JPRS ID: 9070 USSR REPORT LIFE SCIENCES BIOMEDICAL AND BEHAVIORAL SCIENCES

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BIaMEDICAL ANa BEHAVI OfiRL SCIE~~~~
5 MAV 1980- (F~~O 1/80)
I OF 2
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JPRS L/9070
5 May 1980
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- USSR Report
IIFE SCIENCES
BIOMEDICAI AND BEHAVIORAL SCIENCES
= (FOUO W80)
~BOS FOREIGN BROADCAST INFORNIATION SERVICE
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u
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JPR5 L/3070
5 May 1980 _
USSR REPORT
-
_ LIFE $CIENCES
- BIOMEDICAL AND BEHAVIORAL SCIENCES
(FOUO 1/ 80 )
CONTENTS
I. ADVANCED BIOTECHNOLOGY
1
Recovery of Microbial Metabolites
(Prof. A. M. Bezborudov; POLYCHENIYE MIKROBNYKii
= METABOLITflV, 1979)
1 -
Molecular and Cellular Biophysics
(G. M. Frank; MOLEKULARNAYA I KLETOCHNAYA BIOFIZIKA,
_ 1977)
15
Bacteriorhodopsin and the Visual Pigment Rhodopsin: As
- Discussed at Soviet-American Sympoaia
(M. A. Ostrovskiy; VESTNIK ARADEMII NAUK SSSR, No 9,
1979)
22
II. ADVANCED MEDICAL TECHNOLOGY
32
Standards Regulating the Pharmaceutical Service
(M. A. Klyuyev; SBORNIK NORMATIVNYKH AKTOV PO APTECHNOY
SLUZHBE, 3 May 79)
32
Fragment Information Subsystem in Physiology and Medicine
(D. I. Blyumenau, et al; VESTNIK AKADEMZI NAUK SSSR,
No 10, 1979)
47
- Principles of Functional Organization of Tissue Systems
(V. G. Tyazhelova and I. G. Akoyev; PRINTSIPY FUNKTSION'NOY
ORGANIZATSII TKANEVYKH SISTEM, 1976)
51 =
III. ENVIRONMENTAL HAZARDS
77
Effects of Radiation on DNA
(N. :C. Ryabchenko; RADIATSIYA I DNK (RAD?.ATION AND DNA),
1979)
77
- a- [III - USSR - 21a S&T
FOUO]
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CONTENTS (Continued)
Page
Interaction of Ultrasound With the 3iological Environment
(VZAIMODEYSTVIYE UL'TRAZWKA S BIOLOGICHESKOY
SREDOY, 1979) 81
- Interaction of Different Systems Under Radiation In;jury
(I. G. Akoyev and V. G. Tyazhelova; MEZHSISTENITTYYE -
VZAIMODEYSTVIYA PRI RADIATSIONNOM PORAZHENIYI, 1978) 85
LaboraLCry Diagnostics for Toxic Poisoning From Pesticides
(Ye. N. Burkatskaya, et al; LABORATORYNAYA DIAGNOSTIKA
INTOKSIKATSIY PESTITSIDAMI, 1978) 88 -
IV. PHYSIOLOGY 92
Evoked Potentials in Psychology and Psychophysiology
(E. M. Rutman; VYZVANNIYE POTENTSIALY V PSIKHOLOGII I
PSIKHOFIZIOLOGII, 1979) 92
Psychophysiological Aspects of Ultra-Slow Brain Rhythm
- Activity
(N. A. Aladzhalava; PSIKHOFIZIOLOGICHESKIYE ASPEKTY
- SVERKHMEDLENNOY RITMICHESKOY AKTIVN03TI GOLOVNOGO
MOZGA, 1979) 95
- Formation of a Biopotential Field in the Human Brain _
~ (A. N. Shepoval'nikov, et al; FORMIROVANIYE BIOPOTENT-
SIAL'NOGO POLYA MOZGA CHELOVEKA, 1979) 100
a The Forebrain and Elements of Behavior -
(V. A. Cherkes; PERIDNIY MOZG I ELIIMENTY POVEDEIvIYA,
1978) 104
� Autowave Piocesses and Cardiac Arrhthmia
(V. I. Krinskiy; VESTTIIK AKADEMII NAUK SSSR, No 1, 1980) . 107
Collection Summarizes Oculomotor Function Research
(B. F. Lomov; DVIZHENIYE GLAZ I ZR.ITEI.'NOYE
VOSPRIYATIYE; 1978) 115 -
Physiological and Hygienic Aspects of Man's Acclimatization `
in the North
(N. I. Bobrov, et al; FIZIOLOGOGIGIYENICHESKIYE ASPEKTY
AKKLIMATIZATSII CHELOVEKA NA SEVERE, 1979) 121
~ The 'Polar Stress Syndrome' and Some Problems of Human _
Ecology at High Latitudes
(V. P. Kaznacheyev and V. Yu. Kulikov; VESTNIK AKADEMII -
NAtTK SSR, No 1, 1980) 124
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_ CONTENTS (Continued)
Page
V. FiI3MAN FACTORS
136
Psychology and the Problem of Reliability of the Railroad
Engineer
(L. S. Nersesyan and 0. A. Konopkin; INZHENERNAYA
PSIKHOLOGIYA I PROBLEMA NADEZHNOSTI MASHINISTA,
1978)
136
- Effects of Emotions on Cardiovascular Activity
(I. I. Vaynshteyn and P. V. Simonov; EMOTSIOGENNYYE
STRUKTURY MOZGA I SERDTSE, 1979)
~
142
VI. PSYCHOLOGY
149
A National Psychological Service
(B. F. Lomov; VESTNIK AKADEMII NAUK SSR, No 1, 1980)
149
Psychophysiological Bases of the Scientific Organization
of Labor
(S. A. Kosilov; PSIKHFIZIOLOGICHESKIYE OSNOVY
NAUCHNOY ORGANIZATSII TRADA, 1979)
163
VII. SCIENCE POLICY AND ADMINISTRATION
168
Y Academy of Sciences Announces New Members
(VESTNIK AKEIDEMII NAUK SSSR, No 7, 1979)
168
- c -
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I. ADVANCID BIOTECHNOLOGX
`UDC: 663.18:576.8.095.3(047)
RECOVERY OF MICROBIAL METABOLITES
Moscow POLYCHENIYE MIKROBNYKH METABOLITOV Seriya P. Obshchiye voprosy
mikrobiologicheskoy promyshlennosti, Obzor, in Russian 1979 annotation
- page and pp 1-11
[Annotation (by Prof A. M. Bezborodov, doctor of biological sciences)
and introduction to survey "lZecovexlj of Microbial Metabolites. Series P: -
General Problems of the Microbiological Industry," published by the -
- Main Administration for the Microbiological Industry under the USSR , -
Council of 'rlinisters, Department of Scientific and Technical Information,
_ Technical and EconomiG Research of the Microbiological Industry]
[Text] Annotation
This survey furnishes an analysis of the data in the literature pertaining
_ to recovery of mi.crobial concentrates, treatment of culture fluids, as
well as biomasses for isolation of products of secondary synthesis.
Chemical, ion-exchange, diaphragm and other processes for isolation of
metabolites are discussed. Examples are furnished on how special-purpose
- products (atnino-acide,�enzymes, etc.) are recovered.
This survey is intended for bioengineers, chemists, tec,hnologists and
tiochemists at institutes and enterprises of the microbiological industry,
as well as employees of the ministries of the medical, food and chemical
industries.
The survey is 72 pages long; there are 4 tables and 2 figures; biblidgraphy
lists 278 items.
Introduction
The bioma.sses and microbial metabolites--products of microbiological syn-
thesis that are produced in various forms by enterprises of the microbio-
logical, medical, chemical (biochemical reagents and certain drugs), food
industries and Ministry of Agriculture--are very important to development
of the national economy [1-4]. Wide use is made of the following pre-
pared forms: inactivated and live biomasses (feed yeast, baker's yeast,
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bacterial fertilizers and others); concentrates (mainly for agriculture)
obtained by dehydration or partial purification of culture fluid; extra-
cellular and intracellular purified metabolites used mainly as biochemical
- reagents and drugs, as well as to balance feed and foods (amino acids,
vitamins, etc.).
Thus, as compared to 1966, production of feed yeast in 1976 in our country
increased by 6.6 times, that of feed antibiotics by 6.2 times, enzyme pro-
ducts by 14.8 times and lysine by 42.6 times. Production of microbiolo-
gicals is also developing in other countries [5].
Preparation of nutrient media, inoculums, other prefermentation operations,
as well as termentation proper are similar for all finished products, and
they have been described rather well in previous surveys [6-11]. Biomass
is recovered at yeast plants and other enterprises.
There must be broad introduction into biotechnology of new and highly
efficient methods of recovering biologicals, as well as creative use of
the classical methods, in order to expand significantly the microbiological _
industry. Figure 1 schematically illustrates the passible directions of
recovery of products of microbiological synthesis and order of procedure _
for treatment of culture fluid. In the following, we shall adhere to ttLe
same order in discussing the methods for isolation cf microbial metabolites. -
Little-described processes for producing concentrates are interesting.
A particularly large number of problems arises because of the high hygro-
scopicity of most products in this group. They are produced most often
in dry or liquid form for agriculture. In addition to special-purpose
substances, they contain other metabolites, biomass of productive
microorganisms, residues of nutrients and ancillary material (foam quenchers, _
agenta for regulation of inedium pH, etc.). The culture fluid is directly
aubmitted to the simplest technology, i.e., concentration by removal of
fluid; in other cases, some purification procedures oz other are needed to
- remove part of the secondary components and, to some extent, increase
the relative amount of special-purpose elements. As a rule, the concen-
trates contain a substantial share of product mass outside the cells of
microorganisms, even if the specific [special purpose] substance is within
the cell. This preparative form has the following advantages: simpler
technology and, consequently, lower expenses for developing and implement- -
ing production; presence of additional components in concentrates; ab-
sence or smaller amount of industrial waste; with isolation of a crys-
talline product, the useful waste usually has the same technological proper- _
- ties as the concentrates.
