‚eviews

€h—rm—™ologi™ €rophyl—xis —g—inst xerve egent €oisoning

sdo v—yish whD emir urivoy whD ir—n ‚otm—n whD erseny pinkelstein fƒ™D eev „—shm— €hh

—nd ‰o—v ‰ehezkelli wh

ghemi™—lD fiologi™—lD xu™le—r —nd ‚—diologi™—l wedi™ine fr—n™hD wedi™—l gorpsD ssr—el hefense por™e

uey wordsX nerve —gentsD org—nophosphorus poisoningD prophyl—™ti™ tre—tmentD pyridostigmine

—nti™onvuls—nt @˜enzodi—zepineA to tre—t or prevent seizures —nd

e˜str—™t

result—nt neuron—l d—m—ge ‘I“F

xerve —gent poisoning is ™h—r—™terized ˜y the r—pid progression of

„he term ––ph—rm—™ologi™—l prophyl—xis99 for ™hemi™—l poisoning toxi™ signsD in™luding hyperse™retionsD tremorD ™onvulsions —nd

refers to the medi™—l ™ounterme—sures —pplied ˜efore —n exposure profound ˜r—in d—m—geF sn the politi™—l —ren— of tod—y9s worldD the

thre—t of nerve —gent use —g—inst milit—ry troops h—s prompted —rmies in order to prote™tD —t le—st p—rti—llyD —g—inst the deleterious he—lth

to se—r™h for prophyl—™ti™ prote™tionF „he two m—in str—tegies for

effe™ts of the ™hemi™—l —gentF €rophyl—xis must ˜e distinguished

prophyl—xis in™lude ˜iologi™—l s™—vengers th—t ™—n ˜ind or ™le—ve nerve

from pretre—tment even though these terms —re often used

—gents ˜efore they re—™t with —™etyl™holinester—seD —nd —ntidotes —s

inter™h—nge—˜ly in the ™ontext of org—nophosphorus poisoningF prophyl—™ti™ tre—tmentF €yridostigmine is the ™urrent pretre—tment for

€retre—tment is the —dministr—tion of drugs ˜efore poisoning in nerve —gent poisoning —nd is in use ˜y most of the —rmed for™es in

‡estern ™ountriesF roweverD sin™e pyridostigmine ˜—rely ™rosses the order to in™re—se the effi™—™y of tre—tment given postEpoisoningF sfD

˜loodE˜r—in ˜—rrier it provides no prote™tion —g—inst nerve —gentE

—s — result of the pretre—tmentD further medi™—l tre—tment is not

indu™ed ™entr—l injuryF €yridostigmine is ineffe™tive when —dministered

required —fter the poisoningD the pretre—tment is defined —s

without postEexposure tre—tment —djun™tsF „hereforeD other dire™tions

prophyl—xisF prom — pr—™ti™—l point of viewD postEpoisoning ther—py for prophyl—™ti™ tre—tment should ˜e exploredF „hese in™lude ™om˜in—E

will —lw—ys ˜e needed @—nd —dministeredA in ™—ses of severe tions of ™—r˜—m—tes @reversi˜le eghi inhi˜itorsA —nd ™entr—l —nti™E

holinergi™s or xwhe re™eptor —nt—gonistsD ˜enzodi—zepines or p—rti—l poisoningD —nd therefore pretre—tment is pro˜—˜ly — ˜etter termF

—gonists for ˜enzodi—zepine re™eptorD —nd other ™entr—l eghi

inhi˜itors —pproved for elzheimer9s dise—seF „he tr—nsderm—l route is

—n —ltern—tive w—y for delivering the prophyl—™ti™ —gentF edministr—tion

€rophyl—xis is needed due to the r—pid

of prophyl—xis ™—n ˜e extended —lso for ™ivili—n use during w—rtimeF

onset of nerve —gent poisoning

swet PHHSYUXIVP±IVU

—nd its ––—ging99 pro™ess

xerve —gent poisoning is ™urrently the only poisoning for whi™h xerve —gents —re the most toxi™ of the ™hemi™—l w—rf—re —gentsF „he

pretre—tment is employedF „he need for effe™tive pretre—tment is — ™l—ssi™ nerve —gents —re t—˜unD s—rinD som—nD ™y™los—rin —nd †ˆF

