>> GOOD AFTERNOON AND WELCOME TO

TODAY'S GRAND ROUND OUR SPEAKERS

WILL ADDRESS NEW INSIGHT INTO

THE PATHOGENESIS AND MANAGEMENT

OF ANTHRAX AND SEPSIS AND SEPTIC

SHOCK. PRESENTING FIRST IS DR.

PETER EICHACKER HEAD OF THE
CRITICAL CARE

MEDICINE SECTION IN THE CLINICAL

CENTERS CRITICAL CARE MEDICINE

CENTER DEPARTMENT.

DR. AMISHA BROCHIA STAFF

CLINICIAN LABORATORY OF ASTHMA

AND LUNG INFLAMMATION,

CARDIOVASCULAR PULMONARY BRANCH

NHLBI.

DR. PETER EICHAKKER, SENIOR

INVESTIGATOR AND HEAD OF THE

CRITICAL CARE MEDICINE SECTION

CLINICAL CENTER CRITICAL CARE

MEDICINE DEPARTMENT.

HE WAS A PEL HAD MONITOR AREY

FELLOW, CRITICAL CARE MEDICINE

AND HAS BEEN IN THIS CURRENT

POSITION SINCE 1991.

PETER IS THE FELLOW OF THE

AMERICAN COLLEGE OF CHEST

POSITION AND HIS MEMBERS INCLUDE

THE AMERICAN THORACIC SOCIETY

AND THE SOCIETY OF CRITICAL CARE

MEDICINE.

HIS PRIMARY RESEARCH INTERESTS

ARE THE PATHOGENESIS AND

TREATMENT OF SEPTIC SHOCK.

SEPSIS INDUCED LUNG INJURY

ENCOUNTERED TO COMMONLY

ENCOUNTERED BACTERIA AND LESS

COMMON ANTHRAX BACTERIUM AND

CARDIOVASCULAR INJURY.

DR. BAROCHIA EARNED HER MEDICAL

DEGREE AT THE INSTITUTE OF

GIAVAGY INDIA AND HE INTERN

INDEED INTERNAL MEDICINE

ASTERISKS FRANCIS MEDICAL CENTER

IN PITTSBURGH AND COMPLETED

INTERNAL MEDICINE TRAINING AT

PROVIDENCE PORTLAND MEDICAL

CENTER IN PORTLAND OREGON.

SHE WAS A PULMONARY FELLOW AT

JOHNS HOPKINS HOSPITAL, A

CRITICAL CARE FELLOW AT THE

CLINICAL CENTER AND WAS A STAFF

CLINICIAN IN THE CRITICAL CARE

MEDICINE DEPARTMENT PRIOR TO

GETTING HER POSITION AT NHLBI IN

2001.

SHE'S ENROLLED IN THE NIH DUKE

TRAINING PROGRAM IN CLINICAL

RESEARCH.

SHE'S A MEMBER OF THE AMERICAN

THORACIC SOCIETY AND HER

RESEARCH INTERESTS FOCUS ON THE

PATHOGENESIS OF BACTERIAL

SUBSTANCE USING ANIMAL MODELS AS

WELL AS MANAGEMENT OF PHYSICALLY

ILL PATIENTS.

HER RESEARCH INCLUDINGS PATHWAY

PATHOGENESIS IS MANAGEMENT OF

SEVERE ASTHMA SO WE'LL START

WITH DR. EICHACKER.

>> GOOD MORNING, LADIES AND

GENTLEMEN.

EVER SINCE THE ANTHRAX OUTBREAK

IN 2001, THERE'S BEEN

CONSIDERABLE AND INCREASED

AWARENESS OF THIS INFECTION IN

THE DEVELOPED WORLD.

IT'S BEEN--FROM OUR PERSPECTIVE

IN THE FIELD OF CRITICAL CARE,

IT'S BEEN CONCERNING THAT THE

DEVELOPMENT OF SHOCK AND ANTHRAX

IS ASSOCIATED WITH A FAIRLY POOR

PROGNOSIS, HOWEVER OVER THE PAST

10 YEARS THERE'S BEEN QUITE A

LOT OF RESEARCH IN THIS

PARTICULAR AREA AND TODAY

DR. BAROCHIA WHICH I WOULD LIKE

TO PRESENT DATA FROM OUR LAB, AS

WELL AS OTHERS WHICH WE THINK

ARE PROVIDING NEW INVITE INTO'S

THE PATHOGENESIS AND MANAGEMENT

OF ANTHRAX AND SEPTIC SHOCK.

MY LABORATORY HAS RECEIVED

INFORMATION FROM THE STUDY OF

THE LAB IN ROCKVILLE, MARYLAND,

WE HOPE TO IDENTIFY THESE

LEADING SEPTIC SHOCK INFECTION

AND ALSO TO DESCRIBE STRATEGIES

FOR THE MANAGEMENT OF THIS KIND

OF OF SHOCK.

NOW WITH THE OUTBREAK, THE

ANTHRAX OUTBREAK IN 2001,

CONGRESS CALLED UPON THE NIH TO

ACCEPT UP RESEARCH DIRECTED AT

EMERGING BIOLOGICAL THREATS

INCLUDING ANTHRAX.

OUR DEPARTMENT HAS BEEN INVOLVED

WITH THAT EFFORT EVER SINCE,

LUCIANO BOREO CONTRIBUTED TO THE

ONE OF THE FIRST REPORTS ON THIS

OUTBREAK, WHAT WAS INTERESTING

FROM THAT REPORT AS WELL AS

SUBSEQUENT REPORTS THAT HAVE

APPEARED IS THAT SHOCK HAS

OCCURRED FREQUENTLY IN PATIENTS

WITH ANTHRAX AND IT HAS APPEARED

PARTICULARLY RESISTANT FOR

CONVENTIONAL TREATMENT.

IT WAS INTERESTING THOUGH THAT

AT THE TIME OF THE ORIGINAL

OUTBREAK, WE WERE SURPRISED TO

FIND THAT THE TIME OF THE

ORIGINAL OUTBREAK IN 2001 THERE

THERE WAS VERY LITTLE RESEARCH

EXAMINING THE PATHOGEN OF THE

ANTHRAX, THERE WAS REALLY NO

INVESTIGATION REGUARDING THE

MANAGEMENT OF THE SHOCK, HOWEVER

SINCE 2001, THERE'S BEEN

CONSIDERABLE PROGRESS IN BOTH

AREAS.

WE'RE GOING TO DIVIDE OUR TALK

TODAY IN THREE PARTS, I'LL

PROVIDE A BRIEF OVERVIEW OF

ANTHRAX IN. I SHALY AND I

WILL--INITIALLY AND I WILL SPEND

THE BULK OF MY TALK TALKING

ABOUT IMPORTANT COMPONENTS AND

MECHANISMS OF THE SHOCK WITH

ANTHRAX AND DR. BAROCHIA WILL

THEN CONCLUDE BY DISCUSSING THE

KIND OF MANAGEMENT OF THIS KIND

OF SHOCK.

SO ANTHRAX IS CAUSED BY THE

GRAND POSITIVE BACTERIA THAT'S

RELATED TO THE OTHER BACILLA

SPECIES, ANTHRAX EXISTS IN TWO

FORMS, THIS FOURTH FORM PICTURED

IN THIS FOR THE MICRO GRAPH

HERE, IT'S DORMANT, RESIDES IN

THE SOIL AND RESISTANT TO

VIRONMENTAL FACTORS.

HOWEVER, AFTER INTERNALIZATION

BY THE HOST AND EXPOSE TOWER

FACTORS SUCH AS INCREASED

TEMPERATURE AND CARBON DIOXIDE,

THIS SPORE VEGETATES INTO THE

VEGETATIVE FORM, THE REG STATIVE

OR ROD IN THIS EM REPRODUCES AND

SIS DEMINATES IN THE HOST S&P

RESPONSIBLE FOR DISEASE, IF

EXPOSED TO FACTORS SUCH AS

COOLER TEMPERATURES AND REDUCE

CAUTON DISCIPLINARY AXIDE WITH

THE DEATH OF THE HOST, THE

VEGETATIVE FORM AND BECOMES

DORMANT.

THE WHEN RAISING AND SPORE

CONTAMINATED SOIL, AND

CONTAMINATED ANIMAL PRODUCTS

LIKE HIDES, OR BY THE

INTENTIONAL EXPOSURE AS MIGHT

OCCUR DURING THE BIOTERRORRIST

ATTACK.

THE BACTERIA IS DESIGNATED AS A

CLASS A BIOLOGICAL WARFARE

AGENT.

NOW AS THE RED AND PINK AREAS IN

IN MAP PREDICT, ANTHRAX IS LESS

WEPPED IN REGIONS OF THE WORLD

EMPLOYING LIMITED OR MEASURES,

HOWEVER RECENT OUTBREAKS HAVE

INCREASED CONCERN ABOUT ANTHRAX

IN THE DEVELOPED WORLD AS I

MENTIONED EARLIER.

