERE IS

1123
00:41:02,600 --> 00:41:05,320
A VERY, VERY INTERESTING

1124
00:41:05,320 --> 00:41:07,400
PREDELEKS FOR THE CNS THAT IT'S

1125
00:41:07,400 --> 00:41:09,760
IMPORTANT TO UNDERSTAND THE

1126
00:41:09,760 --> 00:41:15,840
ANATOMICAL SIDE BY WHICH THESE

1127
00:41:15,840 --> 00:41:17,440
SPECIFIC ABERRANTS SEEM TO DRIVE

1128
00:41:17,440 --> 00:41:19,920
THESE SO NOT ONLY PULMONARY

1129
00:41:19,920 --> 00:41:21,320
THESE BEING PATHOGENS THAT ARE

1130
00:41:21,320 --> 00:41:22,840
INHALED BUT ESCAPE OF THAT AND

1131
00:41:22,840 --> 00:41:24,200
LANDING INTO THE BRAIN.

1132
00:41:24,200 --> 00:41:27,840
SO I WILL LEAVE YOU WITH THIS

1133
00:41:27,840 --> 00:41:30,560
SLIDE THAT HIGHLIGHTS IN IN

1134
00:41:30,560 --> 00:41:32,680
PARTICULAR REVIEW, THAT WAS

1135
00:41:32,680 --> 00:41:34,080
PUBLISHED RECENTLY, NOT JUST

1136
00:41:34,080 --> 00:41:35,600
STAT 3, BUT ALSO STAT 1 AND 6

1137
00:41:35,600 --> 00:41:37,920
THAT WILL FALL INTO THE PARADIGM

1138
00:41:37,920 --> 00:41:39,560
SO AS AMY SHOWEDDED EARLIER WE

1139
00:41:39,560 --> 00:41:42,200
HAVE A NORMAL ACTIVITY OF STAT 3

1140
00:41:42,200 --> 00:41:44,400
WHEN WE HAVE 2 COPIES THAT ARE

1141
00:41:44,400 --> 00:41:45,560
NOT MUTATED.

1142
00:41:45,560 --> 00:41:47,920
THERE IS A DISEASE ENTITY WE

1143
00:41:47,920 --> 00:41:50,000
DISCUSS TODAY WHICH IS GAIN OF

1144
00:41:50,000 --> 00:41:51,040
FUNCTION STAT 3.

1145
00:41:51,040 --> 00:41:51,760
THOSE ARE UNFORTUNATE PATIENT

1146
00:41:51,760 --> 00:41:53,040
WHO IS HAVE TOO MUCH OF STAT 3

1147
00:41:53,040 --> 00:41:55,000
AND IN THE KOVEN TEXT OF THAT,

1148
00:41:55,000 --> 00:41:57,440
THEY GET VERY SEVERE

1149
00:41:57,440 --> 00:41:59,040
INFLAMMATION AND AUTOIMMUNITY

1150
00:41:59,040 --> 00:42:00,800
AND ACTUALLY JACK INHIBITORS ARE

1151
00:42:00,800 --> 00:42:03,320
USED NOW TO BRING THAT SIGNALING

1152
00:42:03,320 --> 00:42:05,480
DOWN FROM HERE TO NORMAL IN

1153
00:42:05,480 --> 00:42:07,880
ORDER TO AMELIORATE SOME OF

1154
00:42:07,880 --> 00:42:08,480
THOSE DISEASE MANIFESTATIONS.

1155
00:42:08,480 --> 00:42:11,200
BUT IN THE LOSS OF FUNCTION OF

1156
00:42:11,200 --> 00:42:13,920
STAT 3, WE GET, IMMUNO

1157
00:42:13,920 --> 00:42:15,120
DEFICIENCY, SO THE WELL

1158
00:42:15,120 --> 00:42:17,200
DESCRIBED SYNDROME OF AUTOSOMAL

1159
00:42:17,200 --> 00:42:18,840
DOMINANT HYPER IG SYNDROME WHERE

1160
00:42:18,840 --> 00:42:20,760
AS AMY SHOWED YOU ABOUT 75 OR

1161
00:42:20,760 --> 00:42:26,800
80% OF THE STAT 3'S LOST IS A

1162
00:42:26,800 --> 00:42:28,520
SIM DROAM THAT CAUSES FUNGAL

1163
00:42:28,520 --> 00:42:31,440
DISEASE AS WE DISCUSSED IT NOW.

1164
00:42:31,440 --> 00:42:36,040
MANY PATIENTS DEVELOP SEVERE

1165
00:42:36,040 --> 00:42:36,960
STAPHYLOCOCCAL INFORMATIONS,

1166
00:42:36,960 --> 00:42:39,680
THEY GET SCOLIOSIS, IS OTHERS,

1167
00:42:39,680 --> 00:42:44,360
TISSUE REMODELING DEFECTS, VERY

1168
00:42:44,360 --> 00:42:44,720
SEVERE ASTROPHY.

1169
00:42:44,720 --> 00:42:46,080
AND TODAY WE SHOW YOU THAT THE

1170
00:42:46,080 --> 00:42:47,760
PATIENT THAT HER FAMILY

1171
00:42:47,760 --> 00:42:50,520
CONDUCTED, STEVE HERE A FEW

1172
00:42:50,520 --> 00:42:51,480
YEARS BACK, ARE OTHER

1173
00:42:51,480 --> 00:42:52,160
OBSERVATIONS THROUGH THE YEARS

1174
00:42:52,160 --> 00:42:53,800
OF A LOT OF PATIENTS THAT WERE

1175
00:42:53,800 --> 00:42:55,920
LISTED EARLIER BY AMY, THAT

1176
00:42:55,920 --> 00:42:57,440
THERE IS ANOTHER ENTITY OF STAT

1177
00:42:57,440 --> 00:43:02,200
3 DEFICIENCY THAT IS ABOUT AND

1178
00:43:02,200 --> 00:43:03,640
IN THAT PARTICULAR ENTITY ONLY

1179
00:43:03,640 --> 00:43:04,720
FUNGAL DEC HAPPENS.