Recovery of intracellular and extracellular metabolites in the form of pure
substances is technologically very diverse and complex. Extraction of intra-
cellular metabolites involves disintegration of cells. Most of the sub-
stances are thermolabile and have relatively large molecules. Much
2
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theoretical and practical knowhow has been accumulated in the area of pro-
ducing medical antibiotics [12]. As a rule, the first atage of the procesa
coneiste of aeparation of mycelium from the liquid medium. Culture fluid
is pretreated (acid and thermal coagulation, treatment with electrolytea,
- use of filtering powder, formation of fillers directly in fluid) in order
to improve filterability and quality of filtrates, i.e., native aolutiona,
and for subsequent auccessful isolation and chemical purification of producte.
The processes of isolation and chemical purification of antibiotics should
= yield products that are highly pure. In view of the fact that the concentra-
tion of antibiotics in unadulterated [native] solutions is quite low, and
that there are numerous organic and inorganic impurities in solutions, the
methods used for isolation and purification must be highly selective in
capacity for significant concentration of end [special] nroducts.
Extraction, ion exchange and precipitation are the most widely used methods
for isolation and purification. The distinctive feature of all the
methods is that there are many technological stages (repeated separation
_ and filtration of Frecipitates, two- and three-step extraction, crystalliza-
tion, concentration of solutions by vacuum evaporation, use of various
drying methods, etc.), as well as diversity and complexity of equipment
used, difference in size of the latter (at the first stages up to hundreds
of cubic meters anci at the last ones, occasionally several tens of liters).
For example, use is made of the following: drum vacuum filters, press
filters, prESSUre aiid suction[Nutsche] filters, separators and centrifuges
_ varying in capability, various designs of extractors, ion-exchange columns,
different systems of f:tlm evaporators, drying devices operating on the
principle of diffusion� pseudoliquifaction, sublimation of ice and other
- types of equipment. Ic.t view of the fact that antibiotics are complex
organic compounds, usually unstable and sensitive to the environment (high
tEmperatures, change in pH of solutions, etc.), chemical purification pro-
cesses must be conducted under conditions that provide for utmost stability
of the products.
_ There are several specific sanitary requirements for the production of
highly pure drugs, particularly those used by injection. The final stages
(drying, packaging) should be conducted under aseptic conditions, for
which not only special treatment of equipment, ancillary material, rooms
- and appropriate training of service personnel are required, but use of
additional technological procedures, for example, purification of air
going into the rooms.
Recovery of enzymes has been described extensively in the literature [13, 14].
In this survey, we have analyzed information and systematized the general
methods for recovery of microbial metabolites in the form of concentrates
and pure substances. Production of pure substances by enterprises under
Glavmikrobioprom [Main Administration of the Microbiological Industry] is
only at the development stage, whereas some knowhow has already been
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accumulated by other agencies. Some experimental and practical work has
already been done by the authors, which enables them to discuss the pro-
cesses of isolation as they apply to amino acids, organic acids and certain
enzymes.
Factors Affecting the Properties of Culture Fluid
There are diverse methods of preparing culture fluids, depending on the
expected properties of the metabolite to be recovered. However, we can
formulate some general principles of this technological stage:
1. The main fermentation shou?3 be run on clear [colorless] substrates
- that are aa completely assimilable as possible, with the use of active
strains. This provides for a minimal proportion of inert constituents to
- the specific metabolite being recovered in culture f luid and facilitates
isolation of pure substances; it also increases the amount of end product
- in the concentrates. Thus, addition of acetic acid or saccharose to a mo-
lasses medium for recovery ~,f ?ysine increases by 9% the productivity of
ion-exchange equipment [15]. UsE of acetic acid as the only source of car-
bon makes it possible to obtain concentrate with 50-72% lysine monochloro-
hydrate (15-20X on molasses media) or 97% pure crystalline lysine by means
of direct desiccation of eluate on a spray dryer [16, 17]. Accordingly,
the residual concentration of substrates and extraneoue [secondary] metabo-
- lites must be reduced to a minimum. Theae subatances worsen the physico-
mechanical properties of concentrates.
� 2. In most cases, the fermentation process must be intensive and well
controlled in order to rule out the possibility of cell death at the
stationary stage of growth. In addition to lowering the productivity of
the culture, this worsens the rheological properties of culture fluids
and makes subsequent tr2atment (filtration, centrifugation, etc.) difficult.
There is little informatinn in the literature concerning viscosity, snrface
tension and other physical properties of culture fluids. As an example,
= we can refer to the survey in [18].
3. Operational efficiency and quality of postfermentation operations to
- pre.vent access of extraneous microflora into culture fluid and reduce
treatment time of the latter are particularly important. For example,
the microbiological loss during production of feed lysine concentrate
(KKL) could reach 66% of overall losses [19]. There is appreciable loss
of glucoamylase after only a few hours of storage of culture fluid [20].
This is associated with the problem of stabilization of ttie metabolit2s
being recovered. One must know the nature of product loss in order to
select a stabilization method. In general, the losses consist of micro-
biological, chemical thermochemical and combined forms.
It is simplest to control microbialogical loss (change in pH, antiseptic
conditions, cooling, pasteurization and others), and in the other cases
- individual study of the process is necessary.
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Culture fluid
~
Separation
- ~ Filtrate
Preservation and
of biomass
~
purification
- y
Biomass
'Pretreatment
methods:
of solutionsl
vacuum
evaporation
~
dration
De~i
reezin
f
g
y
.
mernhrane processes
precipitaticn
Disintegration
sorption processes
y
,
crystallization
Separation of
drying
cellular
F'Lltrate
i
suspension
~
~ y
Concentrate Biomass Biologically active
substances varying
forms (protein concentrate) in degree of purity
i
' `Figure 1. Diagram of recovery of products of microbiological synthesis
4. Standardizing the culture fluid
a serious problem in producing conci
recovered must be standard and have
logically this operation is simpler
intermediate products, for example,
case of recovery of KKL.
Production of Concentrates
for concentration of inetabolite becomes
:ntrates, since the product to be
a specific composition. True, techno-
to perform with more conce.ltrated
with evaporated culture fluid in the
Microbiological concentrates of the end substance to be recovered can be
divided inta vj.tamin products--feed vitamin B12 concentrate [12], feed
antibiotics--biomycin (biovit), "kormogrizin" and hacitracin; enzymes,
amino acids and bacterials.
AmorLg enzyme products, there is prevalence of the concentrate form, and
only a few products produced on a large scale are 3ubmitted to utmost
purification and crystallization. This is apparently attributable to
the technical difficulty of purifying them and poor crystallizability.
When recovering extracellular enzymes, in most cases the entire culture
fluid is concentrated, or else, aPter removal of producer biomass, the
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fluid is submitted to ultrafiltration, perhaps precipitation of enzyma-
tically active protein and occasionally with additional purification. Ex- _
tracted enzymes are a1EO produced in concentrate form; the liquid form _
of enzyme products is widespread. Dry products are often found to be
highly hygroscopic, and for this reason the product sticks to the surface
- of the dryer. To overcome the difficulties caused by these phenomena,
~ sn airtight container is used, filler is added hefore drying and, in _
particular, syrups are dried together with porous fillers.
Information about recovery of enzyme concentrates has been systematized
rather well and summarized in monographs and analytical surveys tfor
example, [13, 14, 22, 23]).
With respect to am.ino acid production, lysine for �eed purposes is produced
an the largest scale. The original Soviet technology for production of
KKL consists of recovering it in a sensible ["rational"] form, in the form
of concentrates with high feed effectiveness that are produced using a
relatively simple method [24-28].
Among the bacterials (agents to protect plants, bacterial fertilizers), _
there are both products consisting of cell biomass and those containing
- a significant amount of dry substances from culture fluid. The latter, _
- i.e. extracellular concentrates, include, for example, antobacterin,
insectin and others. Extensive studies of questions pertaining to
drying bacterial products are being pursued at the Institute of Heat and
Mass Transfer, Belorussian Academy of Sciences [18]. -
Amorphous structure is the typical property of concentrates [29]; it de- !
groscopicity,
termines the absorptive nature of removal of moisture, high hy,
- thermoplasticity and adhesiveness of the products [30, 31].
In most cases, the microbial concentrates do not meet the requirements,
in their physicomechanical and technological properties, that would perm.it
their direct use in the mixed feed industry and other branches of the
national economy. This is feasible with the addition of fillers or
preparation of premixtures by consumer enterprises [32].
Recovery of Feed Lysine Concentrate (KKL) from Culture Fluici
The concentration of dry substances in culture fluid censtitutes 11-15%,
including 2.8-4.3% L-lysine (monochlorohydrate), 1.6-2.2% bacterial bio-
mass and 0.3-0.6% residual sugars.
During evaporation, after fermentation, the culture fluid is acidulated
with hydrochloric acid to a pH of 5.5-6.0 and 0.17% sodium bisulfite is
added to suppress development of extraneous microflora at different stages
of treatment of this fluid and stabilization of lysi.ne,during heat
treatment.
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When there is incomplete assimilation of sugars by the main producer, after-
fermenr.ation is effected by means of adding a culture of Trichoaporuo cut-
aneum R-3 yeast.
The culture fluid is dehydrated in a vacuum evaporating device.
- The most effective evaporation systems are thoae with a sinking film
for example the Vigant (GDR) brand equipment, which provides for minimal
loss of lysine during evaporation.
The evaporated mass containing 35-40% dry substances is then passed into a
spray dryer with disk sprayer [30] for further dehydration. Air, heated to
- 200-210�C at the inlet and 105-110�C at the ou ' tlet, is used as a drying
agent. After drying, the product is cooled in a pneumatic conveyer [blower]
and packaged in airtight containers. The KKL contains at least 15% L-lysine
(monochlorohydrate) with no more than 10% moisture (first variant of 1:'re-
_ pared form, TU 59-72-74). -
There are some difficulties involved in technology of spray dryin.g of the
evaporated culture fluid due to the hygroscopicity, thermosensitivity of _
active substances, and thermoplasticity of the product. To eliminate them,
a method has been evolved for dr,ying evaporated solution with addition of _
filler into the drying compartment of the unit [33]. The following powders
have been tested as fillers: aerosil [silica] (GOST 14922-69), bone meal
(OST NKPP 463), lime powder (MRTU 21-41-69) and defluorinated phospliate. _
In addition, pneumatic separating devices were installed instead of the _
mechanical gate valves ["sluice gates"J.