THE FIRST OF THESE INCLUDED

OUTBREAKS IN 2001, THEY WERE

LINKED TO THE--THE RECEIPT AND

LARGEST OCCURS IN THE UNITED

KINGDOM IN EUROPE IN 2009 AND

2010, INCLUDED 52 PATIENTS THAT

WERE RELATED TO EXPOSE TOWER

CONTAMINATED HEROINE.

SINCE 2000, THERE ARE SIX OTHER

CASES--ISOLATED CASES, SIX OTHER

ISOLATED CASES REPORT INDEED THE

UNITED STATES AND EUROPE THAT

ARE RELATED TO EXPOSURE AND

CONTAMINATED ANIMAL PRODUCTS OR

HEROINE.

NOW THERE ARE FOUR CLINICAL

FORMS OF ANTHRAX INFECTION

RELATED TO ROUTE OF ENTRY, THE

FORM OCCURS VIA A SKIN BREAK,

IT'S THE MOST COMMON FORM,

OCCURS IN 2000 CASES PER YEAR

AND ESTIMATED MORTALITY WITH

TREATMENT AS FIVE TO 20%.

THE GHAST ROW INTESTINAL FORM

OCCURS VIA THE GI TRACT, OF

CONTAMINATEDDED MEAT, THE

FREQUENCY IS UNKNOWN BUT THE

ESTIMATED MORTALITY IS 2025-60%.

THE RESPIRATORY TRACT AFTER

INHALATION, IT APPEARS UNCOMMON

BUT THE ESTIMATE SIDE HIGH

BETWEEN 46 AND 86% AND FINALLY

THE INJECTIONAL FORM VIA THE

SUBCUTANEOUS TISSUE AFTER

INJECTION OF CONTAMINATED

HEROIN, THE FREQUENCY IS UNKNOWN

BUT BASED ON U. K. EXPERIENCE,

THE MORTALITY RATE APPEARS TO BE

35%.

NOW CUE TANIOUS ANTHRAX PRESENTS

WITH TYPICAL SKIN LESIONS AND IS

RECOGNIZED AND TREATED EARLY

MPLET THE INJECTIONAL ANTHRAX

FOLLOWED BY A PHASIC PATTERN AND

PATIENTS PRESENT IN AN EARLY

PHASE ASSOCIATE WIDE NONSPECIFIC

SYMPTOMS WHICH MADE DELAY

RECOGNITION IN APPROPRIATE

THERAPY OR A PHASE ASSOCIATE

WIDE SHOCK AND IT'S DIFFICULT TO

TREAT.

ALTHOUGH THERE ARE A FEW DATA

DESCRIBES THE CLINICAL

CHARACTERISTICS OF SHOCK AND

ANTHRAX, THERE ARE MUSEUM AN

PATHOLOGY THAT PROVIDE A BASIS

FOR THIS SHOCK.

WOG CAME FROM ANTHRAX SPORES IN

A MILITARY FACTORY IN RUSSIA IN

1979, THIS RELEASE PRODUCED

INHALATIONAL DISEASE AND A LARGE

NUMBER OF PATIENTS AT LEAST 68

OF WHOM DIED.

SHOCK WAS COMMON IN NONSURVIVORS

AND THERE WERE OPSS PERFORM

INDEED 42 CASES.

RELEVANT PATHOLOGY FINDINGS

INCLUDED THE FOLLOWING.

THERE WERE LARGE--THERE WERE

LARGE PLURAL EFFUSIONS OF

PROTEIN 2000 CCs PER PATIENT,

ON MICROTHERE WAS BASILICA

TRACES OF THE BACTERIAL IN MOST

TISSUES EXAMINED THERE WAS WIDE

SPREAD VASCULARRITEIS AND

CAPULITEIS AND EXTENSIVE EXTRA

VASCULAR CLEAR AND TISSUE EDEMA

AND HEMORRHAGE.

SEVERAL CLINICAL FINDINGS GO

SUGGEST THE ANTHRAX MAY DIFFER

FROM OTHER TYPES OF OF BACTERIA.

THERE'S NOTABLE CONCENTRATION

AND THERE'S HYPOPATIENTS

PRESENTING WITH SHOCK FREQUENTLY

DIED DESPITE AGGRESSIVE

HEMODYNAMIC SUPPORT, ALTHOUGH

THE SMALL, AND APPEAR WITH MORE

COMMONLY ENCOUNTERED TYPES OF

BACTERIA.

UNDERSTANDING THE PATHOGENESIS

IMPROVING THE MANAGEMENT OF

SHOCK WITH ANTHRAX IS IMPORTANT.

AND DISCUSSING IMPORTANT

COMPONENTS AND MECHANISMS IN THE

PATHOGENESIS OF SHOCK WITH

ANTHRAX.

SHOCK AND LETHALITY APPEAR

RELATED TO THE ABILITY TO BOTH

AND PRODUCE THE LETH ALT TOXINS

AND EDEMA TOXIN I'LL FIRST

EXAMINE EXPECTS, THIS SLIDE IS A

SIMPLE OVERVIEW OF WHAT ARE

BELIEVED TO BE KEY PATHOGENIC

STEPS IN THE SUBSET GOING LEFT

TO RIGHT, SEPSIS START SAID WITH

INFECTION, BLOOD STREAM INVASION

BY MICROBES OR PRODUCTS, AND

THERE'S AN INFLAMMATORY

RESPONSE, THESE INFLAMMATORY

MEDIATORS INCLUDE THINGS AS

CYTOKINES.

AND OXYGEN FREE RADICALS AND

ENDOTHELIAL AND LEUKOCYTE

ADHESION MOLECULES, AND THIS

RESPONSE IS NECESSARY FOR

MICROBIAL CLEARANCE, IF IT IS

EXEASESSIVE IT'S APPEARS CAPABLE

OF PRODUCING THE SHOCK AND

FAILURE THAT PRODUCE DEATH.

ANTHRAX APPEARS CAPABLE OF

PRODUCING THIS EXCESSIVE

INFLAMMATORY RESPONSE.

THIS SLIDE COMPARES THE EFFECT

OF A LOW AND HIGH DOSE CHALLENGE

ON TNF ILONE BETA AND ILSIX

LEVELS IN NONHUMAN PRIMATES.

AS DEPICTED BY THE TIME LINE OR

OVER THE OBSERVED PERIOD,

OBSERVATIONAL PERIOD, SHOWN ON

THE X-AXIS ON EACH ONE OF THESE

PANELS, COMPARED TO THE LOW DOSE

CHALLENGE IN WHITE, HIGH DOSE

ANTHRAX CHALLENGE IN BLUE

RESULTED INCREASES IN TNF LEVELS

IN THE LEFT HAND PANEL, SILING

95ICABILITY INCREASES IN ILONE

BETA IN THE MIDDLE PANEL AND

EIGHT HOURS 95 CAN'T INCREASES

IN THE SIX LEVELS IN THE HEIGHT

HAND PANEL.

THESE INCREASES IN CYTOKINES

WERE ASSOCIATE WIDE THE

DEVELOPMENT OF SHOCK, AS SHOWN

HERE, COMPARED TO THE LOW

DOSEICAL NENCH WHITE, HIGH DOSE

ANTHRAX CHALLENGE WAS ASSOCIATED

WITH SIGNIFICANT REDUCTIONS IN

BLOOD PRESSURE, OVER THE 10 HOUR

OBSERVATION PERIOD.

NOW INFLAMMATION AND SEPSIS IS

THOUGHT TO BACTERIAL SURFACE

COMPONENT PATHOGEN RECOGNITION

RECEPTORS AND DOWN STREAM

PATHWAYS AND HOST CELLS.

I'VE SHOWN IN THIS ELECTRON

MICROGRAPH, THE VEGETATIVE FORM

OF THE TRACES CONSISTS OF FOUR

SURFACE LAYERS, A MEMBRANE, A

CELL WALL, AN S-LAYER AND A

POLYGLUTAMATE CAPSULE.

GROWING EVIDENCE SUGGESTS THAT

THE ANTHRAX CELL WALL CAN

PRODUCE A ROBUST INFLAMMATORY

RESPONSE WITH ASSOCIATED SHOCK

AND ORGAN INJURY.

RESULTS FROM THE FIRST STUDY TO

SUGGEST THIS, IS SHOWN IN THE

NEXT SLIDE.

THIS SLIDE SHOWS THE EFFECT OF

PURIFIED ANTHRAX CELL WALL ON

TNF ILONE AND ILSIX RELEASE BY

HUMAN PERIPHERAL BLOOD

MONONUCLEAR BLOOD CELLS,

COMPARED TO CONTROLS IN WHITE IN

REACH ONE OF THESE PANELS,

INCREASING CONCENTRATIONS OF

PURIFIED CELL WALL, SHOWN IN

BLUE, RESULTED IN INCREASES IN

TNF, ONCE AGAINOT LEFT, ILONE

BETA IN THE MIDDLE AND ILSIX ON

THE RIGHT.

