JPRS ID: 8471 TRANSLATIONS ON USSR SCIENCE AND TECHNOLOGY BIOMEDICAL AND BEHAVIORAL SCIENCES

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22 MAY i979 CFOUO isrT9~ i OF i
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JPRS L/847].
22 May 1979
~
TkANSLATIONS ON USSR SCIENCE AND TECNNOLOGY ~
BIOM~DTCAL AND ~EHAVIORAL SCIENCES
(FOUA 15/79)
~
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- ~RS z/ea~i ~
22 May 1.9 79
- TRANSLATIONS ON USSR SCIENCE AND TECHNOLOGY
BIOMEDICAi. AND BEHAVIORAL SCIENCES '
� (FOUO 15/79)
CONYENTS � PAGE
AGROTECHNOLOt,'Y
EffecC of Defoliants on the Opening of Catton Bolle ~
(A. Zhuralculov, A. I. Inamaliyev; DOKLADY YSESOYUZNOX
ORDEN~1 LEr1INA AKADEI~iII SEL' SKOIC~OZYAYSTVENNYKH P1AUK
II~NI V. I. LEIIINA, No 2, 1979) 1
BIOCEiElII STRY
- Regulatory Effect of Alpha Tocopherol on Conduction of
- Bilayer Pbosp#~olipid M~mbranes Formed of Rat Brain and
~ Liver Phospholipids in the Presence of Strees ~
(H. I. Agadzhanov, et al~; DOIQ.AI)Y AKADII~QI NAUK
SSSR, No 6, 1979) 4
BIOPHYSICS
Q% 572, a Quaternary Derivative of Lidocaine, Used To Block
Cating Currents in the H~mbrane of Raavier's Node
(G. G. Gusel'nilcova, et al.; DOKLADY AKADF2iIT NAUK
- SSSR, No 6, 1979) 9
, '
INDUST'RIAL PIICROBIOLOGY
New Methods of Purifying Viruses for the Preparatioa of
Vaccinea
(VESTNIK AKADE~III NAUK SSSR, No 1, 1979) 14
. Purifying and ~oncentrating Viral Suap~nsions,
bq S. Ye. Bresler
Admin3stration of Inactivated Vaccines, by
_ E. A. Fridman
- a- [TII - USSR - 22 S&T FOUO)
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= CONTENTS (ConCinued) pgge ~
New Method for Virus Purif icat~nn '
Resolution of the USSR Academy o� Sciences ;
MICROBiOLOGY
Toxigenicity and EntomopaChogenicity of Different Bacteria
Straina o� the Bacillus cereus-thuringiensis Group
(0. Lyaenko, et al.; DOKI.ADY VSESOY'UZNOY ORDENA
LENINA AKADEMII SEL'SKOKHOZYAYSTVF'r(NYi~i NAUK IMENI '
V. I. LENINA, No 2, 1979) 30 i
:~rERINARY MEDICINE
. ~
Immunological ProperCies of 7~?pe C Cattle Oncornavirus !
(Kh. S. Salimov; DOKLADY VSE50YUZNOY ORDENA LENINA ~
AKADEHII SEL~ SKOKHiOZYAYSTVF:NNYIC~i NAIiK IMENI V. I. '
LENINA, No 2, 1979).........~ 34 ;
Duckling RespiraCory Disease Caused by Influenza Virus ,
(U. S. Saidov; DOKLADY VSHSOYUZNOY ORDENA L~iINA
- AKADEMII SEL'5KOK~iOZYAYSTVENNYKH NAUK IMENI Y. I. ~
LENINA, No 2, 1979) 37 `
SCIENTISTS AND SCIENTIFIC ORGANIZATIONS
Poglazov Avarded Prize by USSR Academy of Sciences ~
(VESTNIK AKADEMII NAUK SSSR, No 1, 1979) 39 ;
~
USSR Academy of Sciences Makes Organizational Decisions j-
(VESTNIK AKADPIiII NAUK SSSR, No 1, 1979) 40 ~
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AGROTECHNOLOCY _
UD~ 633.511:546.135+546.46
EFFDCT OF DEFOLIANTS ON THE OPENING OF COTTON BOLIS
Moscow DOKI,ADY VSESOYUZNOY ORDENA LENINA ,\ttAD~MII SEL'SKOKHOZYAYSTVENNYKH
NAtAt II~NI V. I. LENINA in Russian No 2, 1979 p 9
[Article by Cand Ag Sci A. Zhu?rakulov and A. I. Imamaliyev, Academician of
the All-Union Order of I,enin Academy of Argfcultural Sciences Imeni V. I.
Lenin]
[Text] It is known that the time it takes for cotton bolls to develop and
open depends on the cotton variety as well as on the environmental -
� conditions and the aqricultural procedures e~loyed. Boll developaaent
averages 55-65 days for Soviet varieties of lonq-staple cotton (4), and
even longer for thin-staple varieties. In this case a significant pro-
portion of the bolls open late and suffer exposure to autumn fre,ezes,
which reduces the quality and size of the yield and lengthens t,he picking
time. As a result the time of autumn plowing comes later, which has an
unfavorable effect on the productivity of the followinq cotton or other
crop. Better conditions are created for opening of the bolls by defoliation
and removal of leaves. In this case the air temperature around the plants
increases by 4.9-6.1�C in comparison with control, while on the other hand
relative air humdity declines by 8.4-10 p~rcent (3). However, this aqricul- -
tural procedure dces not always accelerate maturation and opening of the
bolls (2). With early defoliation (in the last third of August), trans-
formation of soluble carbohydrates into cellulose is significantly in-
hibited in the fiber of young bolls, this being the cause c:E their slow
openinq (1). In this connection we studied the defoliatior. zimes of cotton
varieties Tashkent l, Tashkent 3, and Tashkent 4. The plants were
- defoliated with magnesium chlorate (Mq(Ce03)2�6H2O) at a dose of 12-15 kq/ha -
and butyphos ((CyligS)3P0) at a dose of 2.5-3.0 kq/ha. Plants processed with
water served as a control. The experimental replication was fourfold=
plot area was 60-120 m2, and there five test raws 2a-40 meters long in each.
~ The research xesults showed that the defoliants had a varying influence on
maturation and opening of bolls depending on processinq time and the chetnical
nature of the defoliant.
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Growth in Percentage o~ Open Bolls of Taehkent Cotton Varieties ~
and Difference witih Respect to Cont~ol ~
on ~he 18tih Day Aftier Proaeseing
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wKerr 1 TawKeetl3 ?~wKexr 4 ~
i '
a� (3) ~~I ~ I
~~u X ~ g, m ~ ~ ~I
� g~~ c� oa R ~n e C. `
I
tf7t .
, rIb,7 ~48,4
~r~ `50,4 1{,b 36,8 10,4 - -
Ib.9 18.7
~-3 31.3 fi~.4 98.1 19.~ - - -
43,1 l8,2 ~8,7 2B,0 - -
~~7a ' ~
ia.i ~~.s i
_ 4-3 ~37.1 19~0 _ _ 3~.6 17.0
~6.1 l8,0 40.8 23.1 ~
29.1 21.0 45.9
3-4 ~41,2 17,8 35.6 1~{,C, ~~,.4 16.1
4a,0 ~~.6 42.~ �21,~ 41,5 44,4
- IfT1 '
20.7 � 28.9 1~.~ ~ i-
4-3 ~39,2 Ia,S b6,6 3i,7 44,5 10.:/
4d.0 47,3 57.4 48,b 34,1 19.9
5 t37.0 17.3 ;3.1 ^O.tl J9.0 18.0 i-
Note: First line of figures--control, second--butyphos, _
third--magnesium chlorate.
. , .Y
K~ey :
1. Processed after opening of 3. Grawth
bolls 4. Difference '
2. Tashkent j-
4
_ , ~ ~
- When one or two bolls were open, 3efoliation weakly stiaaulated their matura- i
tion and openinq, ths effect being stronger when 2-3 and 3-4 were opened. ~
With later defoliation, perfoszned when 4-5 bolls were open, the rate of
- growth in the ntaaber of open bolls decreases for all varieties in comparison ~
with the earlier prxessing time. This is associated with the decxease in ~
air temperature by this time. }
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We can see from ~he c~ata in the table that the greatesti growth in the
~ 'number of open bolla is observed with magneaium chlorate defoliatioa in
relation to all varieties and processing times. The reason for~this lies -
in the fact that tha preparation considerably dehydratiee the bo11 glumes.
7.'hus the optimtun time for defoliating Tashkent varieties of cotton is the
period in which from 2-3 to 3-4 bolls are open on the bushes. Deposition of -
cellulose in �iber and of reaerve nutrients in aeeda basically ends by this
time, and ~herefor~ defoliati4n produces the g~eatest impact. -
HIBLIOGRAPHY =
l. Bar'yetas, P. K., Candidate Dissertation Abstract, Task$nt, 1965.
2. Kristidis, B., and ~arr3.son, Dzh., "Problemy vozdelyvanniya khlopchatnika"
(Problems of Cotton Cultivation), IL, 1959.
~ 3. Mukhitdinov, U., IQiLOPKOVODSTVO, No 7, 1961.
4. Shleykher, A. I., "Khlopchatnik" (Cotton), Tashkent, Gosizdat UzSSR,
Part I, 1959.
COPYRIGHT: IZdatel'stVO "KolOS", "Doklady VASI~IIIL" 1979
11004
CSO: 1870
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BIOCHEMISTRY _
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UDC: 616.45-001.1.3:576.8.094.7:577.161.3
REGULATORY EFFECT OF ALPHA TOCOPHEROL ON CONDUCTION OF BILAYIIt PHOSPHOLIPID '
MEMBRANES FORMED OF RAT BRAIN AND LIVER PHOSPHOLIPIDS IN THE PRESENCE OF
3TRESS ' -
Moscow DOKLADY AKADEMII NAUK SSSR in Russian Vol 244, No 6, 1979 pp 1496-1499
[Article by M. I. Agadzhanov, S. A. Badzhinyan, K. G. IGiragezyan and ~
V. G. Mkhitaryan~ Institute of Biochemistry, Armenian Academy of Sciences, _
Yerevan; Yerevan StaCe Medical Inatitute and Yerevan Inatitute for i
Advanced Training of Physicians (presented by Academician Ye. M. Krepa
23 Nov 77), submitted 13 Apr 78]
[Text] In the presence of many pathological processes, impaired vital
function of cells is based on increased ion permeability of cellular and
subcellular membranes, which is determined, to some extent, by intenaifica-
tion of the process of lipid peroxidation [1~. Ttie latter is associated
with intensification of free radical processes inherent in different stresa
states [2]. For this reason, it was necessary to investigate changes in
- ion condition in the presence of body stress on model bilary phospholipid ;
membranea (BPM). Burn trauma was used as the stress factor. At the same
time, it was necessary to determine the effect of a-tocopherol on these ~
- processes. !
The studiea were conducted on female rats weighing 140-160 g. We produc~d ~
3b de ree burns an 12-15X of the body surface in the region of the hind I
8
legs using water at a temperature of 80�, with 10-s expoaure. We measured
conduction of BPM formed from phospholipids of brain and liver tiseues of
animals sacrificed 1 h, 1, 3, 7 and 15 days after trauma. Vitamin E was
given in the form of a-tocopheryl acetate (which is hydrolyzed in the body ;
to a-tocopherol [3], intraperitoneally at the rate of 1 mg/kg body weight,
- immediately after the burn, then 3, 7 and 12 days later. :
The phospholipid membranes we used were obtained by the method described by
Muellec (4]. Phospholipids were extracted from rat brain and liver tissues
according to Folch [5J. Bilayer membranes were formed from phospholipids
dissolved in heptane,~in ~ concentration of 20 mg/mJ~. Electric readings were :
taken using the method des~ribed in [6] with a direct current electrometer
_ in 0.1 M KC1 solution at pH 3.0, 6.0, 7.4, 8.0 and 9.0. In order to
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- determine the role of a-tocopherol in forming cel]. membranes, we added vitamin
E in a dosage of 0.04 mmole/mR Co BPM from phospholipids isolated from the
organs of burned rats in in vitro experimenCs. We added methyl ether of _
oleic acid and cumyl hydroperoxide (0.05 mmole/mR, of each) to IIPM from
- phospholipide taken from organs of intact raCs to confirm the peroxide
mechanism of impairment of inembrane permeability. All measuremer~ts were
taken at a temperature of 26�C.