To lower hygroacopicity of KKL, slaked lime is added to the evaporated cul-
ture fluid. The amount used depends on the required degree of reduction
of hygroscopicity. At the Livany Experimental Biochemical Plant, 3-6% o`
the additive has been used since 1973, and this ir sufficient for normal
operation of the spray dryer. The amount of lime added is up to 20% (dry
matter) at the plant in the city of Peshtera [illegible] (NRB), and this
normalizes entirely the physicomechanicaZ properties of KKL. At the Insti-
tute af Micxobiology imeni A. Kirkhenshteyn, Latvian Academy of Sciences,
studies conducted in 1968 revealed that upon contact of slaked lime with
evaporated culture fluid there was formation of gel; a study was made of the
optimum conditions for this process and spray drying of the gel.
The evaporated mass, with 45-60% concentration of dry substances and at
least 7% L-lysine content, is passed into a reactor to obtain liquid [32,
34] KKL (second variant of prepared form, T[1 88 Latvian SSR 04-74) or in
order to dry it with filler on an apron dryer or fluidized-bed dryer.
_ In the third variant, the evaporated mass is mixed with filler--wheat bran
(i:l dry substance), and passed through a gr.anulator to a dryer [35].
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Drying time is '1-2.5 h at 90-95�C with the PKS-90 apron dryer and 20-25 min
at 120-130�C with the f luidized-bed dryer desigzed by the Livany Experi-
mental Siochemical Plant. A"vibrofluidized-bed" dryer is also being
developed [36]. The obtained granules are ground and standardized with
filler. The product, kormolysine RST BSSR 621-75, obtained by this method
ie not hygroecopic.
The loss of lysine with evaporation in the "sinking film" system does not l
exceed 3% [37]. The loss constitutes 5-7% in the spray dyer and 3-8% in
the PKS-90 and fluidized-bed dryers. Total loss of L-lysine in the
_ dehydration process ranges from 3 to 18%.
Metering uevices and mi:cers are used to adn vitamins [24] in order to
make more economic use of KKL, and it is produced ir~ the form of dry
~ premixes (fourth variant of prepared form, TU 88, Latvian SSR 010-77).
Several hydrolysis plants produce lysine-enriched (at least 2%) yeast,
- in accordance with TU 59-84-75 [28].
In the course of assim;lation of experir.iental industrial production of
KKL, several technological ref inements were developed and introduced [27], '
which pertain, in particular, to the prepared forms, methods and equipment
for producing them [35, 36]. These methods, which improve the technology
of production of KKL, can also be used in the production of other microbial
concentrates. The evaporators and dryers used to obtain concentrates,
and the dehydration modes were described in [18, 36-401.
Physicomechanical Properties of Concentrates, on the Example of KKL
Parameters and methods characterizing the suitability of concentrates
for pracessing in the mixed feed industry and other consumer branches of
industry have not yet been defined. Accordingly, the perznissible ranges
of parameters used in practice have not been set [41]. Vague descriptions
are encountered, such a.s "bulk powder product," "nonhygroscopic product,"
etc. But most of the concentrates are amorphous substances [29], which
_ can be referred to as highly concentrated aqueous solutions. Consequently, -
retention of fluid by means of absorption is inherent in the concentrates. -
The fluid is uniformly distributed in the product in an equilibrated state.
The amorphic nature of the concentrates also causes a change in their
mechanical properties, depending on the temperature.
It has been demonstrated that KKL conforms well with the law of Raoult, -
expressing equilibrium between voltaile component (water) content in the
solution (concentrate) and pressure of vapor of the volatile component
above the solution. In practice, thisisman.ifested by hygroscopicity of
the concentrates, i.e., a tendency toward more intensive absorption of
fluid under natural conditions, with formation of lumps and a colid mass =
(with further absorption of moisture it changes into a viscous liquid).
8
FOR OFFICIAL USE ONLY
APPROVED FOR RELEASE: 2007/02/08: CIA-RDP82-00850R000200080007-4

APPROVED FOR RELEASE: 2007102/08: CIA-RDP82-00850R000200080007-4
FOR OFFICIAL USE ONLY
a
c
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a

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Figure 2.
Isotherms of moisture absorption by
some microbial concentrates
1)
- 2)
3)
4)
5)
6)
feed lysine concentrate without
filler, 25�C
vitobacterin, 20�C
kormogrizin, standardized, 200 G
biovit, 20�C
baker's yeast, 18�C
feed vitamin B17 concentrate,
25�C
9
Figure 2 shows the isotherms of
absorption by some concentrates.
Although the sorption isotherms are
generally considered as the main
characteristic of hygroscopicity,
the rate of absorption, which de-
termines changes in technical pro-
perties of concentrates, is an
equally important indicator [42, 431.
Table 1 lists the relative atmos-
pheric humldity, at which friability
was impaired [35]. In this case,
loss of friability was determined
on the basis of behavior of a sample
kept for 48 h in a weighing bottle
in a desiccator (o 20 mm) at a
specific relative atmospheric humi-
dity (35.7, 43.1, 53.6, 61.8 and
85.1%). The size of the sample
constituted 107 g. When friability
was lost, the sample did not
scatter [pour] when the bottle was
rctated about its vertical axis.
Methods have been developed and
systematized for reducing hygrosco-
picity of concentrates (Table 2)
[42, 431. In assessing them, ape-
cial attention ahould be given to
the results of zootechnical testing
of the concentrates [26], since the
use of fillers could have an adverse
effect. The best indices were ob-
tained with wheat bran in the pro-
duction of KKL. This filler is par-
ticularly advantageous in the case
of subsequent production of vitamin
and amino acid premixes [24]. It is
desirable to use up to 20% lime, in
relation to dry substances, and
this virtually normalizes the pro-
perties of KKL. The biological
effectiveness and distinctions of
giving animals such a product are
being investigated.
FOR OFFICIAL USE ONLY
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F6R
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There has been a study of the process of vitrification of amorphous micro-
biological concentrates in powder form; determination has been made o`
the temperature of this process and relation of thermal expansion of the
specimen, in particular, KKL, amylosubtilin and yeast, to different
' levels of moisture content [30, 451.
Experimental data have been published on the physical properties of
various commercial forms of KKL [46, 471o
Studies of the properties of concentrates make it possible to comprehend
the causes and mechanism of formation or technical characteristics (speci-
fications?] of products that are unsatisfactory for the consumer, and
they also shuw the basic means of upgrading these characteristics. Zoo-
technical studies of various new commercial forms of concentrates and
intermediate products of production thereof play an exceptionally important
role, since use of additional substances or technological operations may
yield an adverse biological effect in some cases. At the present time,
there are no standard methods or criteria, according to which the suita-
bility of concentrates for processing can be unequivocally determined. -
In the authors' opinion, the first and foremost task for the Al1-Union
Scientific Research Institute of the Mixed Feed Industry to solve this
problem, including coordination of research,
[523-10,657]
COPYRIGHT: Otdeleniye nauchno-tekhnicheskoy informatsii i
tekhniko-ekonomicheskikh issledovaniy mikrobiologicheskoy
promyshlennosti (ONTITEImikrobioprom), 1979
10,657
CSO: 8144/523
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0
UDC 577
NOLECQLAR AND CELLULAR BIOPHYSICS
- Moscow MOLERUI.ARNAYA I iQ.STOCHRAYA BIOFIZIRA (Mo lecu lar and Ce l lu lar
Biophyaics) la Rusaian 1'/77 Uages unknown
LAaaotation, Foreward, Iatzoduction and Table of Contents of book.
G.M. Fcank editor. Introduction by M.V. Vol`kenshteyn, Correaponding
Nember USS~t Acadsmy of Science~7
CText7 This collection c4nsiats of origiaal studies condncted in 1971-
- 1y76 by asaociates of the USSR Academy of Scieacea Institute of Biophysics.
IC contains papess coaceraing the most important results obtainad ia the
areas ot molecular biophysice and cellular biophysics. Problems diacussed
iaclud� probleaa of biological motility, conformational motility of aacro-
molecules, �lectron-coaformational concepts concerning thm structure of
biological macrooolecules and mcdern methods of plrysico-chemical stadies
of biological atructures and processes.
The collection ia intended tor a wide ranga of readera, includiag bio-
physicisti, biochemists, specialists in molecular biology and cellular
Diology, graduate studants and students specializiag in the area of bio-
- physiCS.
- Foreword
The tormation of a new science among the biological disciplines is alwaya
_ a coQplex, and ia some raspects, a eontradictory process. This is the
�ituation today in raspect to biophysics. Skeptics sometimes queation
Whether the formation of this now science is aAmaWhat artificiel or not.
However, if we examiae it attentively, we ahall see that this process is
a progressive step for bialogy as a whole xnd one Which must coatiaue.
_ Ths very seae thing occurrad several docades ago during the genesia of
biochemiatry. Howevar, the establisYment of biochemistry aas facilitqted
by tha evolution from physiology of "physiological chemistry," a term -
about vhich little is noW remembered. However, it is easy to produce
many demonstratioas of the fsct tbat "chemical language," even aa complex
' 15
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as it was, Was atill inadequate to describe even the individual links ot -
- the life procasses. Thia produced the orgenic necesaity for development
of the phyaical examination of Diological phenomena with all the powertul
apperatua of modern phyaics, which includes both general theoretical con-
cepta (especially mathamatical apperatus) and madern methods of axperiment
al phyaics.
First thes� aroae the optimistic attituda which aasumed that participation -
ot physiciats would lead to the rapid solution of biological problems.
However, it soon became clear thxt purauit of such an approach waa im-
poasible without some degroe of aimplifir.ation and schematization. Thus, _
inveatigator3 were once more convinced of the imarense complexity of ques-
_ tions of biology.