NOW TOLL-LIKE RECEPTORS IS

PATHOGEN RECOGNITION RECEPTORS,

THEY'RE CENTRAL TO TRIGGERING

AND EFFECTIVE BACTERIA, AND

THERE'S STRONGLY IMPLICATE

INDEED THE PRODUCTION OF

INFLAMMATORY MEDIATORS

CONTRIBUTING TO SEPSIS AND

SEPTIC SHOCK.

TOLL LIKE RECEPTOR TOO,

RECOGNIZES CELL WALL COMPONENTS

FROM POSITIVE BACTERIA, SUCH AS

ANTHRAX.

CONSISTENT WITH THIS, THE TRI

LOW SHOWED THAT CELL WALL,

ADMINISTRATION, AND HUMAN LUNG

EPITHELIAL CELLS CAUSE

SUBSTANTIAL INCREASES IN ILSIX

LEVELS SHOWN IN THE LEFT HAND

PANEL, IN BLUE, COMPARED TO

CONTROLS IN WHITE.

HOWEVER, COMBINATION OF CELL

WALL, WITH ITS TOLL-LIKE

RECEPTOR TO INHIBITOR SHOWN IN

THE RIGHT HAND PANEL PRODUCED

SUBSTANTIALLY SMALLER INCREASES

IN ILSIX.

THIS KIND OF DATA SUGGESTS THAT

ANTHRAX CELL WALL MAY ELISSITY

AN INFLAMMATORY RESPONSE VIA

EFFECTS ON TLR TWO.

SO BASED ON SUCH INVITRO WORK,

AND IN COLLABORATION WITH

DR. YOSI, SHILOCH, FROM THE

NIDDK, WE INVESTIGATORRED THE IN

VIVO EFFECTS OF CELL WALL

ADMINISTRATION IN A RAT MODEL

AND THIS SHOWS THE CELL WALL,

PURIFIED ANTHRAX CELL WALL ON

PLASMA CYTOKINE AND NITRIC OXIDE

LEVELS IN THIS RAT MODEL.

GOING FROM LEFT TO RIGHT ON THE

SLIDE, COMPARED TO CONTROLS IN

WHITE IN EACH ONE OF THESE

PANELS, CELL WALL IN BLUE RESULT

INDEED SIGNIFICANT INCREASES IN

TNF ALPHAILONE AND SIX AND NOW

IN OUR EXPERIMENT, NITRIC OXIDE

LEVELS, THIS RESPONSE TO

PURIFIED ANTHRAX CELL WALL, JUST

AS WHOLE BACTERIA PRODUCED IN

THE NONHUMAN PRIMATES EARLIER

WAS ASSOCIATED WITH THE

DEVELOPMENT OF SHOCK.

AS SHOWN HERE, COMPARED TO

CONTROLS IN WHITE, PURIFIED

ANTHRAX CELL WALL ALONE WAS

CAPABLE OF PRODUCING SIGNIFICANT

REDUCTIONS IN BLOOD PRESSURE

OVER THE 24 HOUR OBSERVATION

PERIOD.

NOW, THE ANTHRAX CELL WALL IS

COMPRISED OF SEVERAL COMPONENTS

CAPABLE OF STIMULATING AN

INFLAMMATORY RESPONSE, THESE

INCLUDE PEPTIDE GLYCAN, ACID AND

POLYSACCHARIDE.

IN A SERIES OF INVITRO STUDIES,

LANGER PURIFIED AND TESTED EACH

ONE OF THESE COMPONENTS AND

SHOWED THAT OF THE THREE, ONLY

PEPTIDE OR GLYCAN WAS CABLABLE

OF PRODUCING AN INFLAMMATORY

RESPONSE.

BASED ON THAT DATA, WE EXAMINED

THE IN VIVO EFFECTS OF PURIFIED

ANTHRAX PEPTIDE GLYCAN IN A RAT

MODEL.

AND GLYCAN, PURIFIED INTO THE

CELL WALL ALONE ON SURVIVAL IN

THIS RAT MODEL AND WHAT CAN YOU

SEE HERE IS THAT YOU CAN SEE THE

CELL WALL WHICH IS SHOWN IN

WHITE, A SIMILAR WEIGHT DOSE OF

PEPTIDE, RESULT INDEED

SIGNIFICANT REDUCTIONS IN

SURVIVAL; THIS SLIDE SHOWS THE

EFFECTIVE PURIFIED PEPTIDE AND

GLYCAN ON PLASMA CYTOKINES AND

NITRIC OXIDE LEVELS, AGAIN GOING

FROM LEFT TO RIGHT IN THIS

SLIDE, COMPARED TO A BILLION AND

CONTROL HERE IN WHITE, PEPTIDE

AND GLYCAN IN BLUE WAS ABLE TO

INCREASE TNF ALPHA ILONE BETA,

ILSIX AND NITRIC OXIDE LEVELS,

AND PEPTIDE OR GLYCAN DID NOT

PRODUCE SIGNIFICANT REDUCTIONS

IN BLOOD PRESSURE, BUT

PRONOUNCED INCREASES IN HEART

RATE WHICH MASK REDUCTIONS IN

BLOOD PRESSURE.

HOWEVER, AS I SAID EARLIER,

CLINICALLY, ANTHRAX INFECTIONS

ASSOCIATED WITH CO AGUE LOPATHY

AND THROMBOW SIGHTED CYTOPENIA,

SIS SEMESTERINATED CO AGULATION

OR D. I. C.

IT WAS NOTE WORTHY THAT IN THIS

RAT MODEL, PEPTIDE OR GLYCAN IN

BLUE, COMPARED TO CONTROL IN

WHITE IN THIS LEFT HAND PANEL,

PRODUCED SIGNIFICANT INCREASES

IN THE PARTIAL THROMBOW PLASTIN

AND PRO THROMBIN TIMES.

ALSO,--PURIFIED PEPTIDE AS SHOWN

IN THE RIGHT HAND PANEL, IT

RESULT INDEED SIGNIFICANT

REDUCTIONS IN FIB RIN O GEN AND

PLATELET LEVELS, OVERALL PATTERN

WHICH IS CONSISTENT WITH D. I.

C. OR CO AGULATION, SO IN

SUMMARY, ANTHRAX CELL WALL

APPEARS CAPABILITY OF

ELISSITYING THE ROBUST

INFLAMMATORY RESPONSE ASSOCIATED

WITH SHOCK PRODUCED BY MANY

COMMONLY ENCOUNTERED TYPES OF

BACTERIA, THE HIGH BACTERIAL

LOADS OCCURRING IN PATIENTS WITH

SEVERE ANTHRAX MAY PROVIDE A

SUBSTANTIAL AMOUNT OF CELL WALL

TO STIMULATE SUCH A RESPONSE.

BUT AS I SAID EARLIER, ANTHRAX

ALSO PRODUCES TWO HIGHLY

BIOACTIVE EXOTOXINS A LETHAL

TOXIN AND EDEMA TOXIN.

LETHAL TOXIN, IS AN ENDOPEP SID

ACE, IT CLEAVES INTRACELLULAR

MAP KINASE, KINASES AND

ENACTIVATES ERK 12 AND P38 AND

DISTRESS G-KINASE PATHWAYS,

EDEMA TOXINOT OTHER HAND IS A CO

MODULATE PSYCHE LACE TINCREASES

INTRACELLULAR, TO VERY HIGH

LEVELS.

NOW, BOTH LETHAL AND EDEMA

TOXINS AND BINARY TYPE TOXINS SO

SHOWN AT THE TOP OF THE SLIDE,

THE LETHAL TOXINS CONSIST OF THE

PROTECTIVE ABET GEN WHEN IS

NECESSARY BY THE UPTAKE OF TOXIN

BY THE HOST SALE AND LETHAL

FACTOR THE TOXIN MODEL

CITIZENETY, THIS CONSISTS OF

EFFECTIVE ANTIGEN AND EDEMA IN

THE MOEI TY, NOW THIS CARTOON

GOING FROM LEFT TO WRITE, THE

THESE BIND TO SPECIFIC RECEPTORS

ON HOST CELLS, THESE PROTEIN

COMPLEX MERS ARE THEN CLEAVED

AND THE RESULTING MONITOR MERS

COMBINE TO FORM PEP TAKEN--THEY

MERS, LETHAL FACTOR AND EDEMA

FACTOR BIND TO THESE

HETEROGENEOUSA MERS AND THEY'RE

INTERNALIZED, AND ONCE

INTERNALIZED, AND REDUCED FOR

CYCLIC AMP AND RELEASED TO CAUSE

MAP KINASE CLEAVAGE.