1180
00:43:04,720 --> 00:43:08,800
I THINK RAISING VERY IMPORTANT

1181
00:43:08,800 --> 00:43:10,880
QUESTIONS WITH REGARDS TO HOW

1182
00:43:10,880 --> 00:43:12,120
50% MIGHT BE SUFFICIENT TO

1183
00:43:12,120 --> 00:43:14,080
PROTECT AGAINST ALL OF THESE

1184
00:43:14,080 --> 00:43:16,400
OTHER PROBLEMS HERE, HOW THOSE

1185
00:43:16,400 --> 00:43:18,240
RELATE TO THE SPECIFIC TISSUES,

1186
00:43:18,240 --> 00:43:20,200
THE SPECIFIC CELLS, SO SOME OF

1187
00:43:20,200 --> 00:43:22,440
THOSE WE COULD EVENTUALLY ANSWER

1188
00:43:22,440 --> 00:43:23,480
WITH EXPERIMENTAL APPROACHES WE

1189
00:43:23,480 --> 00:43:23,800
HAVE.

1190
00:43:23,800 --> 00:43:24,800
I THINK IT'S ALSO IMPORTANT IN

1191
00:43:24,800 --> 00:43:26,960
THE SETTING OF A LOT OF PATIENTS

1192
00:43:26,960 --> 00:43:29,760
BEING GIVEN JACK INHIBITORS, AND

1193
00:43:29,760 --> 00:43:32,400
WHETHER IT'S 50% OR GREATER THAN

1194
00:43:32,400 --> 00:43:34,120
50% JACK 1, JACK 2 INHIBITION

1195
00:43:34,120 --> 00:43:37,440
AND HOW THIS MIGHT AFFECT

1196
00:43:37,440 --> 00:43:38,720
BACTERIAL FUNCTION AND PERHAPS

1197
00:43:38,720 --> 00:43:40,000
OTHER PROBLEMS AS WELL AS SEEN

1198
00:43:40,000 --> 00:43:40,240
HERE.

1199
00:43:40,240 --> 00:43:41,320
WITH THAT I WOULD LIKE TO THANK

1200
00:43:41,320 --> 00:43:42,440
YOU FOR YOUR ATTENTION AND WE

1201
00:43:42,440 --> 00:43:45,080
ARE ALL HAPPY TO TAKE ANY

1202
00:43:45,080 --> 00:43:45,360
QUESTIONS.

1203
00:43:45,360 --> 00:43:55,560
[ APPLAUSE ]

1204
00:44:04,040 --> 00:44:04,840
>>PAM STRATEGIC PLANON,
THE

1205
00:44:04,840 --> 00:44:05,680
OBGYN IN THE ROOM.

1206
00:44:05,680 --> 00:44:07,560
I WOULD LIKE TO FOCUS ON THE

1207
00:44:07,560 --> 00:44:09,400
FACT THAT THIS WOMAN WAS

1208
00:44:09,400 --> 00:44:12,360
PREGNANT OR THIS OCCURRED AROUND

1209
00:44:12,360 --> 00:44:13,760
PREGNANCY BECAUSE I THINK THAT

1210
00:44:13,760 --> 00:44:15,360
THE VASCULAR CHANGES THAT HAPPEN

1211
00:44:15,360 --> 00:44:17,720
RELATED TO THE CENTRAL NERVOUS

1212
00:44:17,720 --> 00:44:20,000
SYSTEM THAT AREN'T WELL

1213
00:44:20,000 --> 00:44:21,280
UNDERSTOOD MAY CONTRIBUTE TO THE

1214
00:44:21,280 --> 00:44:24,800
FORMATION OF THE CNS FUNGAL

1215
00:44:24,800 --> 00:44:26,640
INFECTION AND SINCE WE CURRENTLY

1216
00:44:26,640 --> 00:44:27,960
HAVE A MATERNAL HEALTH CRISIS IN

1217
00:44:27,960 --> 00:44:30,840
THE UNITED STATES, I ENCOURAGE

1218
00:44:30,840 --> 00:44:33,600
YOU TO THINK ABOUT THE

1219
00:44:33,600 --> 00:44:35,880
RELATIONSHIP THAT OCCURS WITH

1220
00:44:35,880 --> 00:44:36,840
THE INFLECTION POINT OF

1221
00:44:36,840 --> 00:44:41,080
PREGNANCY AND IN DISEASES LIKE

1222
00:44:41,080 --> 00:44:41,560
THIS.

1223
00:44:41,560 --> 00:44:43,040
>>THANK, PAM AND AS STEVE

1224
00:44:43,040 --> 00:44:44,720
ALLUDED TO THERE'S A SELECT

1225
00:44:44,720 --> 00:44:48,040
GROUP OF PATHOGENS THAT ACTUALLY

1226
00:44:48,040 --> 00:44:48,680
CAUSE DISEASE, LISTERIA WHICH

1227
00:44:48,680 --> 00:44:50,280
ALWAYS GOES TO THE BRAIN ALSO,

1228
00:44:50,280 --> 00:44:50,480
SO.

1229
00:44:50,480 --> 00:44:53,120
>>THANK YOU PAM FOR
SETTING UP

1230
00:44:53,120 --> 00:44:54,760
MY QUESTION WHICH IS WITH CASE

1231
00:44:54,760 --> 00:45:00,520
1, TO ME IT SEEMS QUITE

1232
00:45:00,520 --> 00:45:08,920
MIRACULOUS BUT DESPITE THE

1233
00:45:08,920 --> 00:45:09,840
POSSIBLY ITIS DURING PREGNANCY

1234
00:45:09,840 --> 00:45:14,360
THE SON IS NORMAL, SO I WAS

1235
00:45:14,360 --> 00:45:16,680
WONDERING OF COCCIDIOMYCOSIS WAS

1236
00:45:16,680 --> 00:45:18,520
FETAL DEMISE, SO ANY THOUGHTS ON

1237
00:45:18,520 --> 00:45:19,960
WHY THE FETUS WAS SPARED AND THE

1238
00:45:19,960 --> 00:45:22,400
CHILD IS QUITE HEALTHY?