- As can be aeen, conduction of BPM of phoapholipids obtained from the liver
(Fiugre la) and brain (Figure 2a) of normal rata is rather low, and it
dependa on medium pH. It was demonstrated Chat the stresa aCate induced hy
burn trauma is characCerized by increased BPM conduction at all tested Cimes. -
Medium pH had a aignificant influence on this proc~ss, maximum increase in _
conduction in the liver (Figure 1) being noted at�pH 6.0 and 1.4, whereas =
in tt~e brain (Figure 2) these changes were more marked mainly at pR 9.0.
The above changea in BPM conduction were not demonstrable after giving
burned animals vitamin E, particularly with regard to BPM of phoapholipids
isolated from brain tisaue (Figure 2).
:oG a b Figure 1.
,-s Effect of a-tocopherol on conducCion of
-6 ~ BPM of rat liver phospholipids in 0.1 M
-7 ~ o----o--o-i? KCl solution at different intervals after
-8 ~ burn trauma. Y-axis, logarithms of spe-
d ciffc membrane conduction log G(ohm 1�cm-2)
or-
� -w c � ~ a) normal
-3 ` ' b) after 1 h
_ 0,_0,01
_ -6 ~d a.4._~q-.o c) after 1 day
' �~O d) after 3 days
-3 e 1 f e) after 7 days
_y ~ f) af ter 15 days
_s f 1) control
_6 o-`r-~--o-,v~' 2) BPM conduction after burn
- a' b 3) BPM conduction after burn +
~ ~ 1 mg/kg a-tocopherol
J4367I9 J4,~6"B9pH
- This regulatory effect of a-tocopherol is apparently related to its role in
stabilizing cell membranes [1]. It is believed that vitamin E stabilizes
membrane structure by means of specific physicoch2mical interaction between
its lateral core chain and hydrophobic radicals of polyunsaturated phospho-
lipid fatty acids, particularly derivatives of arachidonic acid. From this
point of view, of interest are the data we obtained on quantitative levels
of a-tocopherol and phoapholipids in the brain and liver (Table 1) of rats
who have sustained burned trauma. It was demonstrated that thie is asso-
ciated with a significant decrease in both a-tocopherol and total phoepho-
lipids of the brain and liver at all tested Cimes. Interestingly enough,
the decrease in phospholipids is related primarily to the fractiona of
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' lecithins and phosphatidyl eChanolamines. Concurrently, there is a decrease ,
in degree of uneaturation of fatty acids in pho~pholipide, mainly due to '
- polyene and, in part9.cular, arachidonic acid (Table 2). Administration ~
of a-Cocopherol ae described above normalizea Che teated components.
- Tab1e 1. Effect of ot-eocopherol on level of lipid peroxidation~ endogenoua
a-toccpherol and phoapholip3.d contenk of the rat brain and liver
after burn trauma (X of control)*. ~
. ~ ~
~ Tota1 Phospha- ; �
y~b Lipid Alpha phospho- Leci- tidyl ,
w'd peroxides ocophex+ol lipids thins ett~anol- j
am nes
;
~ Factor ~ ~ ~ ~ ~ r~ ~ ,
b
H~ ~ ~ ~ ~ ~ a ~ ~ ~ ~ ~
A r-I A ~-1 A ~-I A ~-1 A r"~ I
1 h After burn 180 174 65 Bl 64 32 42 24 67 78
Burn + q,-Tp* 112 116 82 100 110 82 84 92 96
1 Af~er burn 163 178 b8 41 47 52 22 29 36 Z2
Burn + C4-Tp 118 102 ' 79 200 126 132 79 7? 94 112 -
3 Af~er burn 147 128 ~ 76 T3 58 54 30 40 43 ~ 26 i
Bu~n + Ol-Tp 116 114 y2 164 112 106 88 80 102 93 ,
7 After burn 144 13~ 84 62 63 82 61 55 67 67 ;
Burn + a-Tp 116 105 100 131 108 80 63 109 82 ~
15 Af~er burn 189 126 109 69 43 48 17 26 ' 28 36 j
Burn + q,-Tp 116 98 127 ll3 141 124 78 68 112 100
*The~control is considered to constitute 100~. '
**a-Tp--a-tocopheryl acetate (same in Ta ble 2). j
~
i
Table 2. Effect of tocopherol on arachidonic acid and phospholipid content ~
of the rat brain and liver af ter burn trauma X,~ i
. . _ . i =
Time Brain i I
after after burn + after burn + ~
trauma, control ~urn a-Tp ontrol burn ct-Tp i~
days ~
~ i4,57t0,i2 � ' 24,35t0,6 � ;
i h i6,3iti~0 l4,05t0,6 iS,4ti.2i 22~44ti~2 :
i i4,02ti,5 l3,50t0,86 li,i2~i,0 22,45tf,7 ~
- 3 i3,68t0,74 i5,38t0,64 l9,bt0,5 24~09ti,22 !
7 ' i0,Ot0,8 ~ i2,38t0,34 20.4t0,9 23,5ti~i
i5 f9,85t2,07 l3,bl~t0,7 27,86_!,f 25,4tl,4 '
*Overall fatty acid content in indicated tissue is considered as 100X. '
In in vitro experiments, we demonstrated that addition of 0.04 mmole/m!Z vitamin ;
E to phospholipids from the liver. of burned rats (burned for 1 h, pH 7.4, .
- 0.1 M KC1 solution) restores BPM conduction from 4.8�10'6 ohm-1�cm 2 to _
normal, i.e., to 8.3�10-e ohm 1�cm 2.
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~9~ The data we obtained are indicative of
a b
-1 g` 9 a certain para11e1 between BPM conduction,
-6 ?�~y,,,~ a-tocopherol and phospholipid content, as
? o-__�~,_-0 well as level af 11pid peroxidation in rat
_s brain and liver tisaues (Tab1e 1) after
austaining burn trauma. It was demonaCrated .
_y ~ � that the burn also leads to significant
Z increase in lipid peroxidea immediately
_3 c d after trauma is susCained; a high level
'~6 ~9 0._r A thereof gersiate for a long Cime (up to
0.__.o--d d ff"O~ 30 days)[8]. Alpha tocopherol also nor-
~ _3 1 malizes Che level of lipid peroxidation. -
2
-e ~ We added 0.05 mmole/mk oxidized methyl
- ~ o-o.-.o--0-.o ~-o~o--o--o ether of oleic acid or cumyl hydraneroxide
-~t e f to phoapholipids from the liv~r of intact
k 3 0 7 s 9 J ~ 3 6 7/ 9 pH rats tn experiments~ in vitro, in order to
prove Che existence o� a peroxide mechanism
of impairment of inembrane permeability in
Figure 2. Che presence of stresa reactiong. It was
- Same as in Fi~ure 1~ but with demonstrated that, in both instances, con-
BPM formed from phospholipids duction of BPM increasea by about a factor
of the brain of 10~. Analogous data were submitted
in [1].
Thus, sCress induces an increase in levels of lipid peroxide in the body,
which intensify oxidation of a-tocopherol, as we11 as unsaturated fatty -
acids, chiefly arachidonic acid, in membrane phospholipids In view of the
nature of the bond between a-tocopherol and phospholipids [9], it is
assumed that conduction pores are formed at the peroxidation sites in the
bilayera, and they cau~e the increase in membrane permeability.
~IBLIOGRAPHY
1. Vladimirov, Yu. A., and Archakov, A. I. "Peroxidation o� Lipids in
Biological Membranea," Moscow, Nauka, 1972.
2. Kaznacheyev, V. Pe "Materialy simpoziuma Vsesoyuznogo -
nauchno-meditsinskogo obshchestva patofizinlogov" [Proceedings of Sym-
posium of the All-Union Scientific Medical Society of Pathophyaiologists],
Yer.evan, 1974, p 73.
3. Gallo-Torres, H. E., and Miller, 0. N. INTERN. J. VITAMT_: ivuTR. RE5.,
Vol 41, 339, 1971.
4. Mueller, R.; Rudin, D.; et al. in "Recent Progress in Surface Science,
New York, Vol 1, 1964. p 379.
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_ 5. Folch, J. M.; Lees, M.; and 51ane-Stanley, G. H. J. BIOL. C~IEM., Vol 226, ;
497, 1957.
: 6. Badzhinyan, S. A. BIOL. ZHUNR. ARMENII [Bi.ological Journal of Armenia], '
_ Vol 2, No 6, 23, 1976. , ;
_ I
7. Diplock, A. T., Lucy, J. A. FEBS LETT~~tS, Vol 29, 205, 1973. ~
~
- 8. Mkhitaryan, V. G.; Agadzhanov, M. I.; and Melik-Agaiyan, Ye. A. "Tretiy i
- Veesoyuznyy biokhimicheskiy s"yezd, Referaty nauchnykh soobshcheniy" i
[AbstracCa of Scientific Papers Delivered at 3d All-Union Biochemicai ;
Congxess], Riga, Vol 1, 1974, p 242. ~
- I~
9. Lucy, J. A. ANN. N.Y. ACAD. SCI., Vol 203, 4, 1972. i
,I
COPYRIGHT: Izdatel'atvo "Nauka", "Doklady Akademii Nauk SSSR", 1979
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~OIt d~~ICIAL U5~ qNLY
BIOYHY5IC5
UbC: 576.331
- QX-57?~ A QUATERNARY DERIVATIV~ OF LIl}aCAINE~ USED TO gLOCK GATING CURRLNTS
IN 7'EI~ M~MBRANE OF ItANVI~R' S NOn~
Moecow DOKt.ADY AKAUEMI: NAUK 555R in Rusaian Vol 244, No 6, 1979 op 1492-1495 -
(Areic?~ by G. G. Gusel'nikova, E. M. Peganov and B. I. Knodorav, Institute
of Surgery imeni A. V. Vishnevskiy, t)SSR Academy of Medical Sciences, Moscow
(preaented by Academician P. G. Koetyuk, 14 Oct 18)~ submitt~d 24 Oct 78J
[TextJ In previous works conducted on isolated frog nodes of Raavier, it
was shown that the tertiary local anesthetic trimecaine [1~ and neutral
anesthesin (benzocaineJ (2j have a blocking effect on aodium gating currenta.
A reversible decrease in gating charge wae obaerved under the effect of
novocain in experimente on the squid's giact axon [3j.
Ou: objective ~ere was to test the effect on sodium gating currents of -
compound QX-572, a charged quaternary derivative of lidocaine.
Experiments were conducted on isolated myelinated fibers of the frog's
sciatic nerve. We recorded the pntential by the ~thod in [4]. We cut the
internodal segmeats on either side of the tested node in isotonic KC1 eolu-
tion. When measuring ion currents, the node aas perfused with normal
Ringer's solution. Potassiwn currente were blocked by adding 10 mM tetraethyl
ammonia chloride ta Che external solution. To measure ahift currente~ the
sodium ion currente were depreesed b~r changing the Na+ in the external
solution to tris+ and adding 3-5�10' M tetrodotoxin. Since compound QX-572,
cnlike most other quaternary analogues of local anesthetics. is quite soluble
, in lipids [5]~ we tested ite blocking effect on sodium channels by means of
_ external application to the node membrane. For all of the aolutione~ pH
constituted 7.2; the temperature varied within the range of 12-YS�C in the
different e~cperimente. -
Gating curreats were obtained as a reb;tlt of algebraic summation of currents
arising in response to switching square-wave voltage pulses on and off;
these pulses were strictly identical in amplitude and duration, but of
opposite signs. The total number of summations for each reading constituted
32. The minimal iaterval was 150 ms. An wTAS-250 digital averaging unit
wae used to average the current. Before averaging, the siRnal was cleaned
by meaas of a passive filter with a gating band o~ up to SO kHz. The data
9
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we~~~ display~d on an ogcillograph ~cre~n. The following ~ymbols arp uged
here: ~--pdtentiial of internal eide df ehe tn~mbrane minus the exCernal,
taken ae 0; V--ghift nf poeential fram base vglue (mginCained by Eh); o
IN~--godium currenC; Ig--gating currene; Qn --charge ehifted during reeponge _
- to gwitrl~ing on; Q~~--roaximum v$lue thereo~; Qoff"charg~ shifted in
responee t~ swiCching off.