Now we can be assured thet the joint development of biochemistry and bio-
- physics has contributed greatl.y to our understanding of the materia] _
essence of life phenomene. _
We ahould not be disturbed by the fact tY:at, evidently, biophysics does _
not have its own specific objectives or problenns such as does, tor example,
- microbiology or the science of photosqnthtisis, which limits its scope.
This same biophyaics is neceasary for suGCOssful developmant of the two
sciencea mentioned above and, in dependence upon the poaing of the problem,
biophyaical approaches are ueed in the solution of problema or aaicrobiolo- -
- gy and photoaynthesis. Nevertheleea We cannot exclude the fact (and real-
ly cann,,t even avoid it) that there will sriae gradually (and already are -
ariaing) some problems in the solution of Which biophysics prevails and
in which the results of tha research are decisive.
In view of tnis, We must L.t attempt to separata from biology individual
problems in Which biophysics operates "autocratically". The role of bio-
physics Will be highly sigaificaat only when it is applied with reason-
abla interactioa with biochemical and general biological approaches.
As the title indicates, this collection contains results of research con-
cerning tWO major groups of atudies conducted in recent years at the USSR
_ Academy of Sciences Institute of Biophysics. Ttiey have been published
in honor of tnia institute on its 25th annivereary.
The division of biophysics into molecular biophysics and cellular bio-
physics is somewhat arbitrary. It is difficult, today, to preaent con-
cepts concerning the cell mithout inclusioa of studias concerning bio-
- logically i.mportant associationa, and, on the contrary, the study of the -
propertiea of biomacromolecules is conducted in conaidaration of their
rold in processes of the vital acl.ivities. Theretore, in spite of the
_ 16
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division of this collection into 2 sections, the reader will find maay
examples of o verlapping ol' levels of the heirarchy of living matter.
Tha first section deals largely Mith the physical aspect ot the structure
and functional Posaibilities of macronwlecules, which play a predominant
role in biologica 1 systems. The mejor contribution of articles in this
section is the formulation of now, thaoretical concepts in the area of
the kinetics of biomolecular procosses in qwntum chemiatry. At the same -
time, ae muat point out that maay of the theoretical conclusioaa are
illustrated by imPrassive experimental contirmations.
Studies in the area of biological motility and muscle contraction are
preaentod in the 2d section. The srbitrariness meationed abo ve of the
separation of the molecular and cellular levels becomes mora obvious heze.
Today, for example, we cannot speak of the mechanism of muecle contraction
while axamiaing only the transverao-striated structure of the muacle with-
out considaring, at the sane tiae, the dahavior of muscle proteias, local-
ized in individual parts of the suscle fibar.
On the Whole, the collection confirma the statement above concerning the
inaeparableness of biophysical studiaa from biochemical aQproaches or, in
goneral form, fron the physico-cbtmical concepts concerain,g the proper-
ties of living atructares.
The USSR Acadeoay of Sciences Inatitute of Biophysica, upon its 25th
anniversary, is utilizing the posaibilities of thaoretical and experi-
mental phyaics in the development of present day coacepts of biophyaics
so that it continues to occupy a place of honor ia some other biological
diaciplinee.
Introduction
Molacular biophyaics involves, pri.marily, a study of the structure snd
propertios of biopolymers proteins and aucleic acids. This aciantific
- trend haa developed over the last 2-3 dacades to a greater extent than
othar arfas of biophysics primarily dne to the rapid prograss in molecu-
lar biology and biocbeeistry and by the olucidation of the molecular
bas.s of the most iaportant phenomena of vital activity, snch aa heredity, -
variability, metabolism, and apecific eazymic procesaea.
Reaearch in the area of the physics of macromolecules underway at the
USSR Academy of Scionces Institute of Biophyaics iacludes studias of both
globular and fibrillar proteias. The fisst area refers to different
enzymes and hem-proteins devoid of enzyoaic activity (myoglobin and hemo-
globin) and also receptor proteina (rhodopsin and others). Fibrillar
proteins include, primarily, contractile protsias of the muaclea such as
17
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actin, myosin, tropomiosin and also collsgen. All of these objects may
be considered to be key products for oae or another of the biological
proceasas.
The study of proteine is not an end in itaelf. There ia an ever increas-
ing number of molecular-phryrsical stud3ea invo lving the most impartant
probloms of the biophysics of cells nembrans transpoxt in conaection
With light and molecular receptiona and muscle contraction.
Such molecular-physical studies properly involve an experimental and
theoretical study of anzymic procerses, tbo study of tha behavior of
prateins in aolations (an actoorycin complex) and the aevelopment of ori-
ginal methods of rasearch (especially, scoustical research).
Studies being conducted in the area of tho pbryrsics of aucleic acids in-
clude stndias of the structure and properties of DNA, RNA, model synthe-
tic polyn.ucleotides in connection with processes of replication and tran-
scription in connection with problems of stabilizatioa of those biopoly-
mers.
A significant part of the research concarning molecular biophysica is
combined With general theoretical concepta of slectron-conformational
interactiona (ERV). The fnnction of biopolymers is chemical aad elec-
tronic. They fuaction eitder as convarters of chemical, molecular aignals
(enzymes and other proteina) or aa chamical matrices in protein bio-
synthesis (DNA mRNA). This functioa is realisad by meana of contormation-
al changea of biopolymera. The problam consiats of the study of the
interactioa of electron and conformational degrees of freedom.
The concept of EKV Waa fa --mulated for the first time at the institute.
The solution of pertinent problems requires a Wide range arsenal of modern
- expsrimtntal matboda and theoretical studies also in the area of quaatum
chemiatry. Effective use is made af diverse optical and spectral methods,
especially the technique of pulse photolysfs and also of the study of
electron paramegnetic resonance (EPR) spactra of spia labeled biopolymers.
Enzyme-proteins may be treated ss the "black box" which reslizes trans-
formation of the iaput mo lecnlar signal, the substrate, into the outgoing
signal, the product. The study of the structure and the operation of such
a"bleck box" is performed by two methodss by tho stody of the conversion
procesa, that is, the kinetics of the eazymic reactions, and by the study
of the structure and dyaamics of the convertar itself. This section
presents results obtained by both methods. Resctions of regulator ensymic
systems are studiad experimentally and the role of comperatively slow
conformational conversions ot proteins are ravealed. The properties and
mtchanisms ot action of RP1A-po lymerasa are studied alongside enzymes of
18
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dehydrogenase type With hem-containing proteins. A theory ot the kinetics
of enzymic reactions based oa methods ot the theory of graphs is coa- _
structed. These methods develaped at the in3titute give the simplest
algorithms tor calculation of the rste of the reactiona. At the same
time, modal quanto-chamical calcylations which permit an understanding
of the aature of EKV in enzymes and in noa-onsymic hen-containing proteins
are undertaken. Tbe proceaees of electron transfer in hem-containing
proteins, directly associated with BKV, are studied experimentally. Aa
original arrangement for the study of photoconveraions of proteins by a -
pulsed photolysis method is constructed. This provided neW fnformation
concerning tha properties of hen-coataining proteias aad rhodop9in the
protein responsible for viaual reception.
- Tha important theoratical method of atoms atoms of potentials is used
- for analysis on nonvalent interactiona and for the study of conformstional
trensitiona oi polynucleotides, for the study ot solvation of organic
_ Molecules and prediction of the structure of crystals of model compounds.
The atructura and propertias -F protein crystals are studied with the help
of X-ray mtthods and other methods.
Original concapts concerning the liquid-crystalline atructure of contrac-
tile proteins provide the basis for some studies devoted to coasideration
of cnuscl� contraction. Nxny studies now involve the liquid crystalline
atructu.r� of inembranQS, which determiaa conformational properties of lip- -
ids.
HoWever, the idea concerning the liquid crystalline atructure of protein
contractile systems, developed for the tirst time at the institute, is of
a different neture. Liqaid crystalline propertiea of contractile pro-
- toins are determined not by the conformational motility of proteins nor
. by the packing of their sub-unita ia the fibrilla but by the behavior of
the fibrillar proteins as integrel systems.
It 18 quite aecessary to mention the development of high speed X-ray
diffractomotry of proteins, an original X-ray method based on the use ot
synchrotron radiatiog.
In studies devotad to the photochemistry of the visual pigment, roentgano-
grapby of muscles, tha structure of collagen, tho peculierities of be- -
haviox of protmina of the actomycin complex ia solution, the "bridgas are
being Duilt" betwean awlocular Diophysics and the biophysics of ce118.
Such a division of biophysics ia, of course, somewhat arbitrary. It has
an historical nature snd there are no rigid boundaries here. The general
problem involves the study of biological phonomena at the mo lecular level.
19
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TABLE OF CONTENTS Page
Foraword . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3 -
MOLBCULAR BIOPHYSICS
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . .
5
Markovich, D.S., "Coaforoatioaal Aepects of. Begulation of $nzymic
"
. . . . . . . . . . . . . . . . . . .
it
i
7
. . . . . . . .
y
v
Act
Gol'dshtsyn, B.N., "A Theoretical Study of Kinetic Models of Re-
gulator Bnrymes" . . . . . . . . . . . . . . . . . . . . . . . .
12
Vol'keaahtsyn, M.V., Golovanov, N.B., Sobolev, V.M., "Blectron-
Conforsational Interactions and Approaches to the Modelling og
Active Centsrs of Easqm~s" . . . . . . . . . . . . . . . . . . .
13
Kamzolova, S.G., Osolin', O.No, Kalontarov, A.I., "A Study of
_
Conformrtioaal Chaages of RrtA-polymerase Qf B.coli B at Differ-
_
ent Stagas of RNA Synthesis on T2-DITA by the Method of Spin La-
. . . . . s . . . . . . . . . . .
l
"
16
. . . . . . . . . . . .
be
s
Vol'kenshteyn, M.V., Atanasov, B.P.9 Postnikova, G.B., Artyulch,
_
R.I., "A Study of Electron and Conformationsl Properties of Hem
Containing Proteins" . . . . . . . . . . . . . . . . . . . . . .