1239
00:45:22,400 --> 00:45:24,000
>>STEVE HAVE YOU
ENCOUNTER

1240
00:45:24,000 --> 00:45:24,800
OTHER COCCIDIOMYCOSIS CASES

1241
00:45:24,800 --> 00:45:27,280
THROUGHOUT THE YEARS WITH

1242
00:45:27,280 --> 00:45:27,560
PREGNANCY?

1243
00:45:27,560 --> 00:45:29,640
MAYBE CAN YOU COMMENT ON THIS?

1244
00:45:29,640 --> 00:45:33,320
>>SO THANKS, I THINK IT'S
A

1245
00:45:33,320 --> 00:45:34,160
CRITICALLY IMPORTANT QUESTION.

1246
00:45:34,160 --> 00:45:36,720
SHE ACTUALLY GOT SICK RIGHT

1247
00:45:36,720 --> 00:45:40,040
BEFORE PREGNANCY WITH A FLU-LIKE

1248
00:45:40,040 --> 00:45:40,320
SYNDROME.

1249
00:45:40,320 --> 00:45:43,440
AND SHE HAD WHAT THEY CALLED

1250
00:45:43,440 --> 00:45:45,400
MONO, AS IS TYPICALLY THE CASE,

1251
00:45:45,400 --> 00:45:48,680
AND HAD A LITTLE BIT OF EMILY

1252
00:45:48,680 --> 00:45:50,240
NODE ADEN OPEN MEETINGATHY AND

1253
00:45:50,240 --> 00:45:51,520
THAT POINT SHE STARTED HER

1254
00:45:51,520 --> 00:45:52,840
TREATMENT AS I UNDERSTAND IT AND

1255
00:45:52,840 --> 00:45:57,040
THEN SHE GOT SICK DURING

1256
00:45:57,040 --> 00:45:57,880
PREGNANCY STILL WAS ABLE TO

1257
00:45:57,880 --> 00:45:59,280
DELIVER BUT I BELIEVE SHE WAS ON

1258
00:45:59,280 --> 00:46:00,480
TREATMENT WHEN THAT HAPPENED SO

1259
00:46:00,480 --> 00:46:05,160
I DON'T KNOW WHAT THE FREQUENCY

1260
00:46:05,160 --> 00:46:06,040
OF TRANSMISSION TRANSPLACENTA

1261
00:46:06,040 --> 00:46:08,280
SENTALLY IS, IT'S NOT A HUNDRED%

1262
00:46:08,280 --> 00:46:11,560
FOR SURE, AND IN THIS PARTICULAR

1263
00:46:11,560 --> 00:46:13,400
CASE THE CHILD WAS NOT ONLY

1264
00:46:13,400 --> 00:46:15,160
HEALTHY AT DELIVERY BUT WHEN WE

1265
00:46:15,160 --> 00:46:17,600
WENT BACK EVENTUALLY AND CHECKED

1266
00:46:17,600 --> 00:46:19,360
HIM GENETICALLY HE WAS

1267
00:46:19,360 --> 00:46:20,160
UNAFFECTED.

1268
00:46:20,160 --> 00:46:22,280
>>AND RELATED TO THAT,
WHY WE

1269
00:46:22,280 --> 00:46:23,040
THINK THE RECURRENCE--I THINK IT

1270
00:46:23,040 --> 00:46:26,480
WAS A YEAR LATER?

1271
00:46:26,480 --> 00:46:27,800
>>I CAN'T ANSWER THAT.

1272
00:46:27,800 --> 00:46:31,720
I THINK, SO YOU KNOW I NEVER MET

1273
00:46:31,720 --> 00:46:33,720
THIS PATIENT IN LIFE AND GETTING

1274
00:46:33,720 --> 00:46:40,720
RECORDS HAS BEEN COMPLEX.

1275
00:46:40,720 --> 00:46:41,720
TO BE BRIEF.

1276
00:46:41,720 --> 00:46:43,520
SO I CAN'T SPEAK TO ALL OF THOSE

1277
00:46:43,520 --> 00:46:44,560
NUANCES, I THINK SHE WAS ON

1278
00:46:44,560 --> 00:46:46,120
TREATMENT FOR AT LEAST PART OF

1279
00:46:46,120 --> 00:46:47,000
THE TIME FOLLOWING PREGNANCY.

1280
00:46:47,000 --> 00:46:49,560
WHAT I DON'T KNOW IS WHETHER SHE

1281
00:46:49,560 --> 00:46:51,400
WENT THROUGH A PERIOD WHEN SHE

1282
00:46:51,400 --> 00:46:54,040
WAS OFF THERAPY AND THAT WAS

1283
00:46:54,040 --> 00:46:56,000
DURING THAT THAT SHE RELAPSED IN

1284
00:46:56,000 --> 00:46:56,640
THE CNS.

1285
00:46:56,640 --> 00:46:59,680
I SUSPECT THAT IT'S TRUE AS PAM

1286
00:46:59,680 --> 00:47:03,000
SUGGESTS THAT HER FUNDAMENTAL

1287
00:47:03,000 --> 00:47:04,720
DISSEMINATION AND SEVERE DISEASE

1288
00:47:04,720 --> 00:47:06,040
WAS DURING PREGNANCY AND IT WAS

1289
00:47:06,040 --> 00:47:07,760
DURING THAT TIME THAT I WAS TOLD

1290
00:47:07,760 --> 00:47:09,520
SHE DEVELOPED A DRAINING SINUS

1291
00:47:09,520 --> 00:47:10,960
OUT OF HER LEFT SHOULDER.