In g11 of the teaCs, ~X-572 (U,2 mM) elicited a disti~.nct dpcline in ggting
currents. I~igur~ 1 illuatr~tes an example of tracinge d� Ig obtained in -
regponse to teeC shifting of potentials V~ 90 mV (g, c~ e) and V ~ 100 mV
(b, d, f) from ~h !-110 mV. In the top row (a, b) are ehown control Ig'e
before treatmene wteh QX--572. The bottom rnw f) are tracinge of Ig
5 min after addition o� QX-572 to thp perfusion liqui~9. We see that QX
lowered the regponees eo Curning the test pulses bcth on and off. There
were no eignificant changes in kinetics. The middle eracings (c, d) ehow
the same reveraible ~hangea in I$ ae ob~erved in the same experiment under _
the influence of dspolarizing prepul~e~, which cause rapid tnactivaCion of _
gating currenta. These tracings were made prtor to applying QX-572 to ~
the nod~. The amplitude of the prepulses (V ~ 50 m'J) and duraCion thereof
(25 ms) were sufficient for virtually c~mplete inacCivation of INa in the
control Ringer's soluCion. We were impres9ed by the greaC similariCy of
effects of prepulsee and QX-572. This similarity becomee even more gpparent
if we e~camiae the curvea of the shifted charge Qo~, ae a function of tiesC !
potential (Figure 2a). QX-572 and depolarizing prepulses iaduced about the
- same decline of1Q~on with all test potentials. There was about 30X decline
of Q~X (Nl� 10' Kl [ coulomb?
The botCom curve [3) corresponde to the difference betWeen curvee 1 aad 2.
It appareaCly characterizes the dependence on potential of the cnmponent
of~
the shifted charge that was sensitivive both to QX-572 and depolari~ing pre-
pulses ("iam~obilized charge"). The eame curves no~alized to the maximum -
- are illustrated in Figure Zb. A acrutiny of thia Figure shovs that QX-572
and inactivatioa elicited aimilar change in parameters of curve Qon-E. The ~
curve of the "nonimmobilized charge" (2) presenta a lesser slope and its ;
mean poinC it~ ahifted to the left, in the direction of negative potentials, ,
ae compared to the curve of distribution of a full charge (1). Accordingly,
the curve of the "immobilized c~iarge" presents a substantially greater �
slope aad ita mean point ia shift~d in Che direction of higher V.
The obtained data can be interpreted as canfirmation of the previously ex-
pounded hypothesis (lJ that the pool of gat~ng particles controlling per-
, meability of the sodium channel is heterogeneous: some of theae particles
may be immobilized by the depolarizing prepulse or anesthetic, while others
are resistant to both these factors. The difference in properties of these ~
two tvpes of particles is emphasized by the difference in parameters of
distributioa of the corresponding Q-E curves.
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g ~r�~o mV ~~~n~ ~ v=roo mV b
. .,,~wiwMt
. �,~,,,,w, l',~.~..
.
~ r
c h'r~-r~-~nn') ~ d
=pw~"' /.'""r`~.~w~e1'~...~
~
Q~Y=.f7t (-u-)-(n-) QX=S~t
.~~~.~w~
_ e ~~'~,w~'~wwa ww+~n4 ,,w~+
� F r
, . t~b
A~~
' o,s ms
Figure 1. Effect of QX-572, quaternary derivative of lidoceine~ on
sodium gating currents ia Raavier aode membrane compared
to effecC of rapid aodium inactivation. Symetrical
square-~vave puls~s were applied from a maintained poteutial of E~ -
-100 mV. Traciaga of gating currenCs with teat pulee amplitude CV) of
90 aad 1tl0 mV.
i a~ b) ia control sodium-freP solution (Na+ is replaced aith tris+)
containing 300 n?i tetrodotoxin and 10 mM tetraethyl ~onia chloside
c, d) effect of depolarizing prepulses (V = 50 mV lastiag 25 ma)
e, f) effect of adding 0.2 mM QX-572 to control solution. Gatiag currents
were recorded siithout pr~pulses
In the opiaion of one of the preaent authors (E. M. Peganov), a basically
differeat interpretation of these phenomena can be offered. It can be
asaumed that the pool of gatiag dipoles is homogeaeous, buC that there is a
type of cooperative relations betweea them, with which immobilization of ~
part of the charges leada to a change in interactioa (cooperatioa) bets+een
the other particles. This leads r.o a change in parameCers of curve Q-E (6~.
According to conceptions prevailing at the present time, quaternary deriva-
tives of local anesthetics are capable of interacting with a reGeptor aituated
_ in the inte=~nal orifice of the Na canal [7-10], binding with this receptor~
QX blocks the canal with its cation head
$
-N /R .
~R
, _
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The moet imporCant prerequl.eiCe �or the block ie opening of activation g~tes
af th~ channel by depolarizing puleea (8~. The question of nature of chemical
groupe of this QX receptor ie of great inCere~e tio identiification af the ~
molecular etrucCure of the Ng channel. The data obCatned ia this eCudy con-
cerning the iahibitory effect of QX-572 on gating curreata~and the similerity
of the effecte of QX 572 and rapid inactivaCion warrant the aseuaq~tion that
ammonia compounds interact with the eame gating parCialeP that, according Co
the hypothesis in [il], are imnobil~~~d br depolarization nf the inactivation
- subuuie (h gatee) of the Na channel. A recently publiehed repore [12) concern- '
ing partial decline of Qon after in~ection of QX 314 (lipid-faet ltdocain~ ~
derivative) in the squid's giant uxon ia quite conaietenC aith the expounded
hypothesis.
;
a,fo
~r a b ~
~ ~ Q/O,a,QS i
_ c- c~"'~?-tt~ ~ ~
h-+t_t1t^nj o I -
~
o ~=(~1~
~ ' D,S '
' 9 � -
o ~
7
,
_ ~
i J ~ ~ -
~ 1ip !00 V~ m ?0 fI/ Y, mV '
Figure 2. Stationary distribution of shifted charge
1) in con.trol solution ~
2) responaes to svi.tching on after depolarizating prepulses~ 25 ms, {
V= 50 mV (triaagles) and effect of adding 0.2 mM QX-572 to control '
~olution (squares)
3) difference between cuves 1 aad 2
a) insert illustraCes pulse program
b) the same curves as in a, but normalized to the maximum
The authore wish to express their appreciation to the Aatra Firm, which ~
kindly supplied compound QX-572 for the experiments.
BIBLZOGRAPflY
1. Peganov, E. H., and IQiodorov, B. I. BYULL. EKSY. BIOL. I I~D. [Bulletin
of Experimental Siology and MedicineJ, Vol 11, 515, 1977.
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,
Z. Khodorov~ B. I.; Guael'nikova, G. G.; and Peganov~ E. M. DAN (Reports
of the USSR Academy of ScienceeJ~ Vol 244~ No 5, 19~9.
- 3. Keyaea, R., and Ro~ae~ E. J. PHYSIOL. (London)~ Vol 239~ 393, 1974.
4,, Dodge, F., and Frankenh~eueer, B. Ibid, Vol 148, 188~ 1959.
S. Hi11e, B.; Courtney, K.; and Dum, R. PROG1tESS IN ANE5Tl~ESIOLOGY, Vol 1,
13, 1975.
' 6. Peganov, E. NEUROSCILNCL. No 4, 1979.
7. Narahashi, T.; Moor, J.; and Poston, R. J. NEUROBIOL., Vol 1~ 3, 1975.
8. 5Crich~rtz, G. J. GEN. PHYSIOL., Vol 62~ 37, 1973.
9. Hille, B. Ibid, Vol 69, 497, 1977.
10. Khodorov, B.; Shishkova, L.; et al. BTOCHIM. ET BIOPHYS. ACTA, Vol 433, -
409, 1976.
11. Armstrong, C., aad Bezanilla, F. J. GEN. PN':~;SIOL., Vol 70, 567. 1977.
12. Almers, W. REV. PHYSIOL. BIOCHEM. PHARMACOL., Vol 82, 87, 1978.
COPYRIGHT: Izdatel'stvo "Nauka'.', "Doklady Akademii Nauk SSSR", 1979 -
10,657
CSO: 1870
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INDU5TRIAL MICR08IOLOGY '
' ,
UDC 576.858:543
- i
NEW MLTHODS OF PURIFYING VIRUSE5 FOR THE PitEPARATYON OF VACCINES ;
1
Purifying and Concentrating Viral Suspenaions
Moscow VESTNIK AKADEMII NAUK SSSR fn Russfan No 1, 1979 pp 32 36
[Addreas by S. Ye. Bresler] I
[Text] Opening the meeting of the Preaidium concerned ;
with new meChode of purifying viruses for vaccine pre- ;
paration, Che preaident of the USSR Academy of Sciences,
Academician A. P. Aleksandrov, apoke on the importance
of results obtained and the nontriviality of the approach
to the solution of this problem. Various aspects of the
problem were discusaed by S. Ye. Brealer (doctor of
chemical science at the B. P. Konstantinov Institute
of Nuclear Physics, USSR Academy of Sciences), E. A.
Fridman (doctor of inedical science at the Pasteur ~
Iuatitute of Epidemiology and Microbiology) and V. M. j
- Kolikov (candidate of technical science at the M. I. ~
Kalinin Leningrad Polytechnic Institute). ~
Preventative vaccination is a moat effective method for fighting viral
infections. But so that an administered doae of virus does not cauae '
- disease, viruses in a vaccine must be either changed from their native ~
form or killed (as in the so-called inactivated vaccines). As is
commonly knowa, viruaes are cultured in large embryos or tisau~e cultures, ~
so even f~r good virus yields in a final culture, viral proteins generally ;
compose less than 1/1000 of the prote~ns of the embryo or tissue. When
an organism is immunized the ~iruses must compete with a thousandfold
excess of other antigeas, i.e. inducers of immunity, and naturally the
final effect ohtained is aeak. Moreover, the introduction of a great
number of foreign proteins into an organism is fraught with many dangera:
allergy, increased temperature and other sometimea serious complications
are possible.
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Obviouely, in the preparation of a vaccine iC ie necessary eo purify
and concentraCe viral euspeneiona. However, even now Chie is ofeen not
done. For example, contemporary rabiea vaccir~e dif�ere little ~rom that
which was used by Pasteur. Agairiet tick-borne encephalirie a poorly
purified~ unconcentrated and consequently poorly effective vaccine is
used. Ag for influenza vaccine, abroad inacti.vated vaccinea are purified -
in u1CYacentri�uges. Since ultiracentrifugeg are expensive and ahort lived,
_ Chia method is not economical and the cost of one dose of vaccine is very
high. Moreover, as ehown by American scientiats in a recent experiment
which was also confirmed in our laboratoriea, high preseures in ultra-
centrtfugea (nearly 1000 atm) cause ~dissociation and loss of neuraminidase,
one of the moat important viral coat ~roteins. As a result the immunolog-
ical properities of the purified virus are altered and do not correspond
to the properties of virua circulating through the population.
Workers of the B. P. Konatantinov Leningrad Inatitute of Nuclear Phyaics,
USSR Academy of Sciences, tr~e M. I. Kalinin Leningrad Polytechnic Inetitute
and the Pasteur InatituCe of Epidemiology and Microbiology developed a
new method for purifying and concentrating viruaes ueing adsorption
chromatography.
For separating molecul~s and ions the chromatographic method was ahown
to be exceptionally effective and highly reaolving. But its application
, to viruses, i.e. complex structurea consisting of thousands of protein,
_ nucleic acid and.lipid molecules, was completely unaCudied. To us,
questiona on the revereibility of adsorption-desorption and on the stability
o~ virions (virus corpuacles) became cardinal. Since ac3sorption-desorption
is repeated many times in the chromatographic process, the requirement of
reversibility is very strict. An experiment ahowed that adsorption and
chromatography of viruaes on a rationally selected adsorbent proceeds
reversibly and that the virions are not damuged in this proceas. Thus
the proposed method vas approbated. Based on this a technological method -
for vaccine preparation was developed. The originality of the method ie
atteated to by the fact that patents have already been given for it in
certain countries.