21
_
Foaenko, Ye.Ye., Orlov, N.Ya., Rulakov, V.N., Lyubarskiy, A.L.,
Fasenlco, N.K., "Photochemlcal Studies of Ham-Containing Pro-
teina and of the Optic Pigmant" . . . . . . . . . . . . . . . .
30
Zhenodarova, S.trl., Klyagina, V.P., Sedal'aikova, E.A., Khabarova,
-M.I., Smol'yaninova, O.A., Poaomareva, V.M., Golovanov, I.B.,
Sobolov, V.M., "A Study of Enzymic Synthesia of ths Intsrnu-
cleotide C , - C ,-bond" . . . . . . . . . . . . . . . . & . . .
"
3
39
A Study oi Protopyro-
T.I.S Troyaaovsk$ya, H.L.,
Siaol'yaainova
"
47 _
. . . . . � � � � � � � � � � �
v~nic States of a D1~lA Molecule
Vazina, A.A., Zhelosaaya, L.A., Lukina, V.I., Mavkh, L.G.,
_
Savel'yov, V.B., SYebnitskaya, L.K., Shaloatov, V.M., Margolina
A.Ye., "A RoentQenogrskphic Stndy of Muscles and Liquid Crystsla
53
of Contractile Proteins" . . . . . . . . . . . . . . . . . . . .
Lazerev, Yu.A., Grishlovskiy, B.A., Lobachav, V.M., Pisachealco,
-
"St
ruc
A.I., Rhromova, T.B., Turkina, T.V., Yesfpova, N.G.,
iral"
S
Ternar
'i`
l
73
y
p
ype
agen
tural-Physical Studies of a Col
S.S., Chetverikova, Ye.P., Rybina, V.V., "Syachronous
Shnol'
,
- (in a Maecrovolume) Confornational Variations in Preparation of
"
. .
Proteias of an Actom}cin Complex and in Creatinase Solutions
,y
Sarvazyaa, A.P., Kherakov, D.P., "Acoustical Stndies of Coaform-
"
93 _

matioaal States of Proteins in Aqudous Solutions
_
Sarvazyan, A.P., "Specific Mectiaaisms of Biological Action of
~
Pulsed Ultrasoand Associated with the Dynamics of Biological

. . . . . . . . . . . . . . . 000 .
lU7
. . . . . . . .
Sys t.~
Gabelova, N.A., Sinarf, V.G., K,obyakov, V.V., "Contormational
"
114
. . . . . . . . . . . . . . . . . . . .
Ane lysis of Tropomyosin
_
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BIOL()GICAL MOTILITY AND MUSCLE CONTRACTION
page
Introduction . . . . . . . 0 0 , * * ~ . ~ ~ ~ ~ ~ ~ ~ , - * *
. 121
Podlubnaya, Z.A., Freydina, NoA., Shpagina, M.D., Orlova, A.A.,
"Study of Molecular Interections in the Structure of Thick 8ad
Thin Muscle F'1laments" . . . . . . . . . . . . . . . . . . .
.
. 124
Kalamkarova, M.B., Kofman, Ye.B.,
Nankina, V.p., "properties
and Intaraction of Coatractile Proteias and Their Enzymes"
. 152
Ladnev, V.V., "A Study of the Structvre o� Actin-Contaiaiag
Filaments by the Method of Diffraction of X-says"
. 164
Filatova, L.G., Shtrankfel`d, I.G., Yesipov, N.G., "A Study of
the Diatribution of Charges on the Surface of Molecules of
Protains of the Contractile Apparatus". . . . . . . . . . . . .
. 173
Zamyatkin, A.A., "Volumetric Effects in Contractile Systems"
. 176
Morozov, V.N., Bulcatina, A.Ye., Shnoi', S.E., "A Study or
Machenochemical Conversions ia Eazymes" . . . . . . . .
lts~
Deshcherevskiy, V.N., Bukatina, A.Ye., Sidorenko, N.N., "A Study
ot the Mechaaochemical Cycle by the Enzymic Kinetics of Acto-
myoain Systams" . . . . . . . . . . . . . . . . . . . . . . . .
. lyb
Bssurmanova, O.K., Bocharo va -Messner, O.M., "Ultrestructure
Changes in Distribution of ATP-ase Activity During Contraction
of the Flying Muscle of an Insect". . . . . . . . . . . . . . .
. 2 10
Lyudlw vakiy, R.G., "Functional and Prysico-Chemical Features of
Difterent Typea of Muscle Fibers" . . . . . . . . . . . . . . .
. 217
Samosudova, N.V., Lyudkovskaya, R.G., "Changes of Ultrastructure
of Cross-striated Muscle Undar Difterent Types of Contraction"
227
Samoaudova, N.V., Rslamkarova, A[.B., Ogiyevetskaya, M.M.,
"Identificetioa of Proteius in tha Structure of Crosa-strieted
Muscle by the Mothod of Labelled Antibodies" . . . . . . . . .
. 238
Karnaukhov, V.N., "Luminescence Studies of Muscle Cells"
. 247
Kryukova, M.Ye., Bocharova-Messner, O.M., "A Comparative Study of
the Ultrastructure of Musales of Dixferent Type of Action in
Insectsn . . . . . . . . . t . . . . . . . . . . . . . o . . .
2 Sts
.
Budnitskiy, A.A., Klimov, A.A., Srebnitskaya, L.K., ",1.Study of
Shortening oi Anisotropic Disks During Contraction of Trans-
versostriated Fibers of Arthropods" . . . . . . . . . . . . . .
. 2bts
Cabelova, N.A., Aleynikova, K.S., "Some Additional Material Con-
cerning the Contractile Apparatus of Skeletal Muscle the
State of Superweakening" . . . . . . . . . o , o o o o o o o a
o 278
Yemel'yanov, V.B., Pechatniicov, V.A., Rizvanov, F.F., Fedorova,
N.
S., "A Study of the Structure of the Contraction Apparetas af
Transversostriated Muscles by the Optical Diffraction Method .
. 288
L0353-2791%
COPYRIGHT: Izdatel'stvo "Nauk.a" 197!
2791
CSOs 8044 /353
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rox ur'FlUlai, uaL uaLY
UDC 576.3
BACTERIORHODOPSIN AND THE VISUAL PIGMENT RHODOPSIN: AS DISCUSSED AT, SOVIET-
AMERICAN SYMPUSIA _ Moscow VESTNIK AKADEMII NAUK SSSR in Russian No 9, 1979 pp 120-127
[Article by M. A. Ostrovskiy, Doctor of Biological Sciences]
[Text] Several Soviet-American symposia were held in recent years on "New
- Directions in Biology." The first symposium, held in Kiev in 1975, was de-
voted to nucleic acids, the second in Chicago in 1976 dealt with research
' on biological membranes, the third in Riga in 1976 was concerned with pro-
tein chemistry and physics, and the latest, held in Kiev in October 1978,
again dealt with biological membranes. The Soviet chairman of the organiz-
ing committee was Academician Yu. A. Qvchinnikov, vice president of the USSR
~ Academy of Sciences.
A great deal of attention was paid at the sompoaia to the structure and
function of biological membranes and membrane proteitis.
The molecular and membrane mechanisms of nerve excitation was extensively
discussed at the last Ki^v symposium. The principal subject was the struc-
ture and function of ionic channels of excitable membranes.
Important information is now available on the electrical and chemical pro-
cesses responsible for the origination and propagation of nerve signals.
It is a well-established f act that the ionic currents in the excitable mem-
branes of nerve cells are created by discrete molecul.3r complexes, the so-
called ionic channels. Facts are being rapidly colla:cted on the properties
of specific ionic channels. The identification and investigation of their
functional properties in model systems is on the agenda. In the Soviet
Union, this research is being cor.ducted on the highest level, particularly
in Kiev by Academician P. G. Kostyuk and his studEnts (Inatitute of Physi-
ology imeni A. A. Bogomolets, Ukrainian Academy of Sciences). Hence Kiev
has quite rightly become the place for holding a Soviet-American symposium
on blological membranes.
The paper of P. G. Kostyuk "Calcium Conductivity of the Nerve Cell Membrane" _
and that of hia student 0. A. Kryshtal' "Study of the Conductivity and Kin-
etics of Solitary Calcium Channels" examined the electrical and kinetic ~
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characteristics of calcium channels. Soviet and American scientista dis-
cussed in detail the functional properties of channels specific for other
_ physiologically important ions, chiefly sodium and p^'assium. Mention must
be made in this connection of C. Armstrong's (USA) paper "Inactivation of
' Sodium Conductivity and Portal Currents," B. Hille's (USA) paper "Selectivi-
ty and Flow in the Ionic Channels of Excitable Cells," S. Hagivar's (USA)
_ paper "Properties of the Potassium Channel of Anomalous Rectification," and
B. I. Khodorov's (Soviet Union) paper "Inactivation of the Sodium Portal
= Current." The studies on chemically regulated (e.g., cholinoreceptor) and
_ electrically excitable membranes are of extreme theoretical and practical
interest, especially for present-day neuropharmacology, psychopharmacology,
surgery, etc.
A subject of ma,jor interest at the symposiums was the structure and function
_ of the visual pigment rhodopsin and bacteriorhodopsin. In the Soviet Union,
research in this field is being actively conducted as part of the Rhodopsin
Project directed by Academician Yu. A. Ovchinnikov.
Rhodopsin and bacteriorhodopsin have now become a"burning issue" in physi-
cochemical biology. Bacteriorhodopsin is a concern of bioenergetics while
rhodopsin is involved in sensory reception and nerve excitation. Bacteri-7
orhodopsin is responsible for the simplest and probably the most ancient
(nonchlorophyll) form of nhotosynthesis while rhodopsin is responsible for
transforming the energy of light into visual (nerve) excitation.
A visual pigment, later called rhodopsin, was discovered more than one hun-
dred years ago (in 1876) by the German physiologist F. Bolle. Bacterior-
hodopsin was found in the purple membranes of halophilic bacterfa by W.