NOW, NOW RETURNING WHILE ANTHRAX

PRODUCES THESE TOXINS THEATRE

APPEARS TO STIMULATE THE

EXCESSIVE INFLAMMATION, BOTH IF

YOU'RE CAPABLE OF SUPPRESSING

KEY IN THE HOST INFLAMMATORY

RESPONSE, SUCH ACTIONS MAY HELP

ESTABLISH EARLY INFECTION AND

CONTRIBUTE TO THE HIGH BACTERIAL

LOOTS NOTE INDEED LATER

INFECTION.

WELL, THESE AMINO SUPPRESSIVE

EFFECTS I WON'T BE DISCUSSING

THEM FURTHER TODAY HOWEVER ONE'S

LEFT WITH THE OBSERVATION THAT

LETHAL TOX AND I KNOW EDEMA

TOXIN CONTRIBUTE THE SHOCK

DURING ANTHRAX, THE MECHANISMS

THAT DO NOT INCLUDE THE

INFLAMMARRATORY RESPONSE, AND

LOOK AT LETHAL TAXIN, THAT

SUGGESTS THAT IT HAS THE ABILITY

TO APPEAR REND O THELLIAL

BARRIER FUNCTION AND EFFECTS ON

ENDOTHELIUM THOUGH THIS SLIDE

LISTS PUB PUBLICATIONS

SUGGESTING LT LETHAL TOXIN AND

BARRIER FUNCTION, SEVERAL OF

THESE LABS HAVE FOCUSED ON

LETHAL TOXINS ABILITY OF THE

ADHERENCE JUNCTIONS THAT BIND

ENDOTHELIAL CELLS CELLS AND
CONTROL

THE MOVEMENT OF FLUID AND

PROTEINS FROM IBT RAVASCULAR TO

EXTRA VASCULAR SPACE, TODAY I'M

GOING TO DISCUSS DATA FROM THE

WAR FOLD GROUP, A REPORT I DO

THEY WILL DISCIPLINARY CUSS

EBBED O THELLIAL BIOLOGY.

HERE I PICTURE TWO ADJACENT

ENDOTHELIAL CELLS CONNECTED BY

AN ADHERENCE JUNCTION, THIS

ADHERENCE JUNCTION CONSISTS OF

OF--WITHIN EACH CELL, YEAH, THE

NORMAL STATE, THE CYTOICLE STONE

IS RELAXED AND THE PROTEINS ARE

IN CONTACT, AND THE ADHERENCE

JUNCTION IS RELATIVELY

IMPERIABLE TO THE MOVEMENT OF

FLU AND I HAD PROTEINS FROM THE

INTRA VASCULAR TO THE EXTRA

VASCULAR SPACE.

HOWEVER WITH STIMULATION, THE

CYTOSKELETON CAN CONTRACT

RESULTS IN THE SEPARATION AND

LOSS OF THE ADJOINING CADMIUM

PROTEINS.

NO, NOW KINASE IS A PROTEIN

SKELETON CONTRACTIONS, AS I'VE

SHOWN IN THE SEQUENCE ON THE

LEFT OF THIS SLIDE, UPON

ACTIVATION, KINASE RESULTS IN

THE PHOSPHORYLATION THAT INTERN

PRODUCES ACTING CROSS BRIDGE

FORMATION AND CYTOSKELETAL

CONTRACTION, THIS INTERN RESULTS

IN THE FORMATION OF ACTIN

STRETCH FIBYS AND MOST

IMPORTANTLY REDUCTIONS IN CAD

HEIR ENSEL IN THE ADHERENCE

JUNCTION, AS A RESULT,

PERMIABILITY BETWEEN CELLS

INCREASES ALLOWING FLUID AND

PROTEINS TO MOVE, FROM THE INTRA

VASCULAR TO THE EXTRA VASCULAR

SPACE.

ALTHOUGH THE MECHANISMS OF

UNCLEAR, LETHAL TOXIN APPEARS

CAPABLE OF STIMULATING THESE

KINDS OF ALLOTERATIONS IN

ADHERENCE JUNCTIONS NOW RETURN

PROGRESS THE DATA FROM THE WAR

FOLD GROUP, THIS SLIDE SHOWS THE

EFFECT OF LETHAL TOXIN

ADMINISTRATION ON ALBUT MIN FLUX

AND MEASURE OF TERMIABILITY

ACROSS A MONOLAYER OF HUMAN LUNG

AND ENDOTHELIAL CELLS, AND AS

SHOWN HERE COMPARED TO CONTROLS

IN WHITE ON THE LEFT OF THIS

SLIDE, INCREASING

CONCONCENTRATIONS OF LETHAL

TOXIN LISTED ON THE X-AXIS AND

SHOWN IN BLUE RESULT INDEED

GRADUAL INCREASES IN ALBUT MIN  

FLUX AND PERMIABILITY ACROSS

THIS MONOLAYER AND AT THE HIGHER

DOSAGES THESE INCREASES WERE

SIGNIFICANT.

NOW MICROSCOPY OF THESE

MONOLAYER SHOWED THAT COMPARED

TO CONTROLS IN THE UPPER TWO

PANELS, LETHAL TOXIN CHANNEL,

LETHAL TOXIN CHALLENGE, RESULTED

IN INCREASED ACTING STRESS FIBER

FORMATION SHOWN BY THESE GREEN

FIB E-PRESCRIBINGS ON THE LEFT

HAND LOWER PANEL, AND REDUCED

ADHERING CELLS BY DECREASED

STAIN NOTHING THE RIGHT LOWER

PANEL.

NOW BISED ON THESE FINDINGS THIS

WENT ON AND EXAMINE - THE EFFECT

ON ROW KINASE STIMULATE TED AND

CHAIN PHOSPHORYLATION IN SIMILAR

MONOLAYERS.

AND AS SHOWN HERE, COMPARED TO

CONTROLS AND LIFE, LETHAL TOXIN

ALONE IN BLUE RESULT INDEED

SIGNIFICANT INCREASES IN MY O

SIGN LIGHT CHAIN

PHOSPHORYLATION, HOWEVER, WHEN

COMBINED WITH TWO DIFFERENT ROW

KINASE INHIBITORS SHOWN IN

YELLOW, LETHAL TOXIN DID NOT

PRODUCE THESE LARGE INCREASES,

THESE INCREASES WERE PREVENTED.

IN ADDITION, WHILE LETHAL TOXIN

ALONE IN BLUE, REDUCED CAD HERE

ENSEL LEVELS IN THESE ECHO

MONOLAYERS, COMBINATION WITH THE

ROGUE KINASE INHIBITOR REDUCED

THESE OR PRODUCED THESE, AND

FINALLY A LETHAL TOXIN ALONE,

INCREASED ALBUT MIN FLUX

COMBINATION WITH TWO DIFFERENT

INHIBITORS THAT PREVENTED THESE

INCREASES IN PERMIABILITY OR

ALBUT MIN FLUX.

BUT LETHAL TOXIN MAY ALTER

ENDOTHELIAL PERMIABILITY BY

STIMULATING ROW KINASE MEDIATED

ACTIN CYTOSKELETAL CONTRACTION.

SO THESE STUDIES AND OTHERS THAT

I LISTED IN THAT EARLIER SLIDE

SUPPORT THE POSSIBILITY THAT THE

TISSUE EDEMA AND HYPOTENSION

OCCURRING IN ANTHRAX RELATED

PART TO LETHAL TOXIN IMPAIRMENT

OF ENDOTHELIAL BARRIER FUNCTION.

HOWEVER, AS I SAID, EARLIER,

OTHER DATA SUGGESTS THAT LETHAL

TOXIN MAY DEPRESS MYOCARDIAL

FUNCTION DIRECTLY.

THIS SLIDE SHOWS THE EFFECTIVE

LETHAL TOXIN ON CARDIAC EJECTION

FRACTION IN MOUSE AND RAT MODELS

COMPARED TO CONTROLS IN WHITE,

IN EACH ONE OF THESE PANELS,

LETHAL TOXINICAL NENCH BLUE,

RESULTED IN REDUCTIONS IN LEFT

VENTRICULAR REDUCTION FRACTION,

AND CARDIOGRAPHY IN THE MOUSE BY

SIX HOURS AND IN THE RAT BY 18

HOURS.