™onsequen™e of its high leth—lity —nd the re™ognition th—t the „heir m—jor mode of —™tion is inhi˜ition of syn—pti™ —™etyl™holiE

™urrent —ntidot—l tre—tmentD given postEexposureD m—y not ˜e nester—seD whi™h prevents hydrolyz—tion of eghF fy this me™h—nism

suffi™ient to prevent de—th or severe d—m—ge to the ™entr—l nervous nerve —gents stimul—te hyper—™tivity in ™holinergi™—lly innerv—ted

systemF sn —dditionD the m—in me™h—nism of —™tion of nerve —gents end org—nsD indu™ing —n —™ute lifeEthre—tening ™holinergi™ ™risisF

is very t—rgetEspe™ifi™D iFeFD the irreversi˜le inhi˜ition of eghi wus™—rini™ symptoms in™lude hyperse™retion ˜y ex™retory gl—nds

throughout the ˜ody tissuesD whi™h results in the —™™umul—tion of @rhinorrhe—D s—liv—tionD swe—tingD —˜domin—l ™r—mpsAD while ni™oE

ex™ess —™etyl™holine in ™holinergi™ syn—pses ‘I“F f—sed on this tini™ symptoms in™lude f—s™i™ul—tion —nd twit™hing of mus™le

spe™ifi™ me™h—nism of —™tionD in ™ontr—st to other ™hemi™—l w—rf—re groupsD ™ulmin—ting in fl—™™id p—r—lysisF fe™—use egh is the most

—gents @eFgFD sulfur must—rdAD it is possi˜le to develop t—rgetEspe™ifi™ widely distri˜uted neurotr—nsmitter in the ˜r—inD severe exposure

—gents th—t —re —imed —t the s—me t—rgets of the nerve —gents @iFeFD m—y ™—use — r—pid loss of ™ons™iousnessD seizures —nd inhi˜ition of

eghiA —nd there˜y p—rti—lly neutr—lize its effe™tsF the medull—ry respir—tory ™enterF xerve —gentEindu™ed seizure

sn this review we ™h—r—™terize the ˜—si™ needs for — prophyl—™ti™ —™tivity —nd ™on™omit—nt motor ™onvulsions ™—n r—pidly progress

—gent —g—inst nerve —gent poisoningD review the pros —nd ™ons of to st—tus epilepti™us —nd profound ˜r—in d—m—geD —s shown in

—ntidotes —s possi˜le prophyl—™ti™ —gentsD —nd dis™uss extending its —nim—l modelsF „he prin™iples of —ntidot—l ther—py for nerve —gent

use for ™ivili—nsF poisoning h—ve not ™h—nged sin™e they were est—˜lished ˜y the

fritish in the e—rly IWUHsD —nd pro˜—˜ly —ll ™ountries worldwide use

‚—tion—le —nd ™h—r—™teristi™s the s—me str—tegies ± n—melyD pretre—tment @eFgFD pyridostigmineAD

‡hy do we need — prophyl—™ti™ tre—tment —g—inst nerve —gentsc —long with postEexposure tre—tment ™onsisting of —n —nti™holinergi™

ixposure to leth—l levels of nerve —gents will produ™e toxi™ities th—t drug @mostly —tropine sulf—teA to ™ounter—™t the —™ute ™holinergi™

—re pre™ipit—te in onset —nd ™—t—strophi™ in effe™tF „hereforeD ™risisD —n oxime to re—™tiv—te —ny un—ged inhi˜ited enzymeD —nd —n

—ntidot—l tre—tment must ˜e —dministered immedi—tely ˜y self or

9˜uddyE—id9 in order to s—ve livesF ‚elying ™ompletely on postE eghi a —™etyl™holinester—se