The choice of adaorbent is very important in solving a problem by chromato-
graphic purification. The dimensions of its pores must allow viriona to
penetrate into the pores. The diameter of an influenza virus is 1100
angatroms. -
A suitable adsorbent, macroporous glass, was firat developed by S. P. -
Zhdanov with coworkers in the Institute of Silicate Chemistry, USSR
Academy c;..` Sciences. Th~ey determined that by fusing silicic and boric
anhydrides and annealing the mixture it is possible to obtain a ayatem
of the finest droplets. After grinding, the boric acid is removed from
_ them by the action of base and acid. This method was firet mastered by _
the Gor'kovakiy Experimental Plant. For the first t~ace in the country
the production of an adsorbent--macroporous glasa with pore dimenaions
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of about .5 micromeCera--was aet up �or use in the production of 3nfluenza
vaccine.
The chromaCographic purif3cat3on of virusea was studied in depth with
reapect to physical chemiaCry. Ie was determined that v3.rus adeorption
is reveraible and depende sCrongly on the concentraeiott of hydrogen ions
in Che medium. In order to quantitatively characeerize the affinitiy of
viruses far the glsas sur�ace, the isothErmal adsorpCiott was measured, i.e.
the dependence of adaorption on tt~e virus concentration in the aqueous
suapension. In working with such an unusual aubatance as virusea, apecial
methods had to be e~pplied for measuring their con.:entraCion. The number
of viriona per unit volume was counted directly wiCh an electron micro-
scope. It wae poeaible to carry out such an experiment, since we posaesaed .
- a method for obtaining viruaeffi in highly purified form. ,
Saeuration of Che adsorbent's aur~ace with in�luenza virus takea place at ~
the very low concentration of 10-11M (the concepta of gram-molecul~ and
molar concentration apply to virus corpuaclea), i.e, the proceas occurs
with a large decrease in free energy (on the order of 20 kcal/mol).
Adsorption increases as the temperature risea (figure 1). Consequently, ;
~ it ie not caused by a reduction of e~tergy but by an increase in entropy.
This is highly characterist~.c of hydrophobic interactione--when adeorbed
particles have water repelling properties. Since influenza virus~ like !
most other virusea, is covered with a film of lipids, such adhesion to ,
glass is quite natural. ~
~o
3 ~
Fi~ure 1. The isothermic adaorption ,
8 of influenza virus A2 on macroporous ~
~ z glasa at varioua temperatures. i
'o '
o ~
fi. 1. 15 C, 24 C, 3. 35 C
� C is the molar concentration of
~ 4 i viruaes in solution. Cm is the i
amount of viru~es adsorbed in gram-
_ 2 , moles per gram of glass.
p I 2 3 4 5 -
' C~10~; ron~
Al1 that has been said applies to electrically uncharged glasa, i.e.,
glass in a neu~ral medium. But the surface of glass is covered With
silanol groups (SiOH), which are negatively charged in a weakly basic
reaction environment. Negatively charged virions are repelled from '
the charged glass, and under critical conditions (when repulaion is
16
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equalized by adheeion) a whole layer of viru~es is washed from Che glses
(figure 2). The procees occurs ao abruptly thaC we c~ll the phenomenon
criCical adsorption~deeorption.
~oo
' Figure 2. The dependence of Che
so desorpCion of A2 influenz+~ viruaea
_ on hydrogen ion concentration.
Key:
:r
~ ' 1. Percent eluted -
- zo
o ~
8 7 8 0 10 11 pH
The physical resenn for the abruptnesa of the phenomenon is clear. The
free energy of binding, as already mentioned, is approximately 20 kcal/mol.
Ther ChermaZ energy of oecillation for the virion relative to the aurface
is G00 cal/mol, which is only 3 per cent of the binding energy. Therefore~
the virusea can be eluted in a small volume with a 20-30 C~mes increase
in concentration.
An underetanding of the role of hydrophobic interactions allowed a subse-
quent increase of desorption by adding organic aolvents. The critical
conditions for deaorption differ aharply not only among different viruses
but even in different straina of the same virus (figure 3). This creates
favorable conditions for Che chromatograptiic proceas--the release of viruses F
is total and aharp. This allows not only purification from all admixtures
but also concentration of the viruaea.
100
o~b Figure 3. The dependence of the
~ ~ ~ desorption of Ap and A2 influenza
viruses on hydrogen ion concentra-
~ tion. 1- Ap, 2-~ A2
2b
2 4 B 8 10 pH 17
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Based on the physicochemicgl atudy of virua gbsorption chromatography e _
tiechnologically acceptable method was developed fo~ preparing vaccinee
against influenza, thick-borne encephaliCie, poliamyelitis and rabiea. In-
fluenza vaccine is aYready produced on a eemi-induetrial sc~le and ie under -
going maseive Ce~ting. Therefore tihe remainder of Chie speech wi 11 refer ,
Co it, although the method of puri�ication and concentration ha~ been shawn
ef f ective for aLt Cested virusea.
The developed method combines several procedures which give poCential f or ~
ad~ uat3ng Che metihod to new influenza virus atrains. Production begins with
- Yep roducCion of an.influenza virua which the World Health Organization re-
porta ae havi,ng a dangerous dietributian in early fall. '
The virus is culCured in ten-day o1d embroys. Two days after an embryo is
infected zlie allaneoic fluid ia drawn off under vacuum. Each milliliter of ~
Chia f luid containa over 109 viriona. The liquid is deveLoped on a chroma- ~
tographic column filled with iarge-pored glaes (pore diameter 5000 angstroma).
The column ~.s eaturated with viruaea which are later eluted in a emall vol-
ume at pH 8.5. About 100 1 of allsntoic fluid ia required to eaturate the
column, and a volume of 3-4 1 ie used for eluti a?. In all, the viruaee are '
purif ied appraocimately 1000-fold and concentrated about 30-f old (figure 4) . ~
E z~
r.~~~~~ TMTP ~
~E
bU00 60 r I
I i '
aooo ao I
` r I ,
a ~ (
Fc�' 3000 3 ~ i
~ (
i
~2000 0~ ( ~
I ~ _
~ ' ,
1000 Ioi (
~
~
200 400 800 800 1000 1200 I400 V, rn
Figure 4. Chramatograms of A2 influenza virusea on a macroporoua glass column _
On the right are curves of desorpticm from the column; curves cn the left
characterize columa alisorption; the dotted curve repreaenta the totalamount
- of protein as measured by light absorption at 280 nm; the continuoua curve
shows the titer of viruses.
Key:
- 1. Titer by hemagglutination inhibition
18
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In the lnboratory of acgdemician G.N. Flerov (Joint inatitute of Nuclear
Reaearch) a method was developed for producing membranea necessary for this
purpose. Hol~s are mad~ ~.n lavean f ilm by ionic bombardment in a cyclotron _
and suba~quent etching in base. Unlike ce~.].ulose membranes, nuclear filters
have etrictly calibrated holee which grea~ly facilitate the eolution of our
problem. -
For the concentration of several virus straina, the adsorption-deeorptian '
method wae applied to tha eurface of eryehrocytes. Sometimee it was poseible
to additionally purify an already concentrated virua suspenaion by gsl fil-
- tration on the same macrQporous g]ass. The gl~sa surface is chemically
treated and as a result becomea extremely hydrophobic, i.e. abeoluCely un-
adsorbing. A viral suepeneion ie paeaed through a sma11 coluain filled with -
the modified g~ass. The glase poree are selected so that impur3ties pene-
Grate into them but virion~ do not. When a auepeneion is paseed through
the column, viruaea pasa more rapid ly and impurities remain behind. This
procesa ie cal].ed gel filtration. It is noC always neceaeary to apply the
whole arsenal of inethoda; the combination aelected 3epende on the virus.
- The final procesa ie inactivation of the virusea with ultraviolet light of
' 254 nm wavel~ngCh. Inactivation proceeda with a etrict dose in epecially
consCructed devices. After passing all of the neceseary control stepe, the
virus is ready for iesue.
The scale of vaccine productian by a semi-industrial p1anC in Leningrad was
200,000 doaea per month in the autumn of 1977. On the average 3 doees are
obtained fram one embryo. The coat of a doae is about 60 kopecke. During
September-November 1977 over 600,000 doaes were isaued and used for vaccina-
tion of the Leningrad population.
During state tests conducted by the L.A. Tarasevich State Inatitute for
Standards and Control of Medicinal Biological Preparations, Che vacciiie was
ehown to be highly effective. The sick rate for people who had been vaccina-
ted was 3.5 timee lesa than for thoee unvaccinated.
The technology of virus purification by chromatography can be realized on
an industrial ecale--for the production of ~.en million doses. In addition
it ia neceseary to extend it to ot3ner viruses, since the described method
~ appliea also to their purificatian and concenCratdon.
COPYRIGHT: Izdatel'stvo "Nauka", "Veatnik Akademii nauk SSSR", 1978
Adminiatration of Inactivated Vaccines
Moscow VESTNIK AKADFMII NAUK SSSR in Russfan No 1, 1979 pp 36-39
[Address by E.A. Fridman]
[Text] Inactivated inf luenza vaccine ia a suapension of virions. It be-
longs to the categorq of corpuscular vaccines, where the virions are not
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damaged and maximally purif3ed. It auff ices to eay thae the protein conrent ;
of vaccine issued in 1977 does not exceed 100 micrograms/ml (not more than
20 micrograms/mi in a dose). Thie is a minimal pro~ein contenti for v~ccinea
in thie category. The concentration of virione is approximate~y 1011 per
milliliter. According to our observations such a conc~enCrat3on gives eat- ~
iefactory immunity~ i.e. abiliCy of the preparatian to cauee the formation i
of protective anCibodies in an organism. t
_ � ~ ~
After each dose of 3nactivated vaccine is adminiatered the content of in-
fluenza antibodiea in the blood of a human sharply increasea (figure 1, ~
table 1). It is commonly known that a Cit~r of 80 hemagglutination unite ~
of antibodies per .2 ml blood s~erum is aufficient to protect an organism i
~ fram homologous influenza virua atrains. A11 the values in table 1 eig- ;
_ nificanCly exceed Chia level. !
~
I
Table 1. The immunological activity of inactivated chromaCographed '
moaavaccinea obtained from various influenza virus etrains
C e,~netl reo~~orpt~veciu~tl i
~ACTqT& � TIITp 81t1'NTOJt
ZIHCJIO Nnd7HOC b(~~
HdKilrgHYll IIIT6MN IIpNgNTp~X ~~C~N ~�~en' 8I (7/ C0pON01t- \
eo II 6 ~
~ ~1 ~ `2J cWOO~lske CW6UpOTtt! BC CNR
(8 ) A(I'ogxoar) 88 20 95 ifl,7 938 i7,! ~
A 23aic~ropns) 72(9~ 3i 83 18 8i5 i9,7 ~
(10~ ~tAC) 1i 30 80 8,7 218 25
A IIloraanAux) 74(~ ~ 42 88,8 34 239 ?
~12~ JIeaearpaR) ?8 21 80.9 18,4 !47 7,4 ~
s ~ 80 78.7 i7,i i47 8,8 ~
3~ B(Aaoses) i8 72,2 34 294 8,8 ,
' i
*in persons with original antibody titer 1:20 i
Key: . -
1. Vaccine type
2. Number innoculated
3. Frequency af serum conversioa 1
4. Geometric mean of antib ody titers j
- 5. In I serum i
~ 6. In II serum
7. Mean multiplicity factor for serum conversian ;
8. A (Hong Kong) 68 '
9. A (Victoria) 72 ,
10. A (MRS) 11
11. A (Scotland) 74 '
12. A (Leningrad) 76 ,
13. B (Japan) ~
i
;
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,
= Figure l. Dietribution of indicators of
humoral immunity. Vaccine A(Victoria) 7~`
30 wae adminietered once (0.5 mi subcutaneou~ly).