Stokkenius (USA) as recently as 1971. And, paradoxical as it may seem,
we now know much more about the structure and function of bacteriorhodopsin
than we do about rhodopsin. The purple membrane of halophilic bacteria
_ proved to be a new type of biological membrane capable of transforming solar
energy. It is part of the cell membrane of the bacterium Halobacterium
- halobium and it contains a singlE protein. This protein uses the energy of
light to transport protons across the membrane. As a result, considerable
electrochemical potential is generated on the membrane. The cell utilizes
this energy to synthesize ATP and perform some other physiological functions.
_ 2'he bioenergetic (photosynthetic) function of bacteriorhodopsin ia directly
related to the photochemical cycle of transformation.
- The visual pigment rhodopsin is also essentially a solitary protein in the
- photoreceptor membrane of the visual cell of the retina (it accolints for
approximately 90% of the entire membrane protein). A direct relationship
was detected long ago, and is by now firmly established between the photo-
transformations of rhodopsin and vision. The photochemistry and biochemistry
of rhodopsin have been fairly well studied, but the mechanism responsible
for coordinating the photolysis of rhodopsin and the generation of photo-
receptor potential (visual signal) is still obscure.
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What is the basis for calling the protein of purple :nembranes bacteriorhodop-
sin by analogy with rhodopsin? The similarity is quite great. Both are _
chromoproteins, typical membrane hydrophobic proteins, and both contain reti-
nal (vitamin A aldehyde). Retinal is bound in both rhodopsin and bacterior-
hodopsin to the amino group of the lyaine radical of opsin. Retinal by it-
self is almost colorless, but in rhodopsin its maximwn abaorption spectrum
strongly shifts to the red region, to 500 nm, while in bacteriorhodopsin it
does so even more strongly, to 570 nm. The nature of this enormous batho-
chrome shiEt has still not been definitively elucidated. It is generally
known that a 14rge part of the ehift in both rhodopsins is due to the pro-
tonizing of the bond between the aldehyde group of retinal (CHO) and the
amino gruup (E-NH2) of lysine. The molecule of retinal, since it is a
. polyene, can occur in several isomeric configurations. It was shown in J.
- Wald's laboratary at the end of the 1950's that of all the possible isomers,
only 11-cis retinal can act as a chromophore of every one of the visual pig-
ments and that the only photochemical reaction in the visual process is the
photoisomerization of retiiial from 11-cis to the all-trans form. So too in o
the bacteriorhodopsin molecule: Only certain retinal isomers (the all-trans
and 13-cis forms) can function as its chromophore group. Some reports have
been published on 11-cis retinal occurring in bacteriorhodopsin, but they
are incorrect. -
That the photoisomerization of 11-cis retinal performa a trigger function in
the mechanism of visual recepCion is beyond doubt. As for the possible func-
tiun of the isomerization of retinal in the bacteriorhodopsin molecule, there
is still no reliable evidence that this reaction is involved in the perform- -
ance of its main function, i.e., proton translocation across the purple mem-
brane.
At the Biophysics Congreas held in Copenhagen in 1975, R. Henderson (Britain)
demonstrated (not on the program of the congress) a tridimensional model of
the organization of the bacteriorhodopsin molecule in a membrane. According _
to this modeo, which is based on an electron-microscopic picture with a reso-
lution c+f 7 A, the molecule consists of seven alpha-spiral fragments that
intersect the purple membrane at an almost 90� angle. In other words, bac- =
teriorhodopsin is a transmembrane protein.
The methods of protein chemistry used for water-soluble proteins are well
established, but they a�re scarcely suitable for hydrophobic membrane pro- _
_ teins. More effort should be made to develop new techniques for investigat-
. ing these proteins, chiefly bacteriorhodupsin. _
A successful method for splitting the bacteriorhodopsin molecule directly
in the purple membrane was devised in the laboratory of Academician Yu. A. _
Ovchinnikov (Institute of Bio-Organic Chemistrv imeni M. M. Shemvakin. USSR
Aca:?emv of Sciences). The proteolytic enzyme papain became the instrument.
Papain attacked fractures of the semifragmented molecule emerging on the
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hydryophilic surface of the purple membrane. It is interesting to note that
the investigators of bacteriorhodopsin traveled here over the path already
marked for rhodopsin.
Academician Yu. A. Ovchinnikov in a paper on "Structure of Bacteriorhodopsin
in the Light of Its Function" read at the Kiev Symposium set forth the com-
_ plete amino acid sequence of the first membrane protein, bacteriorhodopsin
(its molecule consists of 247 amino acid radicals and its molecular weight
is 26534).
The relationship between the structure and function of bacteriorhodopsin is
of particular interest. In this connection it is exceptionally important to
know not only the amino acid sequence (primary structure) of the membrane
protein but its topography in the purple membrane. The absorption of light
by retinal is the primary event in the chain of molecular processes responsi-
ble for proton translocation. According to the data obtained in Ovchinnikov's
_ laboratory, the aldimine group that binds the retinal (chromo$hore) radical
to lysine-41 of the protein part of the molecule is 15 to 17 A away from the
- side of the purple membrane onto which the N-end of the polypeptide chain
exits. Since the first and rapid phase of proton transport across the mem-
brane ia associated with its emergence from the membrane into the environment
while the second and slower phase is associated with protein absorption from
the internal cytoplasmatic side of the purple membrane, Ovchinnikov and co-
workers are right in assuming that the site where retinal combines with op-
sin (the protein part of the molecule) is close to the external side of the
membrane.
This work on interpreting the complete primary structure of the membrane pro-
tein of bacteriorhodopsin is exceptionally important. It opens up realistic
prospects for determining the primary structure of rhodopsin and other pro-
teins.
Let us now examine ir some de*^{' f�_=t'_;,n of bacteriorhodopsin, the
main subject of the papers read at the Soviet-American symposiums by Profes-
sor Stokkeniiis and V. P. Skulachev, corresponding member of the USSR Academy
of Sciences.
a-
In a paper entitled "Outlook for Bio-Organic Chemistry and Molecular Biology"
that Stokkenius read at an international symposium in Tashkent in October 1978
- and before that at a Riga symposium in August 1976, he discussed at length -
the reactions of the photochemical cycle of bacteriorhodopsin. He showed
that the duration of the photoreaction cycle is several milliseconds. In
- the course of the cycle one proton is freed on the external side of the mem-
brane while another is bound on its internal side.
The initial rapid photochemical reactions were subsequently inveatigated by
means of picosecond laser spectroscopy. Upon the absorption of light, bac-
_ teriorhodopsin changes into the so-called batho-form in a few picoseconds.
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At the symposium in Tashkent, Stolckenius demonstrated the photoreaction of
the bacteriorhodopsin cycle. The lifetime (half-life) of each of the inter-
- mediate producta is given for a suepeneion of isolated purple membranes ln
water at room temperature and neutral pH. All-trans and 13-cis are the iso-
meric forma of retinal that were extracted under conditions in which a large
= part of the pigment is in the form of the original retinal and intermediate
product P412. The absorption and liberation of the proton is shown here in
accordance with changes in the pH in the aqueous phase.
G nR570 011~
(11~. ~
o~
~ 12 flo,..Jc,Lw ,;,aHc
~ ( ~ CoF,.a PE;.+Ha'!a
H
10) n6ao - C=N -
fl
U ;ao(2
j)W�4jQ1oPO ocHoeaMre
0 npGio~NpUAano z
M
i
(14) 13-unc 41opwd P(oNNanA
~C3) n530 C=N - nSSO (4
15) ) I1J.+y 4ceo nc-oez.H~ie
Ac npo, G�i+pnEamo
(7)
H;~--- n~~~ .
Photochemical cycle of the transformation of bacteri-
orhodopsin (according to W. Stokkenius)
bR570 - bacteriorhodopsin; P590, P412, P530, P640
Key:
1.
10 picoseconds
6�
P412
2�
P590
7.
til millisecond
3.
1 microsecond
8�
P530
4�
P550
9.
ti3 milliseconds
5.
ti50 microseconds
10�
P640
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11. S milliseconds
12. All-trana form of retinal
; 13. Schiff's baee protonized
14. 13-cis form of rptinal
15. Schiff's base deprotonized
The kinetic parameters of this reaction cycle were recently analyzed in de-
tail by Stokkenius aided by a special camputer program.
To understand the molecular mechanism of proton transfer, it is necessary to
determine the structure of the various spectrally distinguishable intermedi-
ate products. The technique of resonance Raman spectroscopy was successfully
used for this purpose. Lewis, Stokkenius and their co-workers showed that
in the original bacterorhodopsin 570 the binding of Schiff's base between
retinal and the protein (opsin) is protonized but in the intermediate product
P412 it is not protonized. This means that Schiff's base in the bacteriorhod-
opsin molecule is a very likely participant in the process of proton trans-
location. Lewis� very recently published data indicate that deprotonization
occurs in the stage where the product P550 is converted to the product P412.
The kinetics of proteon liberation and absorption in the aqueous phase on
both sides of the membrane was recently investigated in detail in Stokkenius'
laboratory. Using the technique of flash photolysis and pH indicator staina,
Stokkenius found that proton liberation recedes its abaorption and that one
= proton is liberated for each molecule of bacteriorhodopsin that passed through
- a conversion cycle. The H+ yield largely coincides with the rate of accumu-
lation of the product P412 while absorption is consistent with the regenera-
tion of bacteriorhodopsin 570.
= In one of their early studies, Osterheld and Stokkenius (1973) pointed out -
that the main function of bacteriorhodopsin is light-dependent proton trans-
location. This function was clearly demonstrated in models containing bac-
teriorhodopsin and lipids. E,sentially two kinds of models were used: (i)
_ a suspension of small vehicles usually about 100 X in diameter or somewhat
larger and (ii) f lat lipid membranes (f ilms) about a lipid bilayer. As
Stokkenius noted, these models were used most successfully to investigate
purple membranes in the laboratory of V. P. Skulachev, correspon.ding member
of the USSR Academy of Sciences, at Moscow University.
At the Kiev symposium Skulachev presented new data on the temporal character-
istics of bacteriorhodopsin as a molecular generator of electric current. A
method was devised in his laboratory for direct recording of the difference
in electric potentials generated by bacteriorhodopsin. The method involves ~
incorporating fragments of purple membranes into a flat lipid membrane and .
then measuring the transmembrane difference in potentials by the ordinary
electrometric technique. The method was significantly modified by replacing -
the artificial lipid membrane with porous carriers (membrane filters or col- -
lodion films) saturated with a solution of phospholipids, thereby substan-
tially increasing the stability of the membranes.