NOW IN DATA FROM THIS MOUSE

STUDY, WHICH I'LL SHOW NEXT,

THIS SLIDE SHOWS THE EFFECT

EVALUATION PROCESS LETHAL TOXIN

ON BLOOD CARDIAC PROPONENT

LEVELS, THEY'RE A MARKER OF CARD

JACK INJURY IN THAT MOUSE MODEL,

THESE STUDIES WERE DONE BY

MORIARY FROM THE DOCTOR

STEPHEN'S LAB AND WHAT YOU CAN

SEE HERE IS THAT COMPARED TO A

NORMAL RANGE SHOWN BY THE

HORIZONTAL CROSS HATCHED BAR AT

THE BOTTOM OF THE SLIDE, LETHAL

TOXIN CHALLENGE RESULTED IN

INCREASES IN CARDIAC PROPONENT

LEVELS SHOWN BY THE BLUE

DIAMONDS THAT PERSISTED FOR UP

TO 50 HOURS FOLLOWING LETHAL

TOXIN CHALLENGE.

SO, INVITRO AND SMALL ANIMAL IN

VIVO DATA SUGGESTS THAT LETHAL

TOXIN CONTRIBUTES TO SHOCK

DURING ANTHRAX INFECTION BOTH BY

INCREASING VASCULAR AND

PERMIABILITY AS WELL AS BY

DEPRESSING MYOCARDIAL FUNCTION.

TO STUDY THESE POSSIBILITIES

FURTHER, WE DEVELOPED A KININE

MODEL OF ANTHRAX TOXIN

ASSOCIATED SHOCK.

IN THIS MODEL ANIMALS ARE

CONTINUOUSLY SEDATED AND THEY'RE

MECHANICALLY VENTILATED THEY'RE

CHALLENGED WITH A 24 HOUR LETHAL

INFUSION AND THEY'RE MONITORED

CONTINUOUSLY BY A VETERINARIAN

ICU STAFF FOR UP TO 96 HOURS

FOLLOWING THE START OF A LETHAL

TOXIN CHALLENGE.

SERIAL CARDIAL ANIMALS ARE DOING

CENTRAL VENUS CATHETERS AND WITH

DAILY ECHOCARDIOGRAPHY.

NOW THIS SLIDE SHOWS THE

EFFECTIVE LETHAL TOXIN CHALLENGE

ON CHANGES IN MEAN ARTERIAL

BLOOD PRESSURE IN THIS MODEL,

TOXIN CHALLENGE SHOWN BY THE

WHITE CROSS HATCHED AREA ON THE

LEFT HAND PART OF THE SLIDE AND

WHAT YOU CAN SEE HERE IS THAT

COMPARED TO CONTROLS IN WHITE,

LETHAL TOXINICAL NENCH BLUE

RESULT INDEED SIGNIFICANT

REDUCTIONS IN BLOOD PRESSURE

THAT PERSISTED FOR UP TO 40

HOURS FOLLOWING THE CESSATION OF

TOXIN INFUSION.

USING THE SAME FORMAT THIS SLIDE

SHOWS THE EFFECT OF LETHAL TOXIN

ON THE VENOUS PRESSURE IN THE

MODEL.

NOW, IT IS BELIEVED THAT

DECREASED CENTRAL VENOUS

PRESSURE REFLECTS IN PART,

REDUCED INTRA VASCULAR VOLUME AS

MIGHT OCCUR WITH ENDOTHELIAL

INJURY AND EXTRA VIESATION OF

FLUID.

CONSISTENT WITH THE INVITRO DATA

THAT I SHOWED YOU EARLIER,

SUGGESTS THAT LETHAL TOXIN CAN

COMPARE THE BARRIER FUNCTION IN

THIS KINEAIN MODEL, LETHAL TOXIN

WAS ASSOCIATED WITH ASSOCIATION

IN PRESSURE THROUGHOUT THE 96

HOUR OBSERVATION PERIOD.

HOWEVER LETHAL TOXIN ALSO

ALTERED MYOCARDIAL FUNCTION AS

SHOWN HERE, COMPARED TO CONTROLS

IN WHITE, LETHAL TOXIN RESULT

INDEED SIGNIFICANT REDUCTIONS IN

EJECTION FRACTION THAT WERE

MAXIMAL AT 48 AND 72 HOURS.

THUS THE CAINAIN MODEL PROVIDES

STATUS SUPPORTING AN EFFECTIVE

LETHAL TOXIN ON BOTH PERIPHERAL

VASCULAR AND MYOCARDIAL FUNCTION

DURING ANTHRAX INFECTION.

TURNING NOW TO EDEMA TOXIN.

DAT - ON THE ONE HAND SUGGESTS

THAT EDEMA TOXIN JUST LIKE

LETHAL TOXIN MAY BE ANALLABLE OF

REPAIRING ENDOTHELIAL BARRIER

FUNCTION, OTHER DATA SUGGEST

NAYS EDEMA TOXIN MAY CAUSE

DIRECT ARTERIAL BIALATION AND

BASAL DILATION, LOOKING FIRST AT

ENDOTHELIAL FUNCTION, THIS SLIDE

LISTS PUBLICATIONS FROM FIVE

DIFFERENT LABORATORIES

SUGGESTING THAT THE IMPAIRS OR

IMPAIRING ENDOTHELIAL BARRIER

FUNCTION, I WILL QUICKLY REVIEW

DATA FROM THE GRUSHARD GROUP.

THIS SLIDE SHOWS THE EFFECT

EVALUATION PROCESS EDEMA TOXIN

ON THE DYE LEAKAGE ACROSS A

MONOLAYER OF HUMAN MICROVASCULAR

ENDOTHELIAL CELLS.

THIS LEAKAGE IS A MEASURE OF

PERMIABILITY AND YOU SEE THAT

COMPARED TO CONTROLS ON WHITEOT

LEFT OF THE SLIDE, INCREASING

CONCENTRATIONS OF E DEMA TOXIN

RESILT INDEED INCREASES OF DYE

LINKAGE IN THE MONOLAYER

SUGGESTING PERIABILITY, THIS

OCCURS VERY SIMILAR TO WHAT I

SHOWED YOU WITH RESPECT TO THE

FLUX AND THE LETHAL TOXIN

EARLIER, BUT HERE THESE

INCREASES WITH THE EDEMA TOXIN

WAS ASSOCIATED WITH INHIBITION

OF CAD HEREON TRANSPORT AND

ADHERENCE JUNCTION.

EDEMA TOXIN AS ITS NAME IMPLIES

MAYOTER PERMIABILITY LEADING TO

SHOCK WITH ANTHRAX.

HOWEVER, WE'VE NOW DONE A SERIES

OF STUDIES WHICH SUGGESTS THAT

EDEMA TOXIN HAS THE ABILITY TO

CAUSE DIRECT BASAL DILATION OR

ARTERIAL DILATION.

IT'S WELL KNOWN THAT INCREASES

IN INTRACELLULAR CYCLIC AMP

PRODUCE BASAL DILATION BY

STIMULATING SMOOTH MUSCLE

RELAXATION AND BY COUNTERACTING

BASIAN DECODER ASTERISKS

CONSTRICTION CAUSED BY

ENDOGENOUS OR EXOGENOUS CATACO

LINES, IT THEREFORE SEEMED

LIKELY TO US THAT CYCLIC AMP

WITH THE TOXIN WOULD PROMOTE

BASAL DILATION, TO STUDY THIS,

WE USED A RAT MODEL, SECTIONS OF

RAT AORTA, OR RINGS WERE

CONNECTED TO PRESSURE

TRANSDUCERS AND MAINTAIN INDEED

FLUID BATHS AND THEN AFTER

PRETREATMENT WITH EDEMA TOXIN OR

WITH CONTROL, THE CONTRACT TILE

FORCE OF RINGS WHEN STIMULATED

WITH FEIGNAL EPHRIN, A CAT COLA

MINE WAS TESTED, THIS SLIDE

SHOWS THE EFFECT OF PRETREATMENT

WITH EDEMA TOXIN ON FEIGNAL

EFFORT STIMULATED AORTIC RING

CONTRACTILE FORCE OR CONTRACTION

IN THIS RING MODEL AND WHAT YOU

CAN SEE HERE, IS THE CONTROLS IN

RIGHT ON THE LEFT OF THE SLIDE,

INCREASING CONCENTRATIONS OF OF

PRETREATMENT WITH ELIMACON TOXIN

RESULTED IN DECREASING

CONTRACTILE IN RESPONSE TO

FEIGNAL EPHRIN AND HIGHER

DOSAGES THESE WERE SIGNIFICANT.

NOW, THESE REDUCTIONS APPEARED

DEPENDENT UPON PROTECTIVE

ANTIGEN, PRESENCE OF PROTECTIVE

ANTIGEN AS SHOWN HERE, WHILE

EDEMA TOXIN CHALLENGE ALONE

SHOWN IN BLUE, ONCE AGAIN

REDUCED CONTRACTILE FORCED TO

FEIGN ILLEGALS EPHRIN COMPARED

TO CONTROLS IN WHITE WHEN EDEMA

WAS COMBINE WITH THE PROTECTIVE

ANTIGEN WITH THE ANTIBODY, THESE

REDUCTIONS WERE PREVENTED.