- o , -
~ 1-ehe sick rate of unvaccinated pereone
~ 2-the sick rate of vaccinaCed pereone
z
~ ~o ~
M
~ Key:
A. Number of persona with the indicated
antib ody titer (per cent)
� t0 B. Antibody titer
~
y b
3
~ tl 10 90 10 BO 190 3Z0 94011~0 1090
Tnrp ~tN�n ,
~ ~B ~
An experimental seriea of vaccinea was tested against various virus atrains.
It was determined that thia method ia universal; it is posaible to prepare
vaccine againat any strai.n which has appeared (see table 1).
Different doses of vaccine were tested. A final decision on the optimal
doae will be passed by the Inatitute of Standarde and Control o� Medicinal -
Biological Preparations. However, it is already nvw poasible to say that
the dose is not large; .2 ml vaccine prarvides brilliant resulte (table 2).
Table 2. Reaults of a blood serum atudy of persons innoculated with inacti-
vated inf luenza vaccine during fall 1977 at Leningrad induetrial
plants
~4Uta Huc c ttocro- Cpeaentt reoNarpu-
~epawai ~~apacra- vecr.atl rurp ~;~,pTpOCY'ti
u~~ou Tnrpu aHr~~ien ~ atsrcirea
- Iia~ieK- Tloaa Yncao o6caa- HBQACT9N1[R -
- TDH SBNANHbI~ ~08811I1NX C7Q(0 , 1tOC1i0\~+ Tft?pOD
' M+~ n~~4 \ 1 aarnren
~ /n\ a6C. aa rtptlB{tBNII flpAlllBhli /p~
l l~l 1 l7
1 0.i 199 1/5 72~8 ( 15~9 ( 3 8 I 20,8 ~
J~ 2 0,~ 9i2 I !02 I 91
Note-the vaccine was adminiatered by intracutaneoua in~ection. -
Key:
1. Group
2. Vaccine dose (ml) -
3. Number of examined pereons
4. Those with sufficient accumulation of antibodies
5. Abeolute number -
_ 6. Geometric mean of antibody titers
7. Before vaccination
- 8. After vaccination
9. Multiplicity factor f or antibody titers
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~ ~
A very important property of the preparation ie ite safeCy. A weak reaction . j
is very aeldomly observed when Che vaccine ia directly adminiatered. Attempte
were made to determine whether or not administration of the vaccine reduces '
- reeietance Co oCher diseasea. AC the left of table 3 i.s a liating of dieeases ;
which appeared in people during seven manths after innoculat~on; inf luenza
_ and other acute reepiratory diseases are not the only diseaeea included. ~
- It was determined that the innoculated and uninnuculated per-centages of i
those di.d not depend on whether the preparation was adminiatered or not. ~
. Consequently, the vaccine ~can be concluded eafe. ~
Table 3. The total aickness among persons vaccinated with inactivated ~
- chromatographed vaccine during the seven months after vaccination
- (excluding influenza and other acute respiratory diaeases)
~Iucno aaGoneeaFUCtl ~ _
rIlpeVOIIb OOn880A~ it(1NBNTW9 uenpuexrwo ,
` 31(1119 ye~t.) (811 9ea.~1. ~ , I
~ ~ ~i
Aarrtga, OGOCTpBIIHO XpOIIII~ICCI~OTO TOH31[17IRTt1, 6poaxx- 257(18,it?6) 135(22y6) I
~5~ Tbc, nuesrsoarte, ry6epr~�nea. acTp~e x;e:~~�Ao~cuo-xu- ,
rne4nbte au6oneaunun, xpou~cv~cr,rte Goneann ;r,enyRr,a,
b07C3[!ll nenuu~t {I IIORCI~, IICBptl7lC1[I[, IIC8p1It6i 3I Qp0- � , ~
e~e Goaoautt nepesoii cncseni~.r, peabcerna~i, ~rcnepru- ~
noct+no sa6oneeunttn, rnuitIIaie npor;ecc~, 6orceaBa
~ Kox:H i
I ;
Key� '
~1. Liat of disessea � I
2. Number of illnesses '
3. Vaccinated (1419 perao~s) ~
4. Unvaccinated (611 persans) ~
5. Angina, aggravated chronic tonsillitis, bronchitis, pneumonia,
tuberculosis, acute gastric-intestinal disease, ~hronic etomach
sickneas, liver and kidney diseases, neuralgia, neuritis and
nervaus system disorders, rheumatism, allergic diseases, suppura- I
tive processes, skin disea8e
Data from state experiments conducted in 1974-1975 atteata to the high
epidemiological effectivenesa of inactivated vaccine (figure 2). In o~z~ ~
case the preparation was administered at the height of the epidemic. The j
well timed administrationr:of vaccine gives even more convincing reaults =
(figure 3) . ~
_ There is stilY another poasible use of vaccination--for the preparation of
anti-inf luenza donor medicinal gama-globulin. This method has been known ~
and applied since 1964. It is an extraction of blood serum containing ~
great quantities of inf luenza antibodies. Since the preparatian ia made ~
from donor blood, its productian is limited and suitabl~ primarily in '
pediatrica. . (
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A oe �
1
~ ~
- ~A~ ~zd
~ ~ ' ' ~
~ L` rl r'1
_ ~ ~ �
- / 1 ~ I
~
e
~
o �
A~M~bp. Rh~~D?~H~~p~n~ Mipf Anp~e. H0~6p~ AM~P~B~ ~ rMprM MNt
Figure 2. The incidence of influ- Figure 3. The iflcidence of influen~.a
euza and acuCe respiratory infec- in the Poligrafmaeh plant during 1975-
tione among a group observed in 1976. Vaccine A(Scotlaad) 74
1974-1975 (Data from (GISK)
1--sicknese amoag thoBe given a 1--eickaess of the uaveccineted
placebo (ealine solutian aot coa- 2--eickaeee of the vaccLnated
taiaing vaccine, 2--eickaess among '
thoae vaccinated aith A(Victoria) -
72 vaccine
Key: Key:
A. Number sick (per cent) A. Sickness per 1000 people
B. December, January, February B. November. December, January,
March, April February, March
Vacciuation of donore with iaactivated vaccine increaees the content of
influenz+a antibodies ~a their blood 6-12 times more thaa doea admini~tra-
tion of other vacciaes. Thus the activity of the preparation sharply in-
creasea. The Pasteur Inatitute of Epidemiology and Microbiology took ~a
the obligation to provide thia type of vaccine to all plaats ia the couatry
which produce this gama-globulin. Doaora are vaccinated once p~r year.
Observatione are also made on the safety of repeated voccia$tion.
Up to recent times vaccination was quite expeasive. Noi+ the cost of prep-
aratioa has beea reduced to 90 kopecks per doae. A real possibility ~xiets
- for lowering it further.
COPYRIGHT: Izdetel'stvo "Naulcu", "Vestnik Akademii nauk SSSR"~ 1978
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New Metihnd for Viru~ purifica~icxt
~
,
Mn~~dw V~STNIK AKAU~fII NAUK S551t in ~tug~inn Nn 1, lgy9 pp 39-42
_ (Addres~ nf V.M. Kolokov~
(Text~ The baeis of a ttew mpthdd far viru~ parific~ti~n i~ eh~ phpnomenon
of criticai adeorption~degorption.
Th~ probl~m ia a pracricel scheme i~ tn r~aliz~ thie phenomenon and thereby
obtein the n~ce~egry d~gr~~ of virug concentration ~nd purification.
The complexity of Chi~ prablem i~ determined by the prop~rtie~ t~f th~ viral -
suepension. 'Cemponents of the eugpeneion not unly hinder virus adsorpCion
but al~o make iC frequently irreveYSible. In order to develop the effecC
the golution ie eub~ected to preliminery purification (the eubetances in- ~
terfering with virue adsnrption ~re r~moved) and an optimal adaorbent pon~
geseing high ad~drption capgcity is ~elected. . -
The ~deotiption capgcity ie d~termiued by Che amount of surface gcceesible
for virua adeorption, and thie Co a large extent depende on the pore dimen-
sion~. It increases With pore eiz~, eince the larger the pores~ the more
aurface available for virus adeorptien. An increase in the capacity Leads
to a~n increaee in the virus coaceatraticm and purity after deeorption. Thie
tendqncy is demonetrated by a eeries of influensa virug chromatograme.
In thE eluate from a column of macroporoua glaes with pore radii of about
700 angstroms the virus concentration regches several thousand hemagglutina-
tien unite. The degree of concentratioa is 10-15 times. When g Lao vith _
3000 angatrom pore radii is used we obtain a greater degree of concentratiea
- (20-30 times) aad ten thousand hemagglutination units per milliliter. In
_ the eluant fram a glass column vith pore radii of about 8000 angetrome the +
concentration ia increaeed a hundredfold (see figure la,b,c) aad reaches i
a hundred thoueaAd hemagglutination uaits. Such a concentratioa ie obtain- ~
able only with an ultracentrifuge. A eimple column filled with glass ie
becoming competitive urith a moat complex machine-the ultracentifuge.
Close collaboratioa ~rith the I.V. Crebenahchikov Institute of Silicate
Chemistry. USSR Academy of 5ciences, aad particularly with thc laboratory
of S.P. Zhdanov allaied us to obtain and test nes+, more ideal forms of
macroporoua gtass.
All thaC has been said ehaws the posaibilitiee of the adeorbear, gad the
method. Now the task is to work out the technology. i.e. the realization
of critica~ desorFtion on an industrial scale.
, -
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,
a
~ bOdO
i
~ +
(1)~ ~o�~
~
- ~ e _ n zo ze v,.~ '
6
~eooo -
~ iaono
W
~
� '
(1)g eouo
r �
- M
�
" ~ s a a zo a~ ~e v.w -
� -
1
I
aooo~�
~0�h
- ~ .
�ooo~
s~ooo ,
aooo . .
i ~
~ aaooo
~1 ~~~e~0ouo
srooo
~ooo
, ooaoo
~
~eooo .
wooo '
+aooo .
~oooo ~
+
~ooo w~~.r~c_,~,*,r.f_i--
o~ n w sa ao oe ao i~e i~s ia v..~
Chromatograma of influeaza virus oa a column ~rith macroporous glaes gaving
various pore radii: A--radius ie approzimately 700 aagstroma, 8--30p0 -
angatrame, C--8000 angstroma
1Cey: .
1. Virus titer (~iemagglutiastioa unite per milliliter)
25
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FoR o~rc~u us~ ornY ~
A.Y. riudorov (diY~ctor of the In~eitute for Work ~
Hygieae and Profeeeional Dieease) r~poreed thaC approxi- ~
mately five hundrQd thoueuad r~~idente of Leniagrad
were vaccineCed in 1977. Not 6eing abie to epeak nn ;
the ftnal effective:ie~e of Che immuaiaatioa, he lieCed
sev~ral undoubred merits of thc new vaccine. Firee~
it do~s not cause any unfavorable responeee in humanr. ~
Secatdly, the method of admiuietr~tioe ie so eimple
thet many people can be innoculnted in a ehort time~
and vhen a high percent of the popul8tion is vaccinated
a col];ective i~omunity ts cr~ated. t+inglly. instre- i
cuteneoue admini~trgtion of the vaccine gugrantees '
im~unizeCion.
~
K.P. Sel~~nev (Leningrad Polytechnic tnetitute) atreea~d
that the creation of the new method for virue purifica- ~
tion is Che result of cooperation betWeen phyaical chem- ,
iate and engineere. All of the experim~.~ntal apparatua
was developed aad manufactured in the Polytechnic Ineti- '
tute. The faculty of the biophqeics iuetitute are de-
velopir,g several important ecieatific areas a~nd they ;
are also training engineer-biophyaicista. However~ more
than on~ce queatione have been raised on the enclosure :
of the faculty as not conforming to the profile of the '
instieute. K.P. Sele~nov asked the Preeidium of the ;
USSR Academy~~of Sciences Co gupport the faculty'e lines
of work.