1292
00:47:10,960 --> 00:47:14,120
SO I SUSPECT THAT SHE HAD

1293
00:47:14,120 --> 00:47:15,200
DISSEMINATED DISEASE BECAUSE OF

1294
00:47:15,200 --> 00:47:16,920
HER STAT 3 MUTATION, BUT THAT

1295
00:47:16,920 --> 00:47:18,800
GOT WORSE BECAUSE OF PREGNANCY

1296
00:47:18,800 --> 00:47:20,640
AND IT MAY BE THAT DURING

1297
00:47:20,640 --> 00:47:22,560
PREGNANCY SHE CAME BACK INTO

1298
00:47:22,560 --> 00:47:26,520
CARE AND HAD SOME FLUCONASAL FOR

1299
00:47:26,520 --> 00:47:28,120
A WHILE BUT SOMEWHERE ALONG THE

1300
00:47:28,120 --> 00:47:30,160
LINE GOT PRESCRIBING OPERATELY

1301
00:47:30,160 --> 00:47:31,440
ILL AND I CAN'T EXPLAIN WHY

1302
00:47:31,440 --> 00:47:33,880
THINGS GOT WORSE A YEAR LATER.

1303
00:47:33,880 --> 00:47:36,080
I DON'T KNOW THE ANSWER TO THAT.

1304
00:47:36,080 --> 00:47:38,360
>>THANK YOU.

1305
00:47:38,360 --> 00:47:38,920
>>STEVE, [INDISCERNIBLE]

1306
00:47:38,920 --> 00:47:40,840
ALLUDED TO THIS A BIT AS HE

1307
00:47:40,840 --> 00:47:42,520
ENDED THE TALK.

1308
00:47:42,520 --> 00:47:44,240
YOU KNOW JACK STAT INHIBITORS

1309
00:47:44,240 --> 00:47:46,320
ARE USED FOR MORE AND MORE

1310
00:47:46,320 --> 00:47:47,240
INDICATIONS SHOW WORRIED SHOULD

1311
00:47:47,240 --> 00:47:49,120
WE BE ABOUT LOOKING FOR THESE

1312
00:47:49,120 --> 00:47:50,520
KINDS OF INFECTIONS IN PATIENTS

1313
00:47:50,520 --> 00:47:53,760
WHO ARE ON JACK STAT INHIBITORS?

1314
00:47:53,760 --> 00:47:55,160
AND SHOULD WE BE PROVE LACTIC

1315
00:47:55,160 --> 00:47:56,200
ACIDOSEISING PATIENT WHO IS ARE

1316
00:47:56,200 --> 00:47:59,480
ON JACK STAT INHIBITORS?

1317
00:47:59,480 --> 00:48:01,240
>>SO SO, YOU KNOW JACK

1318
00:48:01,240 --> 00:48:04,000
INHIBITORS ARE PUT IN THE WATER

1319
00:48:04,000 --> 00:48:06,040
THESE DAYS AND OF COURSE EVERY

1320
00:48:06,040 --> 00:48:08,240
JACK INHIBITOR IS DIFFERENT WHAT

1321
00:48:08,240 --> 00:48:08,960
THE UNDERLYING DISEASE IS

1322
00:48:08,960 --> 00:48:10,920
DIFFERENT AND THE DOSE OF THE

1323
00:48:10,920 --> 00:48:13,880
JACK INHIBITOR BECAUSE THESE

1324
00:48:13,880 --> 00:48:16,240
EXHIBIT DOSE EFFICACY AND

1325
00:48:16,240 --> 00:48:18,960
TOXICITY AND WHETHER YOU HAVE

1326
00:48:18,960 --> 00:48:20,040
JACK INHIBITOR WHETHER ON

1327
00:48:20,040 --> 00:48:21,800
STEROIDS OR SOMEONE GETS A JACK

1328
00:48:21,800 --> 00:48:23,800
INHIBITOR BUT THERE ARE CLEAR

1329
00:48:23,800 --> 00:48:26,120
REPORTS OF INDEMMIC FUNGAL

1330
00:48:26,120 --> 00:48:27,160
INFECTIONS AND MACROPHAGE FUNGAL

1331
00:48:27,160 --> 00:48:30,040
DISEASE, I THINK THAT TOGETHER

1332
00:48:30,040 --> 00:48:32,200
WITH MICROBACTERIAL INFECTIONS

1333
00:48:32,200 --> 00:48:35,720
AND VIRAL INFECTIONS WITH THE

1334
00:48:35,720 --> 00:48:36,240
INTERRACELLULARLY HANDLED

1335
00:48:36,240 --> 00:48:37,600
PATHOGENS, I THINK THAT'S QUITE

1336
00:48:37,600 --> 00:48:37,840
CLEAR.

1337
00:48:37,840 --> 00:48:40,240
THERE ARE SOME REPORTS OF

1338
00:48:40,240 --> 00:48:41,440
ASPERGILLOSIS, NOT MANY, BUT AS

1339
00:48:41,440 --> 00:48:42,640
YOU ARE AWARE, MOST OF THE

1340
00:48:42,640 --> 00:48:47,840
TRIALS WHEN THE DRUG IS GETTING

1341
00:48:47,840 --> 00:48:49,480
APPROVED, TELLS US HALF IF NOT

1342
00:48:49,480 --> 00:48:51,480
THAT THE TRUE TO SUSCEPTIBILITY

1343
00:48:51,480 --> 00:48:53,720
TO A BIOLOGIC MIGHT BE DOWN THE

1344
00:48:53,720 --> 00:48:54,320
LINE.

1345
00:48:54,320 --> 00:48:55,440
THE QUESTION OF PROPHYLAXIS

1346
00:48:55,440 --> 00:48:56,960
COMES DOWN TO WHAT IS THE NUMBER

1347
00:48:56,960 --> 00:48:59,560
OF INFECTIONS AND HOW MANY OF

1348
00:48:59,560 --> 00:49:01,560
THEM ARE IN THE DENOMINATOR OF

1349
00:49:01,560 --> 00:49:05,160
THE TOTAL NUMBER OF PATIENTS AND

1350
00:49:05,160 --> 00:49:06,800
THEN HOW MANY YOU NEED TO TREAT

1351
00:49:06,800 --> 00:49:08,520
WITH WHAT DRUG AND HOW TOXIC IT

1352
00:49:08,520 --> 00:49:10,440
WILL BE AND A THING I'M

1353
00:49:10,440 --> 00:49:12,480
CONVINCED FOR HISTOAND COX AND

1354
00:49:12,480 --> 00:49:13,680
ENDEMIC LAYERS EVERYBODY NEEDS

1355
00:49:13,680 --> 00:49:17,400
TO BE ON FLUCONASALL.