IVP sF v—yish et —lF swe F †ol U F w—r™h PHHS t

‚eviews

perform—n™e de™rementsF sn order to ˜e —n effe™tive s™—venger exposure tre—tment h—s two key limit—tionsF pirstD due to the r—pid

—g—inst nerve —gent toxi™ityD enzymes should rem—in st—˜le in onset —nd development of the ™lini™—l m—nifest—tions —nd ™entr—l

the ™ir™ul—tion for long periodsD ˜e —v—il—˜le in suffi™ient nervous system d—m—geD nerve —gent —ntidotes might not ˜e

qu—ntities —nd not ˜e immunore—™tiveF „heir m—in dis—dv—nt—ge —dministered f—st enoughF „his is espe™i—lly true in — stressful

is th—t they —re high weight mole™ulesY thereforeD the IXI situ—tion su™h —s — ™hemi™—l —tt—™kF ƒe™ondD the ––—ging99 pro™essD

sto™hiometry implies th—t — l—rge qu—ntity of enzymes is required whi™h o™™urs due to —n irreversi˜le de—lkyl—tion in the eghiEnerve

to neutr—lize — sm—ll —mount of toxi™—nt ‘RDS“F —gent ˜ondD elimin—tes the effi™—™y of postEexposure oxime ther—pyD

espe™i—lly for som—n poisoning @som—nEinhi˜ited enzyme —ges

F g—t—lyti™ ˜ios™—vengersF „hese ˜ios™—vengers @eFgFD p—r—oxoE

within minutesD in ™ontr—st to other vol—tile nerve —gents th—t —ge

n—seA neutr—lize org—nophosphorus ˜y ™—t—lyti™—lly ™le—ving it

within hoursAF fe™—use of these limit—tionsD prophyl—™ti™ tre—tment

into ˜iologi™—lly inert produ™tsF „hey ™—n ˜e —dministered in

is ne™ess—ry to redu™e the toxi™ity of nerve —gent exposure ‘P“F

sm—ller qu—ntities th—n stoi™hiometri™ ˜ios™—vengers —nd

en ide—l prophyl—™ti™ tre—tment is ™h—r—™terized ˜y sever—l

produ™e the s—me degree of prote™tionF „hey —lso h—ve the

elementsF pirstD it should ˜e effi™ient —g—inst — wide r—nge of nerve

—dv—nt—ge of not ˜eing ™onsumed in the pro™ess of nerve —gent

—gents —nd its effi™—™y should not ˜e dependent on postEexposure

detoxifi™—tion —nd —re therefore —v—il—˜le to prote™t —g—inst

tre—tmentF ƒe™ondD it should h—ve — high s—fety profile —nd minim—l

multiple exposures ‘T“F

—dverse effe™ts —s it m—y ˜e —dministered in the milit—ry ™ontext for

— long period ˜efore the —™tu—l exposure to nerve —gentsD —nd —ny

„he use of ™urrent —ntidotes resulting perform—n™e de™rement or limiting —dverse effe™ts would

„hese in™lude —nti™holinergi™ —gentsD oximesD ˜enzodi—zepines —nd

˜e un—™™ept—˜le on the ˜—ttlefieldF „his is —n import—nt requireE

peripher—l or ™entr—l reversi˜le eghi inhi˜itors ‘„—˜le I“F „his mentD sin™e in order to prote™t effe™tively —g—inst nerve —gentsD

—rti™le will fo™us on these —ntidotesF prophyl—™ti™ ™ompounds should themselves ˜e neuro—™tive ± iFeFD

h—ving the potenti—l to imp—ir ment—l perform—n™eF enother

import—nt requirement for prophyl—™ti™ tre—tment is — ™onvenient

tre—tment regimen with — ph—rm—™okineti™ profile th—t provides

€yridostigmine is only — pretre—tment suffi™ient prote™tive ˜lood levels of the drug for — long periodF es

—nd not — ––true99 prophyl—xis mentioned e—rlierD the —™hievement of su™h —n ide—l prophyl—™ti™