Correaponding member of the USSR Acsdemy of Sciencea :
M.H. Shul'ts devoted his addrees to the problem of or-
~ ganizing the production of poreus glasses. The produc- ~
tion of glass vith regular porositq is of fundamental ;
importance for the creation of various vaccinea. Ia ;
the Institute of Silicate Chemistry, USSR Academy of .
Sciences, the laboratory of S.P. 2hdaaov ie euccessfully
workiag ia this directim, but in order to set up ex-
teneive vaccine production ii: ia neceseary to organize '
the production of porous glass oa aa induetrial acale.
A.I. Aublevakiy (Joint Inatitute of Nuclear Physica)
drew attention to the orgaaizatioaal complexities in
the production of nuclear filtere, ahich are uaed for -
additional vaccine purification. It is extremely im-
portaat to arganize their production on a maseive scale.
A.N. Rublevskiy was supported by academician H.A. t~iarkav. i
He stressed that nuclear filters can be used not onlq '
for purifying viruses but also for other moet diverse
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purpo~~~. ~n Ch~ opini~n of M.A. Markov, it ie eeeential
th~t ~tat~ bodies orggni~e Ch~ produatiion and broad intro-
ductia? of the new fiit~re ittto naCiongl induetry.
T.V. Peradse (director of the Paeteur YnetituCe of Micro-
bio~ogy and Spidemiology) epoke on yet another extremeiq
imporCant feature of tl~e n~r method fior vgecine produc-
tion--the epe~d of th~ procee~. While the preparation -
of live inf 1upn~a vgccine~requiree over ten month~, the
n~w method permite theprepgratim of vacciue in ouly
one and a half months (including all control etepe).
Thug~ aie and a half montha after a nev virue appears
in the country, a vaccine caa be prepared and ueed in
practical public h~ith service. The vaccin~ ie aleo
very effective for the prdduction of active aad highly
purified donor gama-giobulin. Whereae 5-6 innoculn-
tiona vere previously required to produce a~ufficient
quanCity of antibodies in the blond of doaore, nosr one
vaccination per year is eufficient. T.V. Peradse nored
that auccees in creating the ne~r method for purifqing
vaccinea waa provided by the collaboration of phyaiciets~
= doctore and engineera. -
The vice preaideat of the U3SR Academq of Sciences, -
Y.A. Ovchiaikw euggested that the wave of virel dis-
eaee ie groving. Inactivated vaccine ia a verq active
agent, and the technolAgy of ite preparation ie origiaal
and pYagreesfve~ The actual prablem is to orgaaise tha
prcduction of vaccine in industrial quantities and to
apply it in general. Y.A. Ovchinkav urgee that the
Yreeidium turn to the USSR Hin~istrq of Public gealth
with a proposal to epeed introduction of the nesi method
for preparing'vaccinee into industry and to draw otber
aervicea into aork on thie task. The vice preaident
also underacored that the methode conaected aith chrama-
tographq on poroua glaes aad uaiversal aad are applied
in sanq fielde of acience and iaduatrq. It ie neceseary
to in every aay pramote i+ork in this area.
In concluaion, the preeideat of the USSR Academq of
Sciences~ academician A.P. Alekeandrw eaid that active
auppart wae contributed to the development of the ne~+
method for virus purification bq both the Academy of
Sciences and the Leaingrad party organization. This
helped Leaiagrad ecientists to rather rapidly obtain
importaat resulte. Th~e time betWeen the onset of aa
epidemic and the firat kna~ledge of the dieeaee ie
about three months. The nea method. ~+hich requiree
anlq one aad a half montha for the preparation of
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vgccine fnr gn id~ntiifi~d virug ~Cr~in, p~rmit~ op~r~-
tional prep~r~dn~~~ for an epidemi~. Acgdemicign
A.1'. Alekeendrov expreeeed ehe opinion that the work
of Leningrad ~pecialiete d~eerves greae ~ppreciaCion
- and i~ worChy Co be nominat~d f or prize coropetition.
COPYRIGliTs Ixdaeel'etvo "Nauka", "Vestnik Akndemii nauk SSS~t"~ 1978
Regolut3on of eh~ U5SR Acgdemy of Sciences
Mo~cow V~STNIK AKAD~ITI NAUK 5551t ~,ri Ruggign No 1, 1579 pp 42-43
(Text] Th~ Preei~ium of the USSR Academy of Sciencea accepted a reeolution
approving the Work of the B.P. KonetgnCinov Inatitute of Nuclear physice~
USSEt Academy of Sciencee, the M.I. It8lirin Leningrad Polytechnic institute, .
and the Paeteur Ynetitute of Epid~miology and Microbiology on creating nea
methode of purifying virueeg �or vaccine preparaeion and for the productian
of inactivated influ~nza vaccine. ;
~ A d~cieion wae made to requeat the ItSFSR Miniatry of Higher and 5econdary
Education and the RS1~5R MinisCr}� of Public Hea1Ch to commiasion the M.I.
Kalinin Leningrad Polytechnic Institute and the:Pasteur IneCitute of
B~idemiology and Microbiology togehter with the B.P. KoneC$ntinov Leningrad
' Inetitute of Nuclear Physics to finish working out technology for the pro-
duction of influenza vaccine. These insCitutiona are to esCimate the
poseible induetrial undertakings on which this technology will be applied
and to accelerate development of the production of vaccieee for tick-borne
encephalitis and rabiea.
The Presidium of the USSR coneidere indiepensablc~ the organizatian of the
production of DV-1 glase with primary thermal treatment according to the -
mebhod proposed by the I.V. Grebenshchikov Institute of 5ilicate Chemistry,
USSR Academy of Sciencea. This glass is to be provided to the Gor'kovekiy i
Experimental Plant of the All-Union Science Research Inetitute of the
Petrolpum Refinery Industry.
The production of macroporou~ glaea from DV-1 glasa ahould be organized at
the Gor'kovekiy Experimental Plant in accordance With technology developed
by the I.B. Grebenshchikw Institute of Silicatie Chemietry, USSR Academy '
of Sciences, together With the plant.
The Presidium of the USSR Academy~~of Sciences d~cided to requeat the USSR
State Committee on Science and Technology and the RSFSR Council of Minis-
ters on the Use of Atamfc Energy to 8ecure Work on the preparation of nuclear
filters in the laboratory of Nuclear Reactions, Joint institute of Nuclear
Research, having given out aeaignmenta, state unita, materials aad equip-
ment necessary for these goals.
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It ig r~~olved td ~sk' th~ ItS~'S~t Miniatry of Highpr and S~condgry Sp~cigl
Bducgti.an gnd the U83Et 3tat~ Pl~nning Commi~eion to etr~ngthen tfie mgeeriai
base of the biophyeice deparCmene ati th~ Leningrgd polytechnic Ynatitutie,
RSFSR Minietry nf Higher Lducational Insei.tutions, and to organize the trein-
ing of young epecialis~s 1n Che epecialty Lngineering Biophysics. Yt ie
~1eo resolved to request the U5SR 5tate Committee on Science and Technology -
to epeed ehe organization of ~ laboratory ~.n thQ Leningrad polyCechnic
Inaeitute for the t~chnology of antivirug preparaCion~.
The Presidium of Chg USSR Academy nf 5cience~ decided eo requ~~C Che 1t3FSR
Ministry of Public Health and the RSI~SR Ministry of Higher and Secondary
~ Speci~l Education to ~~ard prise~ to workere of the Inetitute of ~pidemiology
and Microbiology aad th~ Leningrad Polytechnic InetiCute who have eaken p~rt
in the creation of inactivated influenza vaccine. The Preeidium also
recomimends that awarde be gtven to workere aho have participated in the
application of the new vaccine to vaccination of the Leningrad population.
COPYRIGHT: I~edatel'etvo "Nauka", "V~~Cnik Akademii nauk SSSR", 1978
9342 '
CSO: 1870
.
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_
I
~ox or~rcrnt, u~~ orn.Y ' ~
M~CItO~IdLOCY
UDC 576.093:5~6.9.0097.29 I
TOXIGENICITY AND EtV'i'ONbP~THO~NICITY OF DIFFEI2ENT BAC'1'ERIA STRAINS OF THE ;
&1CTLLUS CEREUS-THUItINGIENSI5 GROUP ;
,
Moscow DOKLADY VSESOYi~2N0Y dRD~NA LENINA AKAD~MII S~L'SKOIWOZYAYSTVENNYKH i
NAUK IM~Ni V. I. I,ENiNA in Itus~ign No 2, 1g79 pp 17-18 '
(Artiale by Dr 5ci 0. Lys~nko, Dr Biol Sci N. V. Kandybin, and A. A. SCus', ,
Czechoslovak Academy of 5ciences Inatiitiute of ~ntomology, and the All-Union
Scientific Research Zns~itute of Agricultural Microbiologyl `
~
[Text1 The toxigenicity of bacteria is oftien utilized in infectious :
entomopathology for thexr ic~entiificatfon. One of the principal diaqnostic
characteristics of BaeiZlus thuringiensi~ is the crystalline entomocidal
endotoxin they forn?.. But under certain conditiions on one hand theee
bacilli lose their ability to praluce cryatalline endotoxin and, on the
othcr hand, they easily recover it on enterinq the body of a ausceptible
insect (5). We know that some microorganisms produce a large nwnber of ;
metabolites havinq entirely dif�erent deqrees of toxicity to insects. It
- would be theoretically valid to assume ~ati the virulence of a microbe
depends ln the end on the cumulative action of ali of the pathogen's i
eoxic metabolites on its host (3~4).
Scientists of the All-Union Scientific Research Institute of Aqricultural -
Microbiology are conducting a detailed study of this problem jointly with
the institute of Entonwloqy of the Czechoslovak Academy of Scienc~g on the
basis of a bilateral CEMA agreement.
The goal of our joint research is to atudy the correlative dependence
between the entomopathogenicity of Baa. thuringiensis and Bae. ae~'~eue and
their enzymatic and toxfgenic activity. We used 10 strains of Bae.
thurittgT,ertsis and five strains of Bao. eer~eus (from the collection of the
insect patholoqy laboratory of the Czechoslovak Academy of Sciencea
Institute of Entomology). For some of them we first determined the extent
of production of enzymes and entomocidal toxins--proteases, phospholipases,
"eqq yolk clearinq" factor, thermostable exotoxin, and crystalline
endotoxin.
The entomopathoqenicity of the bacterial strains was studied with a :
laboratory population of the bee and flower moths (G. meZZonella, ~hestia
30
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kt~hnigZZa), and wi~h natiurai pdpui~tiidn~ c~f tih~ brnwn-ti~iled motih (~upr~d~ze
dhr?~eorrhoag), th~ lackey na~h (MaZaQOgoma n~ugtr~a), the eatin motih
~StiZpnot~a eaZ~ai~), and tihe fruie-eree ermine motih (N~portom~auta pod~~tuv).
Th~ bacterial atraine were grown in 750 ml ~~g~ eub~e con~aining 35 ml
mer~ium (corn extract--3 per~ent, glucog~--0.5 p~~t~en~)= ~h~ tegt ~ub~~ were
- plaoec~ in an agi~a~or (180 rpm) a~ 28� for 72 hc~urs.
7'h~ ing~ctig w~re infecti~d perorally or by in~ec~inn of ~he pa~hogen in~o ~he
body cavity.
For peroral infection, feed treatied with microbial ~u~p~nsion h~ving a gpore
titer of 25, 50, 100, e~nd 200 million/ml wag fed ~o caterpiilars in age
clagges i and ii. Each dose wa~ used on 10-20 caterpillars witih ehree�old
replicaeion.
F'or parentieral infectiinn, ~teril~ culture fluid filtirate or itg 1:10 and
1s100 dflutions were in~ected into the body cavity of CaZZeria meZZoneZZa
age ciass VI caterpillars at a dose of 0.006 ml per specimen. The filtrate
was obtained through a 2eisg bacterial filter. Insect death was determined
after 3, S, 10, and 15 days. To assess the virulence of individual atrains,
we felt it auitable to computie the DLSp for each strain by the qraphical
eampling meChod. Analyzing the data we considered nnly Chose values which -
yielded to computation within the qiven range of doaea, the DLgg o! which
did not go beynnd this range.