1356
00:49:17,400 --> 00:49:20,800
THE ADD COMPLICATION THERE IS

1357
00:49:20,800 --> 00:49:22,440
THAT THERE'S INHIBITORS BETWEEN

1358
00:49:22,440 --> 00:49:25,560
JACK INHIBITORS AND ASOLs, SO

1359
00:49:25,560 --> 00:49:28,320
UNLESS THERE'S A COMPELLING

1360
00:49:28,320 --> 00:49:29,800
EPIDEM YOJICAL SIGNAL SO FOR

1361
00:49:29,800 --> 00:49:37,400
PATIENTS WE PUT PATIENTS ON

1362
00:49:37,400 --> 00:49:38,360
VALCYCLOVIRAND IT IS A SAFE

1363
00:49:38,360 --> 00:49:39,440
DRUG, SO I THINK WE WILL SEE

1364
00:49:39,440 --> 00:49:41,200
MORE OF THEM BUT IT'S GOING TO

1365
00:49:41,200 --> 00:49:43,160
BE DEPENDING ON THE DOSE THAT

1366
00:49:43,160 --> 00:49:44,200
PATIENT POPULATION AND I THINK

1367
00:49:44,200 --> 00:49:45,720
UNTIL WE HAVE MORE OF THAT

1368
00:49:45,720 --> 00:49:47,760
INFORMATION, IT WILL BE MORE

1369
00:49:47,760 --> 00:49:50,120
DIFFICULT TO ESTABLISH

1370
00:49:50,120 --> 00:49:53,640
PROPHYLAXIS REGIMENS.

1371
00:49:53,640 --> 00:49:54,400
>>THANK YOU.

1372
00:49:54,400 --> 00:49:55,720
>>THANKS FOR THE
INTERESTING

1373
00:49:55,720 --> 00:49:56,920
PRESENTATION, I WAS WONDERING

1374
00:49:56,920 --> 00:49:58,400
ABOUT THE AUTOPSIES IF SOMEONE

1375
00:49:58,400 --> 00:50:00,320
COULD LIKE ELABORATE A BIT MORE

1376
00:50:00,320 --> 00:50:03,320
ON INTERESTING FINDINGS IN TERMS

1377
00:50:03,320 --> 00:50:12,680
OF NEUROSTUFF THAT WAS GOING ON?

1378
00:50:12,680 --> 00:50:14,600
>>DAVID?

1379
00:50:14,600 --> 00:50:15,520
>>WELL, I THINK IN THIS

1380
00:50:15,520 --> 00:50:17,240
PARTICULAR CASE, THE MAIN THING

1381
00:50:17,240 --> 00:50:19,680
THAT WE FOUND WAS THE

1382
00:50:19,680 --> 00:50:20,880
DISSEMINATED INFECTION AND THE

1383
00:50:20,880 --> 00:50:21,360
CONSEQUENCES OF THAT.

1384
00:50:21,360 --> 00:50:27,000
SO THERE WAS A STRUCTURAL DAMAGE

1385
00:50:27,000 --> 00:50:28,040
IN THE LUNG.

1386
00:50:28,040 --> 00:50:30,440
BRONCHIECTASIS IS OFTEN SEEN IN

1387
00:50:30,440 --> 00:50:31,560
THESE PATIENTS FOR MECHANISMS

1388
00:50:31,560 --> 00:50:34,280
THAT I DON'T FULLY UNDERSTAND

1389
00:50:34,280 --> 00:50:36,760
MYSELF BUT IT CREATES AN

1390
00:50:36,760 --> 00:50:40,560
OPPORTUNITY FOR MORE INFECTION

1391
00:50:40,560 --> 00:50:45,520
IN THIS ALTERED ARCHITECTURE.

1392
00:50:45,520 --> 00:50:49,840
THERE WEREN'T ANY BRAIN FINDINGS

1393
00:50:49,840 --> 00:50:50,640
SPECIFICALLY OUTSIDE THE DAMAGE

1394
00:50:50,640 --> 00:50:54,040
THAT WAS CAUSED BY THE

1395
00:50:54,040 --> 00:50:56,880
HEMORRHAGE AND YOU KNOW THAT

1396
00:50:56,880 --> 00:50:58,680
PRIMARILY WAS--IS A PRESSURE

1397
00:50:58,680 --> 00:51:03,000
MEDIATED DEATH AND WHEN YOU GET

1398
00:51:03,000 --> 00:51:06,920
HEMORRHAGE INTO THE BRAIN, BUT

1399
00:51:06,920 --> 00:51:10,120
IN GENERAL, IN AUTOPSIES THAT WE

1400
00:51:10,120 --> 00:51:12,560
PERFORM HERE WE DO TAKE KIND OF

1401
00:51:12,560 --> 00:51:15,920
A WHOLISTIC APPROACH TO WHAT WE

1402
00:51:15,920 --> 00:51:18,680
DO AND IN CONTRAST TO SOME OTHER

1403
00:51:18,680 --> 00:51:22,520
PROGRAMS THAT I'M AWARE OF WHERE

1404
00:51:22,520 --> 00:51:24,040
THE PATHOLOGIST WILL ASK, YOU

1405
00:51:24,040 --> 00:51:25,680
KNOW WHAT ARE THE SPECIFIC

1406
00:51:25,680 --> 00:51:27,160
QUESTIONS THAT THE CLINICIAN HAS

1407
00:51:27,160 --> 00:51:31,440
AND JUST GO AFTER THOSE

1408
00:51:31,440 --> 00:51:34,600
PARTICULAR TARGETS, WE WILL LOOK

1409
00:51:34,600 --> 00:51:36,240
AT EVERYTHING WE SUBMIT

1410
00:51:36,240 --> 00:51:39,160
MICROSCOPIC, YOU KNOW TISSUES ON

1411
00:51:39,160 --> 00:51:39,760
EVERYTHING.