THESE REDUCTIONS WERE ALSO

DEPENDENT UPON FUNCTIONAL EDEMA

FACTOR.

AS SHOWN HERE, WHILE ADEMA TOXIN

ALONE REDUCED CONTRACTILE FORCE,

COMBINE WIDE A DOPA VIR,

NUCLEOICIDE WHICH INHIBITS EDEMA

FACTOR, THESE REDUCTIONS WERE

PREVENTED.

THIS SUGGESTS MAKING SHOCK

DURING ANTHRAX, BOTH BY

INCREASING VASCULAR ENDOTHELIAL

PERMIABILITY AS WELL AS BY

PROMOTING OUR ARTERIAL DILATION,

TO STUDY THESE QUESTIONS

FURTHER, WE ONCE AGAIN RETURN TO

OUR KINEAIN MODEL.

HERE IN THIS SLIDE, I'M NOW

SHOWING YOU THE EFFECTIVE EDEMA

TOXIN ON ARTERIAL BLOOD

PRESSURE, THE FORMAT IS THE SAME

AS OUR PRIOR SLIDE LOOKING AT

LETHAL TOXIN AND WHAT YOU CAN

SEE HERE IS THAT COMPARED TO

CONTROLS IN WHITE, THIS 24 HOUR

EDEMA TOXIN CHALLENGE RESULTED

IN SIGNIFICANT REDUCTIONS IN

BLOOD PRESSURE, IN BLUE WHICH

PERSISTED FOR ALMOST THE FULL 96

HOURS OF OBSERVATION, NOW

CONSIST WENT AN EFFECT OF AN

EDEMA TOXIN ON ENDOTHELIAL

PERMIABILITY AND INCREASING

INTRA VASCULAR LEAK, EDEMA TOXIN

WAS ALSO ASSOCIATE WIDE

SIGNIFICANT REDUCTIONS IN VENOUS

PRESSURE IN THE MODEL.

BUT CONSIST WENT AN EFFECT OF

EDEMA TOXIN ON ARTERIAL DILATION

OR PROMOTION OF ARTERIAL

DILATION, IT WAS ASSOCIATE WIDE

SIGNIFICANT AND PRODUCED

REDUCTIONS IN THE RESISTANCE

OVER THE COURSE OF THE STUDY.

SO LETHAL TOXIN AND EDEMA TOXIN

APPEAR CAPABLE OF CONTRIBUTING

THE SHOCK VIA DIVERSE MECHISMS

AND INCLUDING BOTH PERIPHERAL

VASCULAR AND MYOCARDIAL

DYSFUNCTION.

THE PATHOGENESIS OF COMPLEX AND

LIKELY DUE TO MECHANISMS

TRIGGERED BY BOTH THE BIOACTIVE

CELL WALL AND TOXIN COMPONENT.

HOWEVER OTHER BACTERIAL

COMPONENTS AND MECHANISMS MAY

CONTRIBUTE TO THIS PATHOGENESIS

AS WELL.

INTERACTIONS AMONG THESE

DIFFERENT COMPONENTS AND

MECHANISMS, WHILE NOT YET WELL

DEFINED MAY EXPLAIN WHY ANTHRAX

IS DIFFICULT TO TREAT AND HAS

SUCH A POOR PROGNOSIS.

UNDERSTANDING THESE WILL BE

IMPORTANT FOR IMPROVING THE

TREATMENT OF ANTHRAX SHOT IN THE

FUTURE AND WITH THAT I WOULD

LIKE TO INTRODUCE THIS WHO WILL

DISCUSS THE MANAGEMENT OF SHOCK

OF ANTHRAX.

[ APPLAUSE ]

>> THANK YOU GOOD AFTERNOON,

EVERYONE, I HAVE NO CONFLICTS OF

INTEREST TO DISCLOSE.

MANAGEMENT OF SEPTIC SHOCK,

BEGINS WITH THE DIAGNOSIS AND IT

CAUSES SHOCK BY APPROPRIATE

TREATMENT INTERNAL AUDIT CLUEDS

ERADICATION OF INFECTION,

PROVIDING HEMEY DYNAMIC SUPPORT

AND SUBITANTICALLY USING THERAPY

WHICH WILL INHIBIT THE EFFECT OF

ANTHRAX TOXINS.

THE CRITERIA FOR DIAGNOSIS OF

SEPTIC SHOCK BEGINS WITH A

CLINICALLY COPE PATIBLE

PRESENTATION WHICH INCLUDES THE

PRESENCE OF SEPTIC SHOCK ALONG

WITH SUGGESTIVE FINDINGS SUCH AS

HEMOCONCENTRATION AND MEDIA SIGN

UMPIRES THAT CAN BE FOUND IN

ANTHRAX ALONG WITH PROOF OF THE

PRESENCE OF THE SIN TRACEIS OR

PRODUCT, EITHER BY ISOLATION OF

THE BACTERIA IN CULTURE FROM

BLOOD OR CSF OR OTHER SAMPLES.

OR IF CULTURES ARE NEGATIVE, TWO

POSITIVE SUPPORTIVE TESTS USING

TECHNOLOGY SUGGESTS PC R AND

IMMUNOHISTOCHEMISTRY.

FGRAND POSITIVE BACILLA ARE

OBSERVED ON GRAND STAIN, UNLESS

ONE THINKS OF THE POSSIBILITY OF

ANTHRAX, DIAGNOSIS MAY

FREQUENTLY BE MISSED.

IT'S OFTEN CONSIDERED

CONTAMINANTS AND NOT REPORTED BY

THAT LAB.

IT SHOULD BE OBTAIN AS SOON AS

POSSIBLE BECAUSE THEY

STERILEIDES THE BLOOD WITHIN

HOURS AND IF IT'S ISOLATED,

SAMPLES SHOULD BE SENT TO THE

LABORATORY RESPONSE FOR

CONFIRMATION AND HEALTH

AUTHORITY SHOULD BE NOTIFIED AS

EARLY AS POSSIBLE AND

SUSEPTIBILITY TESTING SHOULD

ALWAYS BE PERFORMED, ESPECIALLY

IN CASES OF INFECTION DIE

TERRORIST ATTACKS BECAUSE THESE

BACTERIA MAY HAVE BEEN

GENETICALLY MODIFIED FOR

ANTIBODY RESISTANCE.

HERE AGAIN IS THE OVERVIEW OF

THE KEY STEPS IN THE

PATHOGENESIS OF ANTHRAX SEPSIS

AND SHOCK.

THERAPEUTIC INTERVENTIONS CAN BE

MADE AT VARIOUS STEPS, THE FIRST

AND PROBABLY THE VERY--THE MOST

IMPORTANT WOULD BE TO ERADICATE

THE SOURCE OF INFECTION AS EARLY

AS POSSIBLE, USING ANTIBIOTICS
ANTIBIOTICS

AND IN SOME CASES SURGERY.

IN THE TREATMENT OF SEVERE

DISEASE, WHICH CAN PRESENT AS GI

INHALATIONAL INJECTIONAL OR A

SUBCUTANEOUS ANTHRAX, AND MOSTLY

DRUG ANTIBIOTIC REGIMEN IS

RECOMMENDED, THIS SHOULD INCLUDE

INTRA VENOUS AS A FIRST ASPECT

BODY OF CHOICE.

SO IT'S SUGGESTED THAT ARE

PREFERRED AND THEY ARE BACTERIA

TO [INDISCERNIBLE], AND THEY'RE

POTENTIALLY BETTER AT

PENETRATING THE CSF, NOW

NATURALLY OCCURRING STRAINS OF

ANTHRAX ARE GENERALLY PENICILLIN

SENSITIVE BUT INDUCIBLE HAVE

BEEN DEMONSTRATED AND SO

PENICILLINS ARE GENERALLY NOT

RECOMMENDED AS FIRST LINE

THERAPY.

IN ADDITION TO SUPERPHLOX SIN,

ONE OR POTENTIALLY TWO AGENTS

WITH CNS ACTIVITY, SUCH AS SANK

O MYOSIN SHOULD BE ADDED BECAUSE

[INDISCERNIBLE] INVOLVEMENT IS

NOT UNCOMMON IN SYSTEMIC

ANTHRAX.

IN ADDITION CLEAN O MY O SIGN IS

RECOMMENDED BECAUSE OF THE

POTENTIAL ABILITY TO REDUCE

TOXIN PRODUCTION.

THE TOTAL DURATION OF THERAPY

RECK MEPPED SIDE 60 DAYS AND

INTRA VENOUS THERAPY CAN BE

SWITCHED TO ORAL WHEN

APPROPRIATE, HOWEVER THERE ARE

NO DATA ON WHICH TO BASE A

TIMING OF THIS.