—gent is diffi™ultD —nd postEexposure tre—tment will ˜e needed in

severe ™—sesF

‚eversi˜le eghi inhi˜itors

€yridostigmine ˜romide is the ™urrent pretre—tment —djun™t for f—si™ str—tegies

nerve —gent poisoning in most —rmed for™es of ‡estern ™ountriesD „here —re two m—in str—tegies for prophyl—™ti™ tre—tmentD ˜—sed on

in™luding ssr—elF es — qu—tern—ry —mineD pyridostigmine is ionized the me™h—nism of prote™tion —g—inst org—nophosph—tesX de™re—sE

under norm—l physiologi™ ™onditions —nd penetr—tes poorly into the ing ™on™entr—tions of org—nophosph—tes in the ˜lood ˜y in—™tiv—tE

™entr—l nervous system ‘P“F st is — ™—r˜—m—te ™ompound —nd thus ing them ˜efore they re—™h eghi @˜ios™—vengersAD —nd prote™ting

h—s the ™—p—™ity to reversi˜ly ˜ind eghi —nd render the enzyme eghi —g—inst its inhi˜ition @the use of ™urrent —ntidotesAF

un—v—il—˜le for inhi˜ition ˜y nerve —gentsF „his 4shielding fr—™tion4

fios™—vengers

fios™—venger proteinsD in gener—lD fun™tion either ˜y stoi™hiomeE

„—˜le IF entidotes ˜eing investig—ted —s prophyl—xis for nerve —gent poisoning

tri™—lly ˜inding nerve —gents or ˜y ™—t—lyti™—lly ™le—ving the

qroup ix—mples ‚em—rks org—nophosphorus su˜str—te into inert produ™tsF „his —ppro—™h

‚eversi˜le eghi —voids the side effe™ts —sso™i—ted with ™urrent —ntidotesF

inhi˜itors

€eripher—l €yridostigmine gurrently used —ntidote F ƒtoi™hiometri™ ˜ios™—vengersF „hese —re n—tur—lly o™™urring

gentr—l €hysostigmineD xot pheE—pproved for eh hum—n proteins th—t irreversi˜ly ˜ind —nd sequester org—nophoE

donepezilD pheE—pproved for eh

sph—tes from the ™ir™ul—tion ˜efore they re—™h their physiologi™

riv—stigmine

t—rgets @™holinergi™ syn—psesAF „his ™—tegory in™ludes enzymes

gentr—l fen—™tyzineD B€refer—˜ly in ™om˜in—tion

su™h —s ghis —nd endogenous pl—sm— ™—r˜oxylester—sesD —s well

—nti™holinergi™sB s™opol—mine with reversi˜le eghi

—s spe™ifi™ —nti˜odies —g—inst nerve —gentsF „his —ppro—™h —lters

@ƒ™opodermA inhi˜itors

the irreversi˜le n—ture of the org—nophosph—teEghi inter—™tion

eprophen xot —pproved in the ‡est

from dis—dv—nt—geous to —dv—nt—geousX inste—d of fo™using on g—r—miphen elso xwhe —nt—gonist

the org—nophosph—te —s —n —ntiEghiD one m—y fo™us on the ghi fenzodi—zepines hi—zep—mD lor—zep—m

fret—zenil fx p—rti—l —gonist —s —n —ntiEorg—nophosph—te ‘Q“F sing this —ppro—™hD it w—s

yximes rsET es — tr—nsderm—l p—t™h shown th—t —dministr—tion of fet—l ˜ovine serum eghi or hum—n

@most pro˜—˜ly not serum ˜utyryl™holinester—se prote™ted —nim—ls —g—inst — v—riety

effe™tiveA

of highly toxi™ org—nophosph—tes without —ny toxi™ effe™ts or

swe F †ol U F w—r™h PHHS €h—rm—™ologi™ €rophyl—xis —g—inst xerve egent €oisoning IVQ t