1412
00:51:39,760 --> 00:51:43,360
SO, OUR CHANCES OF PICKING UP

1413
00:51:43,360 --> 00:51:46,240
EXTRA FINDINGS, I THINK ARE GOOD

1414
00:51:46,240 --> 00:51:49,120
AND OFTEN TIMES YOU KNOW LATER

1415
00:51:49,120 --> 00:51:50,120
ON QUESTIONS ARISE, WELL, YOU

1416
00:51:50,120 --> 00:51:51,760
KNOW THIS WAS HAPPENING IN LIFE,

1417
00:51:51,760 --> 00:51:53,800
IS THERE AN EXPLANATION FOR

1418
00:51:53,800 --> 00:51:54,000
THAT?

1419
00:51:54,000 --> 00:51:59,840
AND SOMETIMES WE'RE ABLE TO

1420
00:51:59,840 --> 00:52:00,440
PROVIDE AN ANSWER.

1421
00:52:00,440 --> 00:52:01,800
>>THANK YOU FOR THE

1422
00:52:01,800 --> 00:52:02,120
PRESENTATION.

1423
00:52:02,120 --> 00:52:04,600
I WAS JUST CURIOUS ABOUT THE

1424
00:52:04,600 --> 00:52:06,480
CONCEPT OF PROPHYLACTICS AND THE

1425
00:52:06,480 --> 00:52:08,280
OTHER 1S, SO I'M LOOKING AT IT

1426
00:52:08,280 --> 00:52:10,040
FROM THE POINT OF THE COMMON--I

1427
00:52:10,040 --> 00:52:13,640
THINK SOMEBODY TALKED ABOUT THE

1428
00:52:13,640 --> 00:52:15,520
COMMON VARIANT IN ASPER GILLIS

1429
00:52:15,520 --> 00:52:17,280
THAT HAS BEEN IDENTIFY ALSO, SO

1430
00:52:17,280 --> 00:52:19,080
LOOKING FOR THE FURTHER EVIDENCE

1431
00:52:19,080 --> 00:52:21,280
OF THIS CONDITION SEEMS TO BE

1432
00:52:21,280 --> 00:52:22,760
HIGHER IN CERTAIN POPULATION DOE

1433
00:52:22,760 --> 00:52:26,840
WE KNOW IF SOME OF THESE

1434
00:52:26,840 --> 00:52:27,760
VARIANTS [INDISCERNIBLE]

1435
00:52:27,760 --> 00:52:30,040
POPULATIONS AS WE COULD THINK

1436
00:52:30,040 --> 00:52:36,120
ABOUT PROPHYLACTICS FOR THE

1437
00:52:36,120 --> 00:52:37,320
INDUCED POPULATION?

1438
00:52:37,320 --> 00:52:45,320
>>SO THAT'S A GREAT
QUESTION.

1439
00:52:45,320 --> 00:52:47,720
WHAT WE SAW WAS THE COMMON

1440
00:52:47,720 --> 00:52:52,200
VARIANT, 1 TENDS TO BE NORTHERN

1441
00:52:52,200 --> 00:52:53,240
EUROPEAN TRICKLING THROUGH AND

1442
00:52:53,240 --> 00:52:56,200
THE OTHER TENDS TO BE SPECIFIC

1443
00:52:56,200 --> 00:52:58,440
TO AFRICAN AND AFRICAN DESCENT.

1444
00:52:58,440 --> 00:53:00,000
SO THAT'S 1 AND WE DEMONSTRATED

1445
00:53:00,000 --> 00:53:04,000
IN KEEPING WITH THE IDEA THAT

1446
00:53:04,000 --> 00:53:05,840
TNF INHIBITORS ARE MAJOR RISK

1447
00:53:05,840 --> 00:53:09,040
FACTORS PATIENTS WITH DETECTEDIN

1448
00:53:09,040 --> 00:53:12,240
1 OR PLC12, DON'T STIMULATE SO

1449
00:53:12,240 --> 00:53:14,400
THAT APPEARS TO BE THE

1450
00:53:14,400 --> 00:53:16,400
MECHANISM, THE PLC VARIANT IS A

1451
00:53:16,400 --> 00:53:17,560
NORTHERN EUROPEAN VARIANT SO WE

1452
00:53:17,560 --> 00:53:19,320
DIDN'T SEE IT AMONG THE AFRICAN

1453
00:53:19,320 --> 00:53:23,960
DESCENT PEOPLE IN THE COHORT,

1454
00:53:23,960 --> 00:53:28,560
THE DUOX1 AND DUOXONCEA TEND TO

1455
00:53:28,560 --> 00:53:31,200
BE THE INDIVIDUALS FROM AFRICAN

1456
00:53:31,200 --> 00:53:31,680
HISPANIC DESCENT.

1457
00:53:31,680 --> 00:53:36,440
THE DIFFERENCE THERE IS THAT THE

1458
00:53:36,440 --> 00:53:39,400
PLC GAMMA 2 INDETECTEDIN 1OR

1459
00:53:39,400 --> 00:53:40,040
INDIVIDUAL SPECIFIC MUTATIONS OR

1460
00:53:40,040 --> 00:53:42,840
VALID 

1461
00:53:42,840 --> 00:53:45,480
VARIANTS SO WE CAN LOOK FOR 4 TO

1462
00:53:45,480 --> 00:53:48,880
ENCOMAS ALL OF THAT.

1463
00:53:48,880 --> 00:53:50,080
THE DUOX1 VARIANTS AND HEECH

1464
00:53:50,080 --> 00:53:51,680
PERSON HAD THEIR OWN UNIQUE

1465
00:53:51,680 --> 00:53:53,320
VARIANT SO IT'S HARDER, WE COULD

1466
00:53:53,320 --> 00:53:54,320
MAKE A PREDICTION BUT THEN

1467
00:53:54,320 --> 00:53:57,080
YOU'RE TALKING ABOUT DOING EXOHM

1468
00:53:57,080 --> 00:54:00,960
OR GENOME SEQUENCING ON EACH

1469
00:54:00,960 --> 00:54:01,240
PERSON.