AS WITH SEPSIS AND SEPTIC

AND--COMES FROM A RETROSPECTIVE

LITERATURE REVIEW BY COLLEAGUES

OFF INHALATIONAL ANTHRAX CASES

THAT WERE REPORTED BETWEEN

1,902,000 KNIFE.

THEY ANALYZE--1900-2005.

THEY ANALYZED 18 CASES ASK

COMPARED SURVIVORS TO

NONSURVIVORS AND THEY COMPARED

TO THE U.S. 2001 CASES, THERE

WERE STATISTICS DRAWN FROM

TREATMENT, TIME OF DEATH.

THE DEVELOP THD GRAPH FROM THE

DATA TO PREDICT MORTALITY

SHOWNOT Y-AXIS AS A TIME TO THIS

ORGANIZATION ON THE SYMPTOM

AX-AXIS AND THEY FOUND THE

LONGER TO ENTER THE TREATMENT,

THE HIGHER THE PREDICTED

MORTALITY.

THIS WAS BORN OUT BY THE U.S.

2001 CASES IN WHOM THE MEDIAN

TIME TO ASPECT BIOTICS WAS 4.7

DAYS.

PATIENTS WHO ARE TREATED EARLY,

THAT IS LESS THAN 4.7 DAYS HAD

AN OBSERVED MORTALITY OF 40%.

IN CONTRAST THE U.S. 2001

PATIENT WHO IS RECEIVED

TREATMENT LATE THAT, IS AFTER

4.7 DAYS HAD AN OBSERVED

MORTALITY OF FOUR-SEVEN%.

IN OTHER ANALYSIS, MORTALITY

ALSO APPEARED TO BE LOWER IN

THOSE THAT ARE TREAT WIDE THE

MULTIDRUG REGIMEN.

IN ADDITION TO ANTIBIOTICS

SURGERY CAN BE HELPFUL IN SOME

CASES BECAUSE IT CAN ELIMINATE

THE SOURCE OF INFECTION, SOURCE

OF INFLAMMATION AND POSSIBLY THE

RESERVOIRS OF TOXINS, BECOME

NECESSARY IN SUCH CASES SUCH AS

SOFT TISSUE INFECTIONS, DUE TO

NECROTIC BOWEL DUE TO GI

ANTHRAX, NINE OUT OF 10 CASES

REPORT FRIDAY THE U. K. 2009

SERIES TO DATE, REQUIRED ONE OR

MULTIPETRESSABLE DEBRIDEMENT

SURGERIES.

AS THE DOCTOR DESCRIBED EARLIER

ONCE INFECTION IS ESTABLISHED,

BACTERIA CAN ELICIT A

SIGNIFICANT INFLAMMATORY HOST

RESPONSE, THIS INFLAMMARRATORY

RESPONSE IS MEANT TO BE PRO

TECTIVE AND IT'S HARMFUL AND

INHIBITION OF THE INFLAMMATORY

ISSUE INJURY CAN BE HELPFUL IN

CERTAIN CASES.

IN ANTHRAX INFECTIONS CORD

COSTEROID VS BEEN USED TO LIMIT

INFLAMMATORY INJURY AND TWO

SETTINGS ONE IN SEVERE CUE

TANIOUS DISEASE, AND WITH THE

CHEST WALL EDEMA COMPROMISE

HAPPENING THE AIR WAY AND TWO IN

MENINGITIS WHERE USE WAS BASED

ON STEROID USE IN BACTERIAL

MENINGITIS AND SURVIVORS HAVING

RECEIVED STEROIDS.

THERE IS NOESTED THESE IN EITHER

OF THESE TWO SETTINGS.

ONCE IF INFECTION PROGRESSED TO

SHOCK, CHEMO DYNAMIC SUPPORT

BECOMES VITAL TO PREVENT FURTHER

ORGAN DAMAGE.

IT SUPPORTS CONVENTIONALLY AND

NINE CASEIS, FLUIDS IN ANTHRAX

CAN BE PRETTY HIGH, EXCEEDING 10

LITERS PERDAY OF CRYSTALLOIDS.

HEMODYNAMIC SUPPORT TO MAINTAIN

PROFUSION, BUT AGAIN BASED ON

RECENT EXPERIENCES, SHOGS

SHOGS--SHOCKSS MAY BE RESISTANT

TO COMPRESSORS AND FINALLY,

[INDISCERNIBLE] SHOULD BE

CONSIDERED IF THERE'S CARDIAC

DYSFUNCTION.

IN ADDITION STANDARD SUPPORTIVE

THERAPY AS VENTILATION AND

HEMODIALYSIS SHOULD BE

INSTITUTED AS NEEDED.

PECULIARIARITY OF ANTHRAX, THAT

IS INHALATIONAL DISEASE,

INHALATIONAL ANTHRAX AND SHOCK,

SEEMS TO BE THE NEED FOR FLUID

TRAINAGE AND SOMETIMES

REPEATEDLY.

THE FLUID TRAINAGE RECOMMEND

INDEED THE TREATMENT OF

INHALATIONAL ANTHRAX FOR THE

FOLLOWING POTENTIAL BENEFIT, IT

IMPROVES TO MECHANICS TMAY AGE

DIAGNOSIS AND POTENTIALLY REDUCE

TOXIN BURDEN AND IT MAY BE

ASSOCIATED WITH BETTER SURVIVAL.

HOLDY AND COLLEAGUES REPORT THAD

MORE SURVIVORS THAN NONSURVIVORS

HAD FLUID DRAINED AND 2001 U.S.

CASES WENT DRAINAGE MORE AWIVE

AND WERE LIKELY TO SURVIVE THAN

THE 32,001 CASES.

--THREE, 2001 CASES.

FINALLY, IN LIMITING FINAL

INTERVENTION OF LIMITING THE

PATHOGENESIS OF ADVEERS EFFECTS

OF ANTHRAX, SHOCK, MAY BE

INHIBITING THE INJURY EFFECTS OF

TAXIN THE RATIONAL FOR TOXIN

INHIBITION STEMS FROM THE

KNOWLEDGE THAT DISEASE

PROGRESSION, SHOCK AND DEATH CAN

OCCUR IN ANTHRAX DESPITE

ERADICATION OF INFECTION,

COLLEAGUES SHOW INDEED AN ANIMAL

MODEL THAT ANTIBIOTICS CURED

BACTERIA FROM BLOOD, BUT THESE

ANIMALS DIED ANYWAY, ONE TO

THREE DAYS LATER BECAUSE OF

SHOCK CAUSED BY TOXINS.

THESE TOXIC ANIMALS COULD BE

RESCUE FRIDAY DEATH FROM

TREATMENT WITH ANTITOXIN

THERAPY.

USING THIS CARTOON THAT THE

DR. SHOWED BEFORE, THE FOLLOWING

NEXT FEW SLIDES WILL SHOW THE

VARIOUS TARGET SEATS OF ACTION

AND INHIBITORS OF ANTHRAX TOXIN

MPLET POTENTIAL ANTITOXIN

THERAPIES INCLUDE INHIBITORS OF

PROTECTIVE ANTIGEN INHIBITORS OF

CELL SURFACE, ANTHRAX TOXIN

RECEPTORS, INHIBITORS OF

PROTECTIVE ANTIGEN ASSEMBLY, AND

INHIBITORS OF EXTRA CELLULAR AND

LETHALLENTITY FACTORS AND

INHIBITORS OF TOXIN

TRANSLOCATION AND CYTOSOLIC

DELIVERY OF LETHAL FACTORS.

AND INHIBITORS OF THE

INTRACELLULAR EFFECTS OF THE

LETHAL FACTORS.

THIS SLIDE LIST CLASSES AND

TYPES OF POTENTIAL TYPES OF

TOXINS, OF ALL OF THESE, THE

ONLIA AGENTS THAT HAVE BEEN USE

INDEED HUMANS TO DATE TO, TREAT

ANTHRAX, ARE ANTITOXIN

ANTIBODIES AND THESE WILL BE

FOCUSED FOR THE REMAINDER OF MY

TALK.

IMMUNE GLOBUE LYNN, BEFORE THESE

CAME INTO USE, LATER IMMUNE

GLOBUE LYNN WITH THE ANTHRAX

VACCINE BECAME AVAILABLE AND HAS

BEEN USED CLINICALLY.

RECENTLY SHE'LL GO AGAINST

ANTIGENERATED HAVE BEEN

DEVELOPED AND UNDERGONE PRECLINE

ONICAL TESTING.

THIS IS ONCE AGAIN SUPPORTED BY

RETROSPECTIVE DATA FROM THE

ANALYSIS AND RELATED TO

ANTITOXIN OR ANTISERUM THERAPY,

AND SIGNIFICANTLY MORE SURVIVORS

THAN NONSURVIVORS APPEAR TO

RECEIVE ANTISERUM TREATMENT AND

LIKE ANTIBIOTICS TIMING SEEMED

TO BE IMPORTANT.