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Several phases of the electric response to a laser flash (at a wavelength of
530 nm and flash duration of 15 nsec) were observed in these ehperiments.
The authors attempted to relaee each of the phases to the formation of a
particular intermediate product in the photochemical cycle of bacteriorhodop-
sin. They related the first (nanosecond) phase of generation of inembrane po-
tential to the firat stage of the photochemical cycle, the second (millisecond)
stage to e,jection of the proton into the environment, and the third (milli-
secon3) atage to proton translocation from *_he opposite side of the membrane
(cf. the diagram).
Thus, a qualitative correlation was noted between the phases of generntion of
membrane potential and the spectral transformations of bacteriorhodopsin.
While the function of the bacteriorhodopsin molecule is now solidly estab-
lished, that of rhodopsin is still largely obscure. Rhodopsin is a constitu-
ent of the photoreceptor membrane. In mamalian rods and cones these mem-
branes form numerous flat disks or saccu?es. After a quantum of light is
absorbed by the rhodopsin molecule in the pt?otorecep;.or membrane of the disk,
electric potential (photoreceptor signal) arises on the plasma membrane of
, the visual cell.
An entire chain of processes occurring at the molecular, membrane, and cellu-
lar levele of organization must exist between the primary photochemical events
in the disk and the secondary events on the cell membrane.
In a paper presented at the Kiev symposium, we distinguished at leaet two -
points, two mechanisms of coordination of the absorption of light by rhodop-
sin and the appearance of a photoreceptor (visual) signal. The first is that
between the photoactive (^hotolysis) rhodopsin molecule and the functional _
(enzynic, ionic) changes in the photoreceptor membrane of the disk. The _
second is that between the light-induced processes in the disk and the block-
ing of the sodium channels in the plasma membrane of the rods and cones. It
is the blocking of these channels that provolces a hyperpolarization reaction �
in the cells in response to light, i.e., to the origination of photoreceptor
potential or visual signal in the rods and cones of the mammalian retina.
The key role in the mechanism of the "second" coordination--between the disk _
and the cell membrane--is played by calcium ions and cyclic nucleotides, spe-
- cifically, cyclic guanosine monophosphate. J. Brown (New York University) _
presented at the Chicago symposium the results of direct electroprysiologi- cal experiments in which an increase in the calcium concentration ~'.thin a
- rod in darkness results in hyperpolarization of the cell membrane, thereby
simulating the action of light, whereas a decrease in the free calcium con- -
- centration results in depolarization of the cell, thereby simualting dark-
- ness. This means that calcium is iz fact able to function as an intracellu-
lar mediator between the disk and the cell membrane. However, it still re- -
mains to be proven that under natural conditions in a native vlsual cell
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light actually causes the free calci:sm concentration to increase within the
cytoplasm of a visual cell.
The fact that the photoreceptor membrane of a rod disk becomes more permeable
to calci4-n ions in the presence of light was reported by M. Ostrovskiy in
Chicago ani by W. Aubbell (University cf California, Berkeley) in Riga.
The experiments involved essentially the following. Isolated photoreceptor
disks or a'rtificial liposomes modified by rhodopsin were "loaded" with cal-
ciimm in darkness. The escape of calcium ions.from the disks or liposomes
into the incubation medium was then recorded in the presence of light by
~ three independent methods.
- It followed from the experiments perfor-i::d in Berkeley and ir_ Moscow that
the ionic permeability of a photor=,;eptor membrane increases as a result of
the photolysis of rho::onsin_ nowever, it is still an open question whether
calcium escapes from the disks in native visual cells and does so in an ade-
quate auiount. According to recent data obtained in our laboratory, calcium
does escape from native disks, but it is unclear whether the amount is suf-
; ` ficient to ensure the formation of a visual signal.
Thus, it is likely that calcium plays a role in the mechanism of the "secoi..i"
coordination, i.e., in the mechanism of intracellular transmission of a visu-
_ al signal from a photoreceptor disk to the cell membrane, but there is as _
- yet no conclusive proof of this. Besides calcium, the nucleotide cyclic
guanosine is anather very important factor in the process. .
;
r
The mechanism of the "first" intramembrane coordination is not too clear.
, How does the ionic permeability of the photoreceptor membrane increase as
= a result of the photolysis of rhodopsin? How is the phosphodiesterase
bound to this membrane activated (the concentration of cyclic guanosine
monophosphate in a visual cell decreases as a result of the photoactivation
of this enzyme)? How are other ionic and enzymic processes regulated here?
, Change in the electric properties of the photoreceptor membrane might well
play an important role in the "first, intramembrana mechanism o:~ coordina-
tion.
We cannot at present use the ordinary microelectronic technique to investi-
gate the electric parameters and photoelectric reactions of the photorecep-
- tor membrane of a disk because the size of a native disk is too small. Hence
_ other approaches are needed.
M. Montal (University of :.alifornia, San Diego) and M. A. Ostrovskiy also -
read papers at the last Kiev sytnposium on the photoelectric reactions of a
photoreceptor membrane. -
-
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Montal was able to simulate a membrane system by incorporating rhodopsin
into a lipid monolayer. This aeymmetrically oriented rhodopsin-lipid mono-
layer was placed on a very thin Teflon film separating the two aqueoua phas-
es. A light flaeh eiicited a rapid photoelectric response which, according
to Montal, resulted from the divieion of electric charges in the oriented
rhodopsin molecules. Montal also reported change in the ionic permeability
of a photoreceptor membrane in the presence of light ancl, a matter of espe-
cial interest, the existence on it of potential-dependent I.,^ic channels.
Thus, judging by these data, the electric properties of an artificial lipid
membrane modified by rhodopsin clearly change.
. V. I. Bol'shakov, G. R. Kalamkarov, and the writer using two different methods
were able to observe photopotential of about 10 mv arising on the photorecep-
tor membrane of a disk. In the f irst series of experiments, we used the meth-
od of penetrating ions (anions) suggested 10 years ago by Ye. A. Liberman and
L. M. Tsofina to detect and investigate potentials arising on different con-
jugating membranes of mitochondria and bacteria, including the purple mem-
branes of Halobacterium halobium. When suspensions of closed disks were ex-
posed to light, the anion concentration in the incubation medium decreased
because the anions were absorbed by the photoreceptor disks. This meants
' that the absorption of light by rhodopsin on the photoreceptor membrane gave
rise to electric potential with a"plus" sign on the internal surface of the
disk. The anions entered the disk electrophoretically via the electric field.
- However, the method of penetrating ions has definite limitations. An attempt
was therefore made to measure electric potential directly on the photorecep-
tor disk using the ordinary electrometric technique. We adopted for this
purpose the method of L. A. Drachev and V. P. Skulachev that enabled them to
record the different phases of photopotential on the bacteriorhodopsin purple
~ membrane. The photoreceptor disks "stuck" quite tightly to the flat lipid
membrane (porous filtPrs saturated with a solution of phospholipids were
used). Switching on visible light resulted in the generation of substantial
photopotential, about 10 to 15 mv, on the flat membrane. According to the
Drachev-Skulachev electric circuit, the sign of potential was the same as in
the experiments with penetrating ions, "plus" on the internal surface of the
disk membrane.
Thus, substantial Iight-induced potential could be recorded on a photorecep-
tor disk by two independent methods. It was the direct result of the photo-
lysis of rhodopsin.
It is quite possible that photopotential plays an important role in the mech-
anism of the "first" coordination--between the pholysis of rhodopsin and the
secondary ionic or enzymic ~rocesses in a photoreceptor disk. If the poten-
tial on the nurple membrane generated by bacteriorhodopsin is included in
- the chain of bionenergetic processes, it may also be included on the photo-
receptor membrane ir. the chain of information processes.
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There is still another important difference, in our opinion, between bacteri-
_ orhodopsin and the visual protein rhodopsin: The former apparently performs
only one function, i.e., the function of consuming the energy of light from
a proton pump. The latter, on the basis of all the evidence, is polyfunction-
al, for it triggers and regulates aeveral light-dependent reactions in the
photoreceptor membrane of a disk. However, the functional significance of
- these reactions for the formation of a fairly rapid (milliseconds) photore-
ceptor signal or for the realization of a fairly slow (minutes) process of
light and dark adaptation is still obscure.
The Soviet-hmerican syR:posiums clearly showed that both rhopsin and bacteri-
orhodopsin are now the focus of physicochemical biology, notably, membran-
ology, bionergetics, and receptoi�.
Research on bacteriorhodopsin is opening up new prospects for using solar
= energy. Studies on visual reception are very important for medicine (to -
help understand the causes of serious diseases of the retina and work out
new therapeutic approaches), chemistry, and engineering bionics.
COPYRIGHT: Izdatel'stvo "Nauka," "Vestnik Akademii nauk SSSR," 1979
5 214
CSO: 1840
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II. ADVANCED MEDICAL TECHNOLOGY
STANDARDS REGULATING TAE PHARMACEUTICAL SERVICE
Moscow SBORNIK NORMATIVNXKH AKTOV PO APTECHNOY SLUZHBE (Collection of
Standards Regulating the Pharmaceutical Service) in Russian 1979 signed
to press 3 May 79 pp 2, 3, 647-656
[Annotation, Foreword, and Table of Contents from book edited by M. A. _
Klyuyev , Izdatel'stvo "Meditsina", 55,000 copies, 656 pages]
[Text] Annotation
Official legislative documents concerning the organization of the
pharmaceutical service in the USSR are published in this collection. This
publication includes the principal decrees, orders, and instruction regu-
lating the work of institutions in the pharmaceutical network and the
labor of phaxaiaceutical workers--documents required for organizational
purposes by phazmacy directors, pharmaceutical warehouses, pharmaceuta.cal
- factories (production operations), control and analysis laboratories, and
ot.her pharmaceutical institutions. Documents effective as of 1 April 1979
~ are encompassed.