1470
00:54:01,240 --> 00:54:03,000
IT MAY MAKE MORE SENSE IF YOU

1471
00:54:03,000 --> 00:54:05,280
THOUGHT ABOUT DOING IT

1472
00:54:05,280 --> 00:54:06,480
PROPHYLACTICALLY TO DEVELOP A

1473
00:54:06,480 --> 00:54:07,200
FUNCTIONAL ASSAY WHERE IT

1474
00:54:07,200 --> 00:54:09,840
DOESN'T MATTER THEN WHAT THE

1475
00:54:09,840 --> 00:54:11,280
UNDERLYING GENETICS ARE BUT YOUR

1476
00:54:11,280 --> 00:54:12,920
RISK BACK IN THE ENVELOPE

1477
00:54:12,920 --> 00:54:14,760
CALCULATION SAYS YOUR RISK OF

1478
00:54:14,760 --> 00:54:17,880
GETTING INFECTED IN THE ENDEMIC

1479
00:54:17,880 --> 00:54:20,640
AREA IS 3% OF THE YEAR, SO CAN

1480
00:54:20,640 --> 00:54:21,840
YOU LIVE THERE 30 YEARS AND

1481
00:54:21,840 --> 00:54:23,320
NEVER GET INFECTED SO YOU'RE

1482
00:54:23,320 --> 00:54:24,080
PLAYING THAT GAME, TOO.

1483
00:54:24,080 --> 00:54:28,320
IF YOU THINK ABOUT THE

1484
00:54:28,320 --> 00:54:31,240
POPULATION AND THERE ARE ONLY

1485
00:54:31,240 --> 00:54:33,720
150,000 INFECTIONS PER YEAR.

1486
00:54:33,720 --> 00:54:36,440
>>YEAH, MAYBE SOMETHING
LIKE

1487
00:54:36,440 --> 00:54:37,480
[INDISCERNIBLE] WHERE YOU

1488
00:54:37,480 --> 00:54:38,600
[INDISCERNIBLE] JUST HAVING LIKE

1489
00:54:38,600 --> 00:54:41,160
AN AREA OF THOSE SPECIFIC GENES

1490
00:54:41,160 --> 00:54:43,000
[INDISCERNIBLE] FOR THEM AND

1491
00:54:43,000 --> 00:54:45,160
THOSE POPULATION FOR

1492
00:54:45,160 --> 00:54:46,840
SO--[INDISCERNIBLE] MAYBE THAT'S

1493
00:54:46,840 --> 00:54:47,640
SOMETHING YOU CAN--

1494
00:54:47,640 --> 00:54:48,800
>>YEAH, YEAH, I THINK THE
OTHER

1495
00:54:48,800 --> 00:54:53,000
THING THEY ARE DOING IS A

1496
00:54:53,000 --> 00:54:57,000
VACCINE IS IN DEVELOPMENT AND

1497
00:54:57,000 --> 00:54:58,920
IT'S--THEY'VE DONE DOG TRIALS,

1498
00:54:58,920 --> 00:54:59,640
THEY'RE STARTING A FIRST IN

1499
00:54:59,640 --> 00:55:02,280
HUMAN TRIAL AND IT MAY MAKE MORE

1500
00:55:02,280 --> 00:55:03,440
SENSE TO SIMPLY VACCINATE PEOPLE

1501
00:55:03,440 --> 00:55:06,880
WHO MIGHT BE AT HIGHER RISK

1502
00:55:06,880 --> 00:55:09,280
VAGHTER THAN DOING GENETICS.

1503
00:55:09,280 --> 00:55:12,040
>>THANK YOU.

1504
00:55:12,040 --> 00:55:12,920
>>YEAH.

1505
00:55:12,920 --> 00:55:16,480
>>HI, I'M A GENETICIST
AND A

1506
00:55:16,480 --> 00:55:19,120
STAFF CLINICIAN AT NHGRI AND I

1507
00:55:19,120 --> 00:55:22,720
WAS JUST  CURIOUS ABOUT THE

1508
00:55:22,720 --> 00:55:25,120
PATIENT AND HOW THE PATIENT WAS

1509
00:55:25,120 --> 00:55:26,400
PARENTALLY HEALTHY BEFORE SO I

1510
00:55:26,400 --> 00:55:27,880
THINK IT WAS JUST SO

1511
00:55:27,880 --> 00:55:28,360
INTERESTING.

1512
00:55:28,360 --> 00:55:30,360
HAVE YOU CONSIDERED LOOKING AT

1513
00:55:30,360 --> 00:55:33,680
DATABASES LIKE THE ALL OF US

1514
00:55:33,680 --> 00:55:35,720
WHERE IT'S WHOLE EXOHM

1515
00:55:35,720 --> 00:55:38,240
SEQUENCING OF LARGE NUMBER OF

1516
00:55:38,240 --> 00:55:38,840
APPARENTLY HEALTHY INDIVIDUALS

1517
00:55:38,840 --> 00:55:41,720
AND IF YOU CAN PICK UP ANY OF

1518
00:55:41,720 --> 00:55:43,800
THOSE INDIVIDUALS WHO HAVE

1519
00:55:43,800 --> 00:55:46,200
HETEROZYGOUS LOSS OF FUNCTION

1520
00:55:46,200 --> 00:55:47,480
MUTATIONS EEVALUATE THEM WHEN

1521
00:55:47,480 --> 00:55:49,400
THEY'RE HEALTHY, I DON'T KNOW.

1522
00:55:49,400 --> 00:55:49,920
>>RIGHT.