MORE SURVIVORS THAN NONSURVIVORS

RECEIVED EARLY TREATMENT WITH

ANTISERUM THERAPY.

THE ONLY ANTIBODY PREPARATIONS

IN THE NATIONAL STRATEGIC TOCK

STOCK PILE ARE IMMUNE GLOBUE

LYNN AND THE BACKA NAB.

ANTHRAX IMMUNE GLOBUE LYNN OR

AIG IS A POLYCLONAL MIX NUR THAT

DERIVE FRIDAY HUMANS IMMUNIZED

WITH THE ANTHRAX VACCINE, THE

PRINCIPLE COMPONENT IN THE AX

THRAKS VACCINE IS PROTECTIVE

ANTIGEN COME IS SMALL AMOUNTS OF

LETHAL AND EDEMA FACTORS AND

PRODUCED BY THE CORPORATION IS

AVAILABLE FROM THE CDC FOR

CLINICAL USE.

UNDER AN EMERGENCY IND PROTOCOL.

THERE ARE NO PUBLISHED ANIMAL

DATA REGUARDING THE EFFICACY OF

AIG.

PHASE ONE CLINICAL TRIAL VS BEEN

COMPLETED BUT THE RESULTS ARE

UNPUBLISHED AND SO WE HAVE NO

INFORMATION REGUARDING THE

SAFETY OF AIG IN LARGE

POPULATIONS.

IMPORTANTLY, HOWEVER, AIG HAS

NOW BEEN USED IN HUMANS TO TREAT

SYSTEMIC ANTHRAX.

THIS LIGHT SUMMARIZES SIX CASES

THAT REPORTED THE USE OF AIG,

WITH VARIOUS FORMS OF ANTHRAX

DISEASE, RESULTING FROM

DIFFERENT EXPOSURES.

AS YOU CAN SEE IN THE COLUMN ON

THE RIGHT FOUR OF THESE CASES

SURVIVED.

SEVERAL OTHER CASES FROM THE

2009 U. K. OUTBREAK HAVE ALSO

BEEN TREATED WITH AIG TODAY, AND

THE DETAILS ARE YET TO BE

PUBLISHED.

, THIS ON THE OTHER SHORTHAND A

FULLY HUMAN RECOMBINANT

MONOCLONAL ANTIBODY AGAINST

PROTECTIVE ANTES GEN, IT IS

DERIVE FRIDAY A HUMAN ABET BODY

MASSAGE DISPLAY LIBRARY AND

PRODUCED USING THE CELL LINE,

MANUFACTURED BY HUMAN GENOME

SCIENCES BASED HERE IN MARYLAND.

UNLIKE AIG, IN VIVO PROTECTION

HAS BEEN DEMONSTRATESSED FOR

THAT IN ANIMALS, HUMAN SAFETY

DATA ARE AVAILABLE, IT HAD

NONAPOPTOTIC SIGNIFICANT SIDE

EFFECTS COMPARED TO PLACEBO IN

RANDOMIZED STUDIES AND HEALTHY

VOLUNTEERS KNOW TEARS, HOWEVER,

IT HAS NOT YET BEEN USED TO

CLINICALLY TO TREAT AN AX THRAKS

TO DATE.

THE POTENTIAL EFFICACY OF

RETINAL LOCATION TAX MACK WAS

DEMONSTRATED USING THE MONKEYS

CHALLENGED WITH 200 IF I'MS THE

MEDIAN LETHAL DOSE OF THE TRACES

FOR IT INTRA NAISALLY.

THESE ANIMALS WERE RANDOMIZED TO

A SINGLE INJECTION AFTER PLACEBO

OR ONE OF TWO DOSES OF THIS IT.

TREATMENT WERE ADMINISTER WIDE

PROTECTIVE ANTIGEN WERE FIRST

DETECT INDEED SERUMS OR WHEN THE

TEMPERATURE INCREASED.

OF NOTE, ANTIBIOTICS WERE NOT

USED IN LIFE IN THIS STUDY.

HERE ARE THE RESULTS, WITH THE

RABBIT STUDY ON THE LEFT AND THE

MONKEYS ON THE RIGHT.

COMPARED TO THE ANIMALS WHO ARE

TREAT WIDE PLACEBO SHOWN IN

BLUE, ANIMALS RECEIVED EITHER 20

OR 40-MILLIGRAMS SHOWN IN YELLOW

AND GREEN RESPECTIVELY, HAD A

SIGNIFICANTLY BETTER PROBABILITY

OF SURVIVAL.

RACKETTA BAT NAP WAS STUDIED IN

COMBINATION WITH ANTIBODIES, BUT

THE ANTIBODIES ALONE WERE HIGHLY

EFFECTIVE IN THIS MODEL AND IN A

ZERO MORTALITY.

SO INVESTIGATORS WERE UNABLE TO

DEMONSTRATE ADDITIONAL VALUE OF

RETAX MACK, STUDIES USING MORE

LETHAL BACTERIAL DOSES ARE UNDER

WAY TO DETERMINE IF IT OFFERED

ADDITIONAL BENEFIT OVER THE USE

OF ANTIBODIES ALONE.

NOTABLY, ANIMAL MODELS TESTING

JUST DESCRIBED, DID NOT EMPLOY

SHOCK THERAPY SUCH AS HYDRATED

FLUIDS AND THE BASE AT

REPRESSORS SO WE ASKED THE

QUESTION, DOES TOXIN INHIBITION

SUPPORT IN THE TREATMENT OF

ANTHRAX SEPTIC SHOCK.

TO ANSWER THIS, WE USED THE

PREVIOUSLY DESCRIBED INSTRUMENT

TED MECHAN ALLOWED TOLY

VENTILATED CAININE MODEL WITH

CONTINUOUS MONITORING OF HUMAN

DYNAMIC VARIABLES, ANTHRAX SHOCK

WAS INDUCE BY 24 HOUR INTRA

VENOUS TOX AND I KNOW THE

ANIMALS WERE ABDOMEN

RANDOMIZEDDED TO ONE OF THREE

GROUPS, CONTROLS, ANIMALS THAT

WERE TREATED IN THE SUPPORT

ALONE OR TREATED WITH

HEMODYNAMIC SUPPORT, PLUS RAKES

MAX NAB, SURVIVAL FROM THE STUDY

SHOWN NEXT.

SHOWN HERE IN WHEAT, ARE CONTROL

ANIMAL WHICH IS RECEIVE NO

THERAPY.

OTHER THAN MAINTENANCE FLUID AND

THE 96 HOURS, SHOWN HERE IN

YELLOW ARE ANIMALS SHOWN HERE,

AND CONSISTED OF FLUID, THERE

WAS HYDRATED TO PULL NONEARY

OCCLUSION PRESSURE AND HYDRATED

TO THE ARTERIAL PRESSURE.

HEMODYNAMIC SUPPORT PRODUCED A

SIGNIFICANT BUT SMALL INCREASE

IN SURVIVAL COMPARED TO CONTROL.

SHOWN HERE IN GREEN IS A HIRED

GROUP OF ANIMAL WHICH IS

RECEIVED BOTH HEMODYNAMIC

SUPPORT AND RAKES MAX NAB, THE

COMBINATION OF RAKES MAX NAB TO

HEMEEE DYNAMIC SUPPORT PRODUCED

SIGNIFICANT INCREASES IN

SURVIVAL COMPARED NOT ONLY TO

CONTROLS AS SHOWN HERE BUT ALSO

COMPARED TO ANIMALS THAT RECEIVE

HEMODYNAMIC SUPPORT ALONE.

IN URGTER ANALYSIS OF OUR DATA

AND IMPROVED LEFT VEPT RICKULAR

FUNCTION--VENTRICULAR FUNCTION.

SO THE DATA PROVIDED SO FAR IS

THAT THEY ARE PROMISING OPTION

FOR ANTHRAX SEPSIS AND SHOCK,

CURRENT RECOMMENDATIONS INCLUDE

CONSIDERATION OF AIG FOR

SEVERELY ILL PATIENTS.

  IN THE FUTURE, ALTHOUGH

CLINICAL EFFICACY WILL BE

DIFFICULT TO DEMON STRAIGHT.

IN SUMMARY, EARLY DIAGNOSIS AND

TREATMENT ARE VITAL TO GOOD

OUTCOMES FROM ANTHRAX SEPSIS AND

SHOCK.

MULTIPLE TREATMENT MODALITIES

INCLUDING ABET BIOTIC, DRAINAGE

AND POSSIBLY SURGERY MAY BE

NECESSARY AND DESPITE LACK OF

EFFICACY DATA, ANTITOXIN THERAPY

MAY HAVE ADVABTAGES AND DESERVES

CONSIDERATION WHEN CHEATING

SYSTEM ANTHRAX.

THANK YOU FOR YOUR ATTENTION.

[ APPLAUSE ]