- Foreword
_ The pr2sent stage of development of the socialist economy and growth in
- the scale of social production are imposing new, higher reguirements on -
legal regulation of economic activities.
Economic legislation must promote further growth of social production, and _
it must raise its effectiveness in the tasks of communist development. It -
- must insure efficient operation of all elements of the economic mecharzism,
_ attainment of a correct relationship between the rights and responsibilities ~
of all levels of the national economy's control, promote all-out development
of the initiative of the ministries and departments, as well as of -
associations, enterprises, and other economic organizations, and encourage
expansion of khozraschet relationships, growth in the role of business
contracts, and further reinforcement of socialist legality and state
discipline. _
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This collection is one of systematized official regulations on the main
problems of the organizational, pharmaceutical, and business activities
of pharmaceutical institutions in the USSR, regulations that are binding
upon workers in all pharmaceutical institutions irrespective of their
departmental subordination.
The regulations presented here are those effective as of 1 April 1979.
Table of Contents
Page
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Chapter 1.
Management and Control of the Pharmaceutical Service 4
Fundamental Principles of USSR and Union Republic Public Health
Legislation (Excerpt) . . . . . . . . . . . . . . . . . . . . . .
4 .
Statute on the Main Pharmaceutical Administration of the USSR Ministry
of Public Health (Excerpt) . . . . . . . . . . . . . . . . . . .
6
Statute on the All-Union Market Information Bureau of the Main
Pharmaceutical Administration of the USSR Ministry of Public
Health (ExEerpt) - . . � � � � � � � � � � � � � � � � � � - � � �
g
Statute on the Pharmaceutical Council of the Main Pharmaceutical
Administration of the USSR Ministry of Public Health
11
Charter of the Soyuzkhimfarmatorg Office of the Main Pharmaceutical
Administration of the USSR Ministry of Public Health (Excerpt) .
12 -
Statute on the State Inspection for Control of the Quality of Drugs
and Medical Equipment of the USSR Ministry of Public Health
(Excerpt) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
Statute on the Administration for Introduction of New Drugs and
Medical Equipment of the USSR Ministry of Public Health
(Excerpt) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Statute on the Pharmacopeia Committee of the Administration for
Introduction of New Drugs and Medical Equipment of the USSR
Ministry of Public Health . . . . . . . . . . . . . . . . . . . . 17
- Statute on the Soyuzmedtekhnika All-Union Association for the Sale,
Installation, and Repair of Medical Equipment of the USSR Ministry -
of Public Health (Excerpt) . . . . . . . . . . . . . . . . . . . 19
' Statute on Technical Service, Repair, and Installation of Medical
Equipment (excerpt) . . . . . . . . . . . . . . . . . . . . . . . 20 _
Standard Statute on the Main Pharmaceutical Administration of the Union
Republic Ministry of Public Health . . . . . . . . . . . . . . . zl
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Classification of the Main Phannaceutical Administrations of
Union Republic Ministries of Public Health . . . . . . . . . . . . 26
Standard Organizational Structure of Group 1 Administrations of
the Union Republic Ministry of Public Health GAPU's [Main
Pharnaceutical Administrations] . . . . . . . . . . . . . . . . .
27
Standard Organizational Structure of Group 2 Administrations of
Union Republic Ministry of Public Health GAPU's . . . . . . . . .
27 -
Standard Organizational Structure of Group 3 Administrations of �
Union Republic Ministry of Public Health GApU's
28
Standard Statute on the Organizational-Pharmaceutical Division of
the Union Republic Ministry of Public Health Main Pharmaceutical
Administration . . . . . . . . . . . . . . . . . . . . . . . . . .
24
Standard Statute on the Supply and Marketing Organization Division of
-
the Union Republic Ministry of Public Health Main Pharmaceutical
Administration . . . . . . . . . . . . . . . . . . . . . . . . . .
32
Standard Statute on the Sector Director of the Union Republic Ministry
of Public Health Main Pharmaceutical Administration
35
Standard Statute on the Senior Inspector-Pharmacist of the Union
Republic Ministry of Public Health Main Pharmaceutical
Administration . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Standard Statute on the Senior Pharmacist-Merchandising Specialist
of the Union Republic Ministry of Public Health Main
Pharmaceutical Administration . . . . . . . . . . . . . . . . . . 38
Standard Statute on the Marketing Infoxmation Division (Group) of
the Union Republic Ministry of Public Health Main Pharmaceutical
Administration . . . . . . . . . . . . . . . . . . . . . . . . . 40
Standard Statute on the Pharmaceutical Administration of the ASSR,
Kray, Oblast, and City . . . . . . . . . . . . . . . . . . . . . 42
Standard Organizational Structure of Different Categories of ASSR,
Kray, Oblast, and City Pharmaceutical Administration Staffs 53
Standard Statute on the Pharmaceutical-Organizational Division of the
ASSR, Kray, Oblast, and City Ph-arma.ceutical Administration 55
_ Standard Statute on the Supply and Marketing Organization Division
- of the ASSR, Kray, Oblast, and. City Pharmaceutical
Administratian . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Standard Statute on the Personnel Division of the ASSR, Kray, Oblast,
- and City Pharmaceutical Administration . . . . . . . . . . . 60
Standard Statute on the Financial-Planning Division of the ASS R, Kray,
Oblast, and City Pharmaceutical Administration . . . . . . . . . . 62 Standard Statute on the Sector Director of the ASSR, ICray, Oblast,
and City Pharmaceutical Administration . . . . . . . . . . . . . . 65 ,
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Standard Statute on the Senior Pharmacist-Inspector of the ASSR,
Kray, Oblast, and City Pharmaceutical Staff . . . . . . . . . . . . 66
Standard Statute on the Senior Pharmacist-Merchandising Specialist
of the ASSR, Kray, Oblast, and City Pharmaceutical �
Administration . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Chapter II.
Pharmaceutical Institutions
69
Nomenclatur
e of
Public Health Institutions (Excerpts) . . . . . . . .
69
Statute on
the
?Chozraschet Pharmacy . . . . . . . . . . . . . . . . .
69
Statute on
the
Central Rayon Pharmacy . . . . . . . . . . . . . . . .
72
Statute on
the
Therapeutic-Preventive Institution Pharmacy
74
Statute on
the
Interhospital Pharmacy of the USSR Ministry of
PubZic Health . . . . . . . . . . . . . . . . . . . . . . . . . .
76
Statute on
the
Pharmacy-School of Advanced Skills . . . . . . . . . .
78
Statute on
the
Pharmacy Reference Bureau of the Union Republic
Ministry of
Public Health GAPU . . . . . . . . . . . . . . . . . .
79
Statute on
the
Drug Store . . . . . . . . . . . . . . . . . . . . . .
80
Statute on
the
Phar.maceutical Sales Booth . . . . . . . . . . . . . .
81
Statute on
the
Control and Analysis Laboratory (Excerpt)
82
Statute on
the
Pharmaceutical Warehouse of the USSR Ministry of
Public Health Pharmaceutical Administration (Excerpt) . . . . . . .
83
Statute on
the
Admissions Commission of the Pharnaceutical Warehouse
.
84
(Excerpt) .
. . . . . . . . . . . . . . . . . . . . . . . . . . .
Statute on
the
Pharmaceutical Warehouse Division (Excerpt) . . . . . .
$5
Statute on
Pharmaceutical Points (excerpt) . . . . . . . . . . . . . .
86
Statute on
the
Medical Equipment Store (Excerpt) . . . . . . . � �
88
Statute on
the
Medical Equipment Base (Warehouse) (Excerpt)
89
Statute on
the
Khozraschet Pharmacy Director-Pharmacist
90
Statute on
the
Khozraschet Pharmacy Deputy Director-Pharmacist
91
Statute on
the
Khozraschet Pharmacy Division Pharmacist-Director
92
- Statute on
the
Khozraschet Pharmacy Division Pharmacist-
Deputy
Director . . . . . . . . . . . . . . . . . . . . . . . . . .
93
Statute on
the
Khozraschet Pharmacy Division Druggist-Director
93
Statute on
the
Khozraschet Pharmacy Division Druqgist-
Deputy
Dire
ctor . . . � � � � � � � � � � � � � � � � � � � � � � �
94
Statute on
the
Central Rayon Pharmacy Pharmacist-Director
95
35
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Statute on the
Central Rayon Pharmacy Senior Pharmacist
95
Statute onthe
Therapeutic-Preventive Institution Phaznacy
Pharmacist-Director . . . . . . . . . . . . . . . . . . . . . . .
96
- Statute on the
Therapeutic-Preventive Institution Pharnacy Pharmacist-
_ Deputy Director . . . . . . . . . . . . . . . . . . . . . . . . .
98
Statute on the
Phannaceutical Base (Warehouse) Pharmacist-Director .
98
_ Statute on the
Pharmaceutical Base (Warehouse) Pharmacist-
Deputy Director . . . . . . . . . . . . . . . . . . . . . . . . .
99
Statute on the
Pharmaceutical Base (Warehouse) Division Pharmacist-
Director .
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
100
Statute on the
Pharmaceutical Base (Warehouse) Division Pharmacist-
Deputy Director . . . . . . . . . . . . . . . . . . . . . . . . .
101
= Statute on the
Phaxmaceutical Base (Warehouse) Division Druggist-
Direotor .
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
101
- Statute on the
Pharmaceutical 3ase (Warehouse) Division Druggist-
- Deputy Director . . . . . . . . . . . . . . . . . . . . . . . . .
102
Statute on the
Drug Store Pharmacist-Director . . . . . . . . . . . .
103
Statute on the
Drug Store Druggist-Director . . . . . . . . . . . . .
103
Statute on the
Drug Store Druggist-Deputy nirector
104
Statute on the
Pharmaceutical Sales Booth Druggist-Director
105
Statute on the
Medical Equipment Store Pharmacist-Director
106
Statute on the
Medical Equipment Store Pharmacist-Deputy Director
107
_ Statute on the
Medical Equipment Store Division Pharmacist-
Director and Division Druggist-Airector . . . . . . . . . . . . .
108
Statute on the
Medical Equipment