1523
00:55:49,920 --> 00:55:51,840
WE HAVEN'T PURSUED THE ALL OF US

1524
00:55:51,840 --> 00:55:55,320
DATABASE YET, I MEAN IT WASN'T

1525
00:55:55,320 --> 00:55:56,960
AVAILABLE FOR PUBLIC COMSUMPTION

1526
00:55:56,960 --> 00:55:58,560
UNTIL RECENTLY, SO WHEN WE DID

1527
00:55:58,560 --> 00:56:02,520
THIS, THIS WAS A YEAR AGO WHAT

1528
00:56:02,520 --> 00:56:03,680
WE WELL TO WORK WITH WAS

1529
00:56:03,680 --> 00:56:04,640
NATIONAL LIBRARY OF MEDICINEAD

1530
00:56:04,640 --> 00:56:07,320
AND THERE WAS 1 PATIENT IN NOMAD

1531
00:56:07,320 --> 00:56:09,880
WITH A STAT 3 VARIANT.

1532
00:56:09,880 --> 00:56:14,320
BY CONTRAST THE DETECTEDIN 1 AND

1533
00:56:14,320 --> 00:56:16,600
PLC 2 VARIANTS ARE 7%

1534
00:56:16,600 --> 00:56:17,160
POPULATION.

1535
00:56:17,160 --> 00:56:17,600
>>MUCH MORE REAL.

1536
00:56:17,600 --> 00:56:19,400
>>AND THOSE WE CAN GET
HERE

1537
00:56:19,400 --> 00:56:20,920
FROM THE NIH BLOOD BANK.

1538
00:56:20,920 --> 00:56:23,000
WE CAN FIND PEOPLE WHO ARE

1539
00:56:23,000 --> 00:56:27,320
HETEROGENEOUS ORY ZYGOUS,

1540
00:56:27,320 --> 00:56:28,600
DUOX DUOX1, BECAUSE EACH PERSON

1541
00:56:28,600 --> 00:56:30,440
HAS A SPECIFIC VARIANT THEN YOU

1542
00:56:30,440 --> 00:56:32,200
HAVE TO DO FUNCTIONAL STUDIES

1543
00:56:32,200 --> 00:56:33,600
FIRST TO DEMONSTRATE WHETHER OR

1544
00:56:33,600 --> 00:56:35,080
NOT A VARIANT IS DELETERIOUS

1545
00:56:35,080 --> 00:56:37,200
BEFORE YOU GO ON AND LOOK AT

1546
00:56:37,200 --> 00:56:40,640
ADDITIONAL THINGS.

1547
00:56:40,640 --> 00:56:41,320
>>THANK YOU.

1548
00:56:41,320 --> 00:56:42,920
>>I MIGHT VERY, VERY
QUICKLY AN

1549
00:56:42,920 --> 00:56:46,080
IMPORTANT POINT FROM THAT SO

1550
00:56:46,080 --> 00:56:47,760
EXPOSURE IS CRITICAL AS AMY

1551
00:56:47,760 --> 00:56:52,440
ALLUDED TO SO ACTUALLY IN THE

1552
00:56:52,440 --> 00:56:54,600
FAMILY THAT [INDISCERNIBLE] BEEN

1553
00:56:54,600 --> 00:56:56,240
ALERTED FOR, EVEN WITHIN THE

1554
00:56:56,240 --> 00:56:58,600
SAME FAMILY THE PEN STRANTS OF

1555
00:56:58,600 --> 00:56:59,720
THE DISEASE IS INCOMPLETE

1556
00:56:59,720 --> 00:57:01,080
MEANING NOT ALL THE PATIENTS IN

1557
00:57:01,080 --> 00:57:03,840
THE SAME FAMILY BEING AFFECTED

1558
00:57:03,840 --> 00:57:06,360
HAVE FUNGAL DISEASE, SO THAT

1559
00:57:06,360 --> 00:57:08,440
GOES TO PERHAPS 50% INSUFFICIENT

1560
00:57:08,440 --> 00:57:09,960
FOR SOME TO HANDLE CERTAIN

1561
00:57:09,960 --> 00:57:11,600
EXPOSEDDURES, SO I THINK

1562
00:57:11,600 --> 00:57:13,480
IT'S--IT HAS THE INFECTIOUS

1563
00:57:13,480 --> 00:57:15,120
EXPOSURE IN THE AMOUNT OF IT, I

1564
00:57:15,120 --> 00:57:20,280
THINK IN THE EQUATION HERE.

1565
00:57:20,280 --> 00:57:22,960
>>THANK YOU.

1566
00:57:22,960 --> 00:57:24,720
FROM THE COHORT BEFORE I ASK MY

1567
00:57:24,720 --> 00:57:27,480
QUESTION, I WANT TO PUT IN AN

1568
00:57:27,480 --> 00:57:29,000
AD ARE THE RESEARCH FESTIVAL FOR

1569
00:57:29,000 --> 00:57:31,520
HOW TO USE IT AND SIGN UP, MY

1570
00:57:31,520 --> 00:57:37,160
QUESTION IS HOW CAN YOU TELL THE

1571
00:57:37,160 --> 00:57:40,880
STAT 3 MUTATION FOR THE GERM

1572
00:57:40,880 --> 00:57:43,080
LINE OR SOMATIC ALSO HAS CASES.

1573
00:57:43,080 --> 00:57:44,000
>>GERM LINE.

1574
00:57:44,000 --> 00:57:45,920
GERM LINE.

1575
00:57:45,920 --> 00:57:46,160
>>YEAH.

1576
00:57:46,160 --> 00:57:47,920
>>ALL RIGHT.

1577
00:57:47,920 --> 00:57:48,760
THANK YOU EVERYONE FOR

1578
00:57:48,760 --> 00:57:49,040
ATTENDING.

1579
00:57:49,040 --> 00:57:50,080
IF YOU HAVE ANY FURTHER

1580
00:57:50,080 --> 00:57:51,680
QUESTIONS YOU CAN STILL SUBMIT

1581
00:57:51,680 --> 00:57:53,120
THEM AND WE WILL TRY TO GET BACK

1582
00:57:53,120 --> 00:57:56,000
TO YOU BY E-MAIL.

1583
00:57:56,000 --> 00:57:56,320
THANKS.

1584
00:57:56,320 --> 00:58:06,560
[ APPLAUSE ]