Al1 strains were subdivided into three groups in relation to their virulence
with respect to the listed insects. The ffrat, most virulent group contained
four strains of Bad. thuringi8neis, two of which were of the firat serotype
(No 898 and No 058), one was of the third (No 751), and one was of the
sixth (No 902). All of these strains had a pathogenic actfon on experimental -
insects in relatively small doses. The second, le$s virulent qroup contained
seven strains, of which five were Bac. thuringiensis and two were Bao. e~r~eus
(No 905 and No 906). The virulence of this group was significantly different
fromthat of the first. The third, least virulent group contained four atrains,
to include one strain of Bae. thuringiensis var finittimue and three atrains
of Baa. aereus. The entomopathoqenicity of strains in the third qroup
turned out to be very low, while the enzymatic activity of this qroup was
not inferior to that of strains in the first and second qroup, and in
relatfon to production of proteases, phospholfpases, and hemolyeins one
- strain of Bae. eer~eus was significantly superior to all of the other
- 14 strains.
Evaluation of the strains in relation to their enzymatic activity, toxiqeni-
city, and virulence to insects would demonstrate absence of a correlation
betwoen these indices.
- Thus all strains of the first, most virulent qroup form crystalline toxin.
The latter fs also formed by four strains of the second, less virulent
31
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grr~up, in which ~a~e g~rain Nn 902 0� +~he �ir~~ group ~nd ~tir~in N~ 903 0� ~
the gecdnd group ~re algo gimi.lar in ~ntiigenic etrua~t~r~. Strain N~ 904 of
the gecond group prdduce~ no~ only crygti~lli.ne tioxing bu~ al~o tihermo~tabl~
exotioxin, and in r~latiion tio virulence i~ is inf~rior to g~rain~ of t.he
Eirgti group, eom~ of which do not form ~xotioxin.
Cons~quentily the amounti of toxic metaboli~~g form~d by ~h~ gtra3n~ ~n vitm
and th~ir N-an~ir~nic gtiructure are not gufficienti tio d~scribe the entcmo-
pa~hogenic ch~rac~eris~l.cs of the a~rain i� v~UO. There c~n b~ no doubt
tihat suah a generalizatiott containe a nwnb~r of limitia~iong stienaning from
tih~ choice o� the matierial for atur~y and the methods ~mplnyed. Yti ie
probabl~ th~~ giv~nnure-thor~ugh multivaria~ional analysis of all of the
~xperim~ntial matierial, gome otiher depend~ncieg could havQ be~n revealed.
Moreover the accuracy of DL50 valueg obtained by means o� per os infe~tion :
ar~ relatiive. On the other hand infection through feed is cloeer tio
- n~rurai conditions than forc~d-f~~ding. The advan~age ~nd tihe relative
dependabili~y of our resultg 11~ in the multifactorial. natur~ of our
experim~ntial materi~i, which was obtain~d witt? many bac~eriai gtraine and
geveral insect species. Hence the obtiained values are mutually comparable, ~
and their rele~ive dependability is satisfactory.
From a theoretical stanc~poin~ the rejection of a dependence between toxin
�ormation and virulence sounds paradnxical. But such cases are no~ in-
fr~quent, and they require explanation. Similar paradoxes were revealed in
research on the mutual relationships between entomopathogenic bacteria,
nematodes, and insect hosts (4). Hacterial strains exhibitinq the highest
virulence to insects lost this property when in associatian with paraeitic
nematodes, while weakly virulent atrains, on the other hand, cauaed exteneive
death of insects when in such an asaoaiation.
Uifferent atrains of Bac3. cez~BUe, Bae. pumiZus, and Bacs. Ziaheniformis
differed noticeably among one another in relatfon to entomopathogenicitys ~
Some caused 100 percent mortality of bee moth caterpillars injected with ~
- 40,000 celis, while others had no effect when injected at a dose of 250,000-
1,000,000 celle (1). in our opinion such anomalies can be explained
mainly by the instability of action of toxic metabolitea, which depends on ~
the conditions and place of manifestatfon of this action, not to mention the
susceptibility of the macroorganism and its protective mechaniema. Moreover,
we knaw that many microbial metabolites becane toxic onYy when coaibined with
other nontoxic metabolites.
Consequently the entomopathogenicity of a microbe cannot be redueed to juat _
the action of its toxic metabolites alone.
Many important problems in the pathoqenesis of insect bacterial infectfons
have not been studied yet, which is even true for infection elicited by
Bae. thurzng'iertsis. D~eeper joint research on microbial entomopathoqenicity _
under CEMA sponsorship will doubtlessly promote further development of
mfcrobioloqical science in qeneral and infectious insect patholoqy in
particular.
32
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BIBLIOGRApHY
1. Kandybin, N. V., ati $1., in "Vopro~y ekologi3 i fi~ioloqii mikrn-
- orqeni~nwv, i~pol'zuyemykh v eel'akom khozyayetve" (Problem~ of the
Fcoloqy and Phyeiology nf Microorg~ni~ms Used in Agriculture),
Leningrad, 1976.
2. Kandybin, N. V., ~t gl., in "Bakter3.al'nyy~ sredstva i metiody bor'by
e naseDcomymi i gryzunami" ~Ba~tarial Re~ources and Me~hods of Inaect -
and Rodenti Control)~ Leningrad, 1972.
3. Lysenko, 0. J., HYG. EPIDEMiOL. MICROBYOL. IMMUNOL., Vol 18, 1.974, p 347.
9. ~yaenko, 0., an8 Kucera, M., in Burgeg, H. D., and Hussey, N. W. ~Editors),
"Microbial Control of xngects and Mtce," ACAC18t[l~C Pregg, London ana
Naw York, 1971, p 205.
5. Lysenko, 0. and Weiser, J., J. iNV~RT. PATHOL., Vol 24, 1974, p 332.
G~OPYRIGHT: IZdatel'8tvo "KoloB", "DOk1Ady VA3KhNiL", 1979
11004
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VETERINAItY M~UICINE
,
~ I
~
UDC 636.2:616.155.392 ;
i
IMMUNOLOGICAI, PRpPERTIE5 OF TYPE C CATTLE ONCORNAVIRUS
I
MosCnw DOKLADY VSESOYUZNOY OFtDENA LENINA AKADEMII SEL'SKOKHOZYAYSTVENNYi~i
NAUK iN~Nt V. I. LENiNA in Itussian, Nn 2, 1979 pp 35-36 �
[Article by Cand Biol Sci Kh. S. Salimov, Uzbek SSR Order o� the Red Labor ~
Hanner Scienti�ic Research Veterinary Institute~ ~ ~
I
(Textl One of the main tasks in research on cattle leukosie ie timely ~
diagnosis of diseaae and implementation of the appropriate control meaeurea.
Diagnosis of leukosis in the living animal on the basis of clinical hema-
tologfcal analyses is very laborious, and it is unable to reveal all eick
catitle suffering and a leukemic disease courae.
As a consequence there is much interest in developing immunol~qical diaqnostic !
methoQs. Immunological analyses of type C oncornavirus isolated from pri- ~
mary cultures of leukocytes from cattle stricken with leukosis have been ,
acquiring special significance in recent years (1-8). Accordfng to a ~
number of authors (8,9) type C oncornaviruses tsppear firat in the leuko- ,
cytes in orqans of animal stricken with leukosis, while precipitating i
antibodies to these viruses are detected in blood serum: hematological and
histologiCal changes are detected subsequently. Considering this, research ~
on precipitating antibodies to oncornavirus in animal blood serum has
great siqnificance to leukosis control measures.
The research was conducted jointly with colleagues, of the Moscow ;
Veterinary Academy's Problematic Laboratory of Leukosis Research and the
- USSR Academy of Medical Sciences' Institute of Virology imenf D. I. ,
Ivanovskiy.
Oncornavirus isolated from primary leukocyte cultures and lymph node cells
from cows stricken with leukosis was used as the antigen.
The (Oukhterloni) precipitation reaction in agar qel was employed. We used
1.2-1.5 percent Difko agar in physioloqical solution, pH 7.2 in the reaction.
Craters in the aqar were seeded with standard strains using seven tubular
punches with an outer diaaieter of 4 mm, the distance between the outsi~ie
and central tubes beinq 5nm. Z'he reaction was allowed to proceed at room
34
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temperature in a chamber humidifiad wi~h 0.6-1.5 ,percen~ carbolic acid.
The reaction was observed after 24-48 hours of incubatiion, an~ the resultis
were recorded photographically. The precipitation bands were intenaified
with 0.065 peroent caclmium aulfate solu~ion after rinsing the sample with
0.15 M sodium chloride solution.
Blood aerwn from five groupg of animals was atudi~ed ~o reveal precipitating
~ antibodies ~o the pur3fied oncornavirus.
A B
,`~~,'~~>'J' 21 yV.-. .~t~!'R..~{>. ~V~' ,X, -
' ;'k.Ati`~i*2)~~:� t;,a
4'i2�`,:>;.'#`
7~ ;.x... ,~y
C ~y�::'?:"~ :vtiF
,~3
A::~i:':�K' .r;,.;}:
~::;~k;~; ;?:'�x:oi;`~
f:.~' ~.;:":is
. .'t,;'~4,."~'''
x:~.
~ ~ . .
:~u. ti:~
V
`j
t
hyi~~: i: \t~~.~\:
ti.~.
.
-
~
a ~ ' ,
~
~ ; ` ~
S,{~:~~ ~ l ~
`t ~ ~ti l i~,v~ ~ ~,Z~
\ k Z S'C� ant; e~;. a i~
,a ; ` s ~~v t ; "`.~k~ ~~.1'~. lz`~ t o . .
. t~. ~ . ~~1 i t >
`,~".k4v,\}v\ z: ~~':l`ti y
.a...s :,tS~ia�~w:ti:;
y..kcs,cYa~~3G.vnwvd~:~.i~ ~~s.~
B D
~ Diffusional Precipitation Reaction: Center--
oncornavfrus antiqen, peripheral craters--blood -
serum: A--From cow No 101, stricken with leukosis= .
B--from cow No 355, stricken with leukosisj C--
control--antioncornavirus serum; D--Fran experimentally
infected calf No 681.
- Precipitatinq antibodies to type C oncornavirus were revealed by the iamauno-
diffusion reaction in blood serum from two cows infected with cellular
suspension when 1-10 days old, and in blood from a cow showing clinical
signs of leukosis.
A precipitation band was discovered in the immunodiffusion reaction for
blood serum fran 7 out of 18 calves (38.8 percent) infected with purified
oncornavirus, indicating presence of precipitating antibodies in the blood -
35
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serum. It should be noted that type C oncornavirus having all of the
physicochemical properties inherent to it was de~ected and 3solated in !
leukocyte cultures from two calves and in lymph node ce11s �rom two calves ~
6-12 months following infection. The blood indices of these animals are i
within the phyaiological norm. ~
~
Precipitation antibodies to cattle oncornavirus were not revealed in blood ,
serum from four caLves infected with MycopZasma. ~
Precipitating antibodies were detected in blood serum from 31 out of 42 ~
(73.8 percent) cows testing hematologically positive for leukosia (the .
_ leukocyte count averaged 31,700t1,580, the percentage of lymphoid cells ~
per milliliter of blood was 88.88�3.00 percent). i
Precipitating antibodies were revealed by tY?e immunodiffusion reaction in ~
the blood serum of only 6 out of 98 healthy cows (6.12 percent). !
- I
Thus we established oncornavirus infection in 38.8 percent of the calves f-
6-12 months after infection, in 73.8 percent of the cows stricken with ~
leukosis, and in 6.12 percent of hematologically healthy animals. ;
' BIBLIOGRAPHY ~
i
i
1. Valikhov, A. F., VETERINARIYA, No 3, 1974.
I
2. Zhdanov, V. M., et al., VETERINARIYA, No 3, 1974.
3. Kukayn, R. A., et al., in "Etiologiya leykozov (materialy Vs. simpoziuma)"
(Etiology of Leukosis (Proceedings of an All-Union Symposium)), Sukhumi, ~
1972.