‚eviews

of ™—r˜—myl—ted eghi sust—ins ˜—si™ fun™tions through the supply gom˜in—tions of —nti™holinergi™s —nd reversi˜le

eghi inhi˜itors of — de™—r˜—myl—ted —™tive enzyme until the enzyme is synthesized

de novoF gurrent pretre—tment regimens @QH mg three times — d—yA e short™oming of neuro—™tive ™ompounds is th—t they m—y p—rti—lly

—llow PH±RH7 of —v—il—˜le enzyme to ˜e ˜oundD — pro™ess th—t does imp—ir gxƒ fun™tionF e possi˜le solution to the ™entr—l —nd

not imp—ir neurotr—nsmission due to the existen™e of suffi™ient peripher—l ™holinergi™ —dverse effe™ts of ™—r˜—m—te ™ompounds is

ex™ess of eghi —™tivity in the ˜ody ‘P“F to —nt—gonize them ˜y the simult—neous —dministr—tion of

ƒurviv—l during the immedi—te postEexposure period is ™holinolytesF ‡hile offsetting the side effe™ts of e—™hD ™holinolytes

dependent on postEexposure tre—tmentF „he prote™tive r—tioD —nd ™—r˜—m—tes —™t together —g—inst org—nophosphorus intoxi™—E

iFeFD the f—™tor ˜y whi™h — ™ompound lowers the nerve —gent9s tion ‘IU“F r—rris et —lF ‘IV“ ™om˜ined physostigmine pretre—tment

leth—lity @™—l™ul—ted —s the r—tio of the vh with sever—l —nti™holinergi™s @—tropineD ˜en—™tyzineD —prophenD in pretre—ted —nim—ls SH

s™opol—mineD —z—prophenAF i—™h of the ™om˜in—tions showed high to the vh in untre—ted —nim—lsA is PFS±TFV in sm—ll —nim—ls SH

effi™—™y in preventing org—nophosphorusEindu™ed leth—lity —nd ™h—llenged with som—n —fter pyridostigmine pretre—tment —nd

™onvulsionsD with r—pid ™lini™—l re™overy up to norm—l fun™tionF sn —tropine C oxime tre—tmentD ™omp—red with IFI±IFU for —tropine

—dditionD some of these ™om˜in—tions were effe™tive —g—inst s—rin C oxime tre—tment —lone ‘U“F sn nonEhum—n prim—tes exposed to

—nd †ˆ intoxi™—tion in ™ontr—st to physostigmine —loneF sn —nother som—nD the prote™tive r—tio with pyridostigmine is even higher

studyD pretre—tment ™om˜in—tion of —z—prophen —nd physostigmine ‘V“F €yridostigmine h—s — good s—fety profile with only mild

h—d synergisti™ effe™ts in redu™ing som—nEindu™ed in™—p—™it—tion in peripher—l ™holinergi™ signs —nd symptomsD without interferen™e

guine— pigs ‘IW“F elthough there is mu™h eviden™e from —nim—l of ment—l fun™tion perform—n™eF sn — group of PIQ soldiers in

studies to suggest th—t physostigmine is — useful pretre—tment for ssr—el who took pyridostigmine during the first qulf ‡—r in IWWID

nerve —gentsD —nd —t le—st in theory it is possi˜le to offset its side symptoms in™luded n—use— @PPFI7AD —˜domin—l p—in @PHFR7AD

effe™tsD the dr—w˜—™k is its short ˜iologi™—l h—lfElife in hum—ns @QH di—rrhe— @TFI7AD ex™essive swe—ting @W7A —nd urin—ry frequen™y

minutesA —nd the interEindividu—l v—ri—tion in its ˜io—v—il—˜ility ‘PH“F @IIFQ7A ‘W“F elthough not in line with the s—fety profileD it w—s

„hereforeD in order to ™onfer longEl—sting prote™tionD it must ˜e ™onsidered to ˜e — possi˜le risk f—™tor for the development of the

given frequently —nd in high or—l dosesD tr—nsderm—lly or —s —n somewh—t v—guely defined illness known —s qulf ‡—r †eter—ns9

ongoing infusionF sndeedD the ™om˜in—tion of tr—nsderm—l physosE sllness —mong FƒF —nd xe„y veter—ns of th—t w—r ‘IH“F e

tigmine —nd s™opol—mine @ƒ™opoderm „„ƒA —fforded full prote™tion possi˜le expl—n—tion is th—t under stress ™onditions pyridostigE

—g—inst Pvh mine w—s shown to ™ross the ˜loodE˜r—in ˜—rrier —nd enh—n™e of som—n in pigs —nd IFSvh in guine— pigs ‘PI“D —nd SH SH

neuron—l ex™it—˜ility ‘II“F nfortun—telyD ˜e™—use pyridostigmine w—s shown in — hum—n study to h—ve no signifi™—nt side effe™ts in

does not penetr—te the ™entr—l nervous system @—t le—st under ˜eh—vior—l tests @HFQ ngGml physostigmine with HFI ngGml s™opol—E

norm—l physiologi™ nonEstress ™onditionsAD it does not provide mineA ‘PP“F

prote™tion —g—inst nerve —gentEindu™ed gxƒ injuryF enother

dis—dv—nt—ge of pyridostigmine pretre—tment is th—t it did not

show —ny ˜enefit in tri—ls on —nim—ls ™h—llenged with s—rin —nd

yther ™entr—l reversi˜le eghi inhi˜itors †ˆ ‘IP“F

sn order to —™hieve gxƒ prote™tionD other ™—r˜—m—tes th—t ™ross —re —ttr—™tive ™—ndid—tes for nerve

the ˜loodE˜r—in ˜—rrier were investig—tedF enim—l studies utilizing

—gent prophyl—xis physostigmineD — shortE—™ting terti—ry —mine ™—r˜—m—teD given —s —

pretre—tment for som—n in guine— pigs —nd other rodentsD showed

promising resultsF sn ™omp—rison studiesD physostigmine w—s found

to ˜e more prote™tive th—n pyridostigmine —g—inst the detriment—l enother prophyl—™ti™ ™om˜in—tionD €ex€evD is ™omposed of

effe™ts of som—n —nd s—rin ‘IQ“F ƒin™e the m—in pro˜lem with pyridostigmineD ˜en—™tyzine @— ™entr—l —nti™holinergi™A —nd trihexE

physostigmine is its high toxi™ity —nd r—pid remov—lD rese—r™hers yphenidyle @—nother ™entr—l —nti™holinergi™AD —nd w—s introdu™ed

—ttempted to supply the drug through — tr—nsderm—l p—t™h ‘IR“F into the gze™h ermy ‘PQ“F e™™ording to the —uthorsD the presen™e of

„his will ˜e dis™ussed ˜elowF ipt—stigmineD — nonE—pproved drug two —nti™holinergi™s suppressed some of the pyridostigmine side

whi™h is — deriv—te of physostigmineD is more lipophili™ —nd less effe™ts —nd —llowed —n in™re—se in pyridostigmine doseD whi™h

toxi™th—nphysostigmine—ndw—sshownto˜eevenmore produ™ed —n in™re—se in its prophyl—™ti™ —™tivityF €ex€evD given

prote™tive in som—nEpoisoned mi™e @prote™tive r—tio PFI vsF IFQ —loneD prote™ted —g—inst PFPQ —nd PFSS vh of t—˜un in r—ts —nd SH

with physostigmineA ‘IS“F mi™e respe™tivelyD —nd signifi™—ntly in™re—sed the ther—peuti™

€retre—tment ™om˜in—tion with the two ™—r˜—m—tesD pyridostigE effi™—™y of —ntidot—l postEexposure tre—tment ‘PQ“F st w—s effi™ient

mine C physostigmineD did not yield —ny —ddition—l ˜enefit over —g—inst other nerve —gents —s wellF xo he—lth pro˜lems or —dverse

physostigmine —loneD ˜oth in the degree of eghi inhi˜ition —nd effe™ts were o˜served in volunteers following us—ge of €ex€ev ‘PQ“F

improvement of surviv—l r—te ‘IT“F roweverD —s st—ted ˜y the FƒF ghemi™—l g—su—lty g—re yffi™e —nd

true for —ll these ™om˜in—tionsD there is fe—r th—t the —dministr—tion

of — mus™—rini™ ˜lo™ker to he—lthy su˜je™tsD espe™i—lly when we—ring

prote™tive ™lothes —g—inst ™hemi™—l —gentsD m—y le—d to elev—ted gxƒ a ™entr—l nervous system

IVR sF v—yish et —lF swe F †ol U F w—r™h PHHS t

‚eviews

oximes is in the IHH mg r—ngeAF „he ˜isEqu—tern—ry rsET does not he—t stress in — hot —tmosphere due to inhi˜ition of swe—ting ‘PR“F

fulfill this prerequisiteF enother —ttr—™tive pretre—tment ™om˜in—tion for nerve —gents is

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g—psule

ƒtrepto™o™™us proph—ges —nd infe™tivity

inv—sive group e strepto™o™™—l infe™tions reve—led — popul—tionE ƒtrepto™o™™—l dise—ses h—ve m—ny disguisesD r—nging from minor

˜—sed shift from soft tissue infe™tions to pneumoni—D espe™i—lly in sore thro—ts to lifeEthre—tening toxi™ sho™kF „he epidemiology of

womenF rollmEhelg—do —nd —sso™i—tes @ strepto™o™™—l dise—ses h—s long ˜een pro˜lem—ti™D m—nifesting —s imerg snfe™t his PHHSY

suddenly emerging —nd dis—ppe—ring epidemi™s of disp—r—te IIXUUA suggest th—t underlying ™onditions in the vi™tims m—y ˜e

syndromes with no —pp—rent ther—peuti™ ™orrel—teF sn — popul—E ™—using this shiftF „hey found th—t the risk of softEtissue

tionEwide genomi™ study of II ye—rs with d—t— from PSS isol—tes strepto™o™™—l infe™tions in™re—sed —fter †—ri™ell— infe™tions or

from ynt—rioD g—n—d—D feres et —lF @ drug inje™tionD ˜ut ultim—tely ™ould not expl—in the in™re—se in €ro™x—tl e™—dƒ™i ƒe

pneumoni—F rowever — st—tisti™—l link ™ould not ˜e m—de PHHRYIHIXIIVQQA impli™—ted the sour™e of w—ves of inv—sive

˜etween —ny p—rti™ul—r serotype —nd spe™ifi™ ™lini™—l symptomsF dise—se to the —™quisition or loss of proph—gesD whi™h r—pidly

st is possi˜le th—t — proph—ge m—y ˜e —t work ˜ehind the s™enesF gener—ted unique ™om˜in—tions of virulen™e genes —nd their

™h—r—™teristi™ dise—sesX toxi™ sho™kD ˜—™teremi—D or ne™rotizing

f—s™iitisF roweverD —nother U ye—r g—n—di—n study of QHT ™—ses of iF ssr—eli

g—psule

i—r origins

ell living m—mm—ls h—ve — distin™tive e—r ™ont—ining three ˜ones from m—rsupi—ls —nd pl—™ent—lsF ‚i™h et —lF show th—t the e—r of

@h—mmerD —nvilD —nd stirrupA —nd — single j—w ˜oneF „hese the e—rliest known monotremeD from the i—rly gret—™eousD h—s

stru™tures evolved from four or more ˜ones th—t m—de up the j—w only one ˜oneF „husD the ™omplex e—rs of m—mm—ls —rose

of their reptili—n —n™estor in the wesozoi™ —geF st h—s ˜een sep—r—tely —nd ™onverged in different m—mm—li—n line—gesF

thought th—t this evolution o™™urred in — ˜—s—l m—mm—lD prior to ƒ™ien™e PHHSYQHUXWIH

the split of monotremes @the few ext—nt m—mm—ls th—t l—y eggsA iF ssr—eli

swe F †ol U F w—r™h PHHS €h—rm—™ologi™ €rophyl—xis —g—inst xerve egent €oisoning IVU t