4. Kukayn, R. A., et al., DOKLADY VASKhNIL, No 6, 1976.
i
5. Nadtochey, G. A., et al., DOKLADY VASKhNIL, No 5, 1976. ~
6. Parfanov, M. I., et al., in "Mery bor'by s leykozom krupnogo rogatoqo
� skota" (Cattle z,eukosis Control Measures), Belaya Tserkov', 1975. -
7. Van der Maaten, et al., J. OF THE NATIONAL CANCER INST., Vol 52, 1974, _
p 491.
. ~
8. Olsen, C., et al., J. OF THE NATIONAL CANCER INST., Vol 49, 1972, p 1463. ;
9. Ressang, A. A., et al., "Enzootic Bovine Leukemia," M., 1976, p 75.
i
COPYRIGHT: Izdatel'stvo "Kolos", "Dok]ady VASKhNIL", 1979 ;
- 11004 ~
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- 36
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V~T~RtNARY M~DICIN~ .
UDC: 636.597e616.921.5
DUCKLING Tt~sPIRA20RY DISEASE CAUSED BY INFLUENZA VIR~S
Moecow DON.ADY VSESOYtlZNOY ORDENA LENINA AKAD~MII SEL'SKOKHOZYAYSTVE~YKH
~ NAUK IM~'NI V. I. LENINA in Rusai~n No 2, 1979 pp 36-37
(Article by Cand Biol Sci U. S. Sagdov, Republic Scientific-Production
Vetierinary Laboratory of Avian Diseases)
(Text] An outbreak of disease occurred among ducklings of one of the duck _
farcns of Tashkentskaya Oblast in October 1977, exhibitinq siqns of affliction
of the upper respiratory tract. The disease was observed in younq birds
from 5 to 30 days old. Disease was not noted amonq birds alder than 30 daye.
The disease struck all broods, causing mass bird mortalitf (up tio 64 percent).
The disease proceeded in i~ts acute form, and in most cases the sick birds
died. It beqan with the followinq clinical aiqns--sneezing and serous
dischar4~s from the nose, the discharqe becoming purulent later. Breathinq
- was encumbered and shallow. The ducklinqs breathed throuqh open beaks
since the external nares were clogqed with fibrinous-caseous mattAr. Con-
junctivitis was observed. The mucous-purulent exudate undes'went thickeninq
and was discharqed beneath the~~ictitatinq mesabrane as a cheeay masa, cloaing
the eye. Infected subocular sinuses were filled with exudate. R~ecoverinq
ducks suffered retarded grawth and development.
Pathoanatomical signs: Hyperemia of mucous membranes of the nose end sub-
ocular sinusesj edeinic lungs, with hemorrhaginq fn some areas= qrayish
~ yellow ffbrinous deposits in air sacs, coverinq a significant amount of
surface areas ~iver sliqhtly enlarqedf cardiac muscle pale. The patho- ~
anatomical chanqes were less pronounced in acute cases.
The various antibiotics and cheaaotherapeutic preparatfons used for pre-
vention rsnd treatment did not have any effect.
Analysis of the clinical and pathoanatomical pattern as well as absence of
a therapeutic effect raised the suspicion of infection caused by influenza
virus.
Infected mucous membranes from the nasal passages and subocular sinuses, and
brain, pulmonary, and hepatic tissue from dead and slr~uqhtered ducklings
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_ were ~ubjectied tic~ viroloqi~~1 analy~i~. Suep~n~iong of ~h~~e nrgens, from
which microflora were removed with peniCillin and streptomycin (2,0~0 A~
p~r m~), were injected intio ehe chorio~llaneoic cevitiy of 9-10-de?y ~hi~~c
~mbryoe. Pregence of multiplying agent w~g determin~d by th~ hemaqglu-
tinatiion reactiion, whict~ wag perfotza~d wieh r,oogter erythrocytie ~usp~nsion.
The inf~ce~d enibryos w~re vi~wefl tihrough a candling dpvice tiwice a dey
(morning ~nd eveninq) for 72 hours.
Hemaqglutinatinq aqene 20~ aas isolated from organg of c~cklinga killed by
th~ diaeaee and ducklingg sub~ected to forced slaughter. The isoigtiec~
virus gggluttneted rooster erythrocytes to a titer of 1:16-1:32, and in
eubsequent pagsages the ttter increas~d to a 8ilutinn of 1:64-1s25b. The ;
virua n?ultipli~d well in th~ chick embryos, and it had an infectious titer
(EID50) of 10~6.
The isolated virug wae tentatively identified by the hemagglutinntion-
inhibition test using diaqnostic ~erums for Newcastle disease virus and
Rostok and Chekhov avian influenza virus, as well as by tihe complement-
ffxation reaction usinq flfaqnostiic serums for type A and A1 influenza virus ,
and for rat viruses A/Victoria/3/~5 and A/Tashkent/~17/77. The latter ia ~
identical to A/Victioria/3/75 virus. The experiments establiahed that a
positive compleiaent-fixation reactinn was obgerved with diagnoatic serum _
for type A and rat A/Tashkent/717/77 virus to half of the homaloqous titer.
We called the virus strafn we fsolated A/Duck/Tashkent/207/77.
The hemagglutination-inhibition test was performed with guinea piq serum
in order to study the strain's sensitivity to inhibitors. It turned out
to be insensitive to inhibitors.
Because type-apecific serums against human, animal, and avian influenza `
- were unavaflable, the strain we isolated was identffied to qreaCer detail t
by the respiratory virug laboratory of the Institute of Viroloqy imeni
D. I. Ivanovskiy (with the participation of V. A. Isachenko and Ye. V. ~
Molibog)� .
In cross hemagglutination-inhibition tests the isolated virus A/Duck/
/Tashkent/207/77 was inhibited by serums against strains with tt?e hemaqqlutinin ;
- antiqenic formula NZ, while in (RPNA) tests it was inhibited by sertuns
against strains with neuraminidase antigenic formula No 1.
Our preliminary viroloqical analyses provide the grounds for hypothesizinq
that enzootic influenza discovered amonq the duckYings was elicited by a
new hybrid variant of human influenza virus with the antigenic formula
NZ No 1. This strain has been recorded by the USSR Regional Influeaza
Center.
Th~s hybrid is apparently the result of recombination of viruses havinq -
different biological properties in the presence of antigens NZ No 2 and
NO No 1.
COPYRIG~iT: Izdatel'stvo "IGolos", "Doklady VAS1QiNIL", 1979
38
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pox or~YCini. us~ om.Y
3CI~"C~5r3 AND 3CIENTII~I~ O1tGANIZATIUN5
POGLAZOV AWA1tbLD pRI2E BY U5SR ACADN~IY OF SCI@iCES
Moscoar VESTNIK AKADF2~III NAUK 5SSR in Rugeien No 1, 1979 p 141 .
[Text) The A.N. Bakh Prize for 19~8 in rhe amount
` of 2000 rubles was a~+arded by decieion of the
Preeidium of the USSR Academy of Scieaces to
' ~oris Federovich Poglazov~ doctor of biological
`~~ft,; sciences~ (Institute of Biochemistry, imeni
A.N. Bakh USSR Academy of Sciences). The prise
_ Was given for hie mdnographe "The Assembly of
- Biological Structurea", "Mechanisme for ~he
t,~;.
Asaembly of Elementary Biological Structuree".
and "The Morphogenesis of T-Even Bacteriophages".
i ~
i;
In the prize winning monographs B.F. Poglazov--a
t~ Well kaown ecientist who has etudied probleas of
the molecular organization of biochemical etruc- -
turee--correlated reeulta of hia many yeare vork
oa etudying the phenoaa,ena of self aeaembly, oa
artificial reconstruetion of the simpleat bio-
logical atructures, aad aa aa explaaatioa for the mechanism of genetic regu-
]gtim of aesembly procesaea. Particularly sigaificaat are his etudies of
bacteria 1 morphogeneais aad the mechaaism of the assembly of bacterial
f lagelta.
B. F. Poglazov vas Che first to succeed in dividing the corpusclea of T-
even bacteriophages into their coastitueat camponenta aad to atudy their
campositioa aad physicochemical propertiee. He aas also the firet to arti-
ficially reconetruct the individual elemeats of bacteriophagea. Electron
microscopy etudies using the methods of optical diffraction aad circular
dichroism alloved the scieatist to decode the molecular organizatien of
severa 1 atructural cemponente of bacteriophage particles and to determine
the aature of structural changes occuring When hoet cell DNA is infected.
Studies conducted by B.F. Poglazov on protein eubunit interactions aad his
conclueions base~i oa these studies repreaeat a large contribution to the
theory of epantaneous eelf-assemblq.
COPYRIGHT: Izdatel'stvo "Nauka", "Vestnik Akademii nauk SSSR"~ 1978
9342 39
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~
FO~t OtrFICIAL US~ ONLY I
3CIENTI5r5 AND SCIENTIFIC ORGANYZATIO:iS
~
USSR ACADPl~iY OF SCIENCES MAKLS ORGANYZATIONAL DECISIONS
Moscow VESTNIK AKADFMII NAUK SS5R in Russi~n No 1, 1979 pp 142-143 ~
[Excerpta] The decieiaa was made to orgac?i~ee an Inat3tuCe of Phyeiologically
Ac�ive Subetancea, USSR Academy of Sciences. '
The primary directions af ecientific activity in Che new instituCe are: ~
research, atudy of the struceure and the relations between sCructure
and physiological function of varioua synthetic and naCural eubstances
including pesticides and pheramones (which are primarily of lrow toxicity
to Warm blooded animals and man), proCein-peptide substances ~rith diverae
activitiea including hormones and other campounds, proetaglandine, medi-
- cal preparatdoae for the treatment of infectious dieeases, nervoue
syatem afflictiona and other diseasea, polycyclic compounda for medicine.
agriculture and other fields;
;
development of a syatem for reaearching and eatimating the effectivenees ,
of manufactured aubetaaces with the uae of biocheriical and phyaicamathe- ~
- matical methods, and a18o the development of recacmnendationa on practical
uses of these substancea in medicine, agriculture and other branchea of
the people's economy. ~
Supervision of the Institute of Phyaiologically Active substances ig en-
truated to the Section of Chemical Technology and Hiological Sci~nce. The
Division of Biophyaics, Biochemiatry, and Chemiatry ia charged with guidaace
in scientific methodology.
Doctor of cheaistry I.V. Martinov has been appointed as director of ~he
Inatitute of Physiologically active substances.
The Institute of Mariae Biology of the Far East Scientific Center, USSR
Academy of Sciencea, is to organize a Far East Game Iteaerve at the Bay of `
Petr Velikiy based at the laboratory of the Marine Game Reaerve Inatitute.
40 '
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~Utt O~~ICIAL US~ ONLY -
~Th~ b~giC direc~idng fnr gcientific reg~~rch ~nd nctivity ge thp g~me re~erve
~r~: eo ~~gr~nC~e ehe preg~rv~tinn df rpgtricted w~terg ~nd e~rritorie~, ru
_ repdrt on sea and island bioceno~e~~nf the g~me rpg~rve gnd th~ir dyn~mic~
- re~ulting from natural gnd anChropogenic influen~es, to d~velop geieneiCically
bg~~d pregervation ~nd reestgblighment of ~nd igland biorendge~ of th~
game r~servp dir~Cted towards pre~~rv~tion di the gene poo1~, ed d~vplop
g~i~ntifiC r~coam~pndationg for mgrin~ g~me regerve matt~rg, to prdpgg~ndize
the protection of gea life ehrdugh the publiC~tian of r~chnical and popular
ecipnc~ literature, and to d~v~lop g perman~nt gea n~tu~e exhibit.
The prnposal of th~e Preeidiuro of th~ far ~ast Scientific Center, U55Et A~cad~my
of Sciencee, hag been ~ccepCed to form a division of hydrology and hydro~ -
geoingy ~C th~ pacific Oc~~n 2~1~eitute of Cedgr~phy, ~~~C U55Et Ac~demy of
5cienceg, in Che Khab~rov~kiy Complex Science-Resegrch Institute, ~'L5C US5R
Academy of SCiettces.
The requesC by doctor of biologi~al sci~n~~s A.I. Cherepgnnv for release
from his duties as director of the Biological Institute, 50 U5SR Academy of
5cienceg, has b~en satisfied.
9342
C50: 1870
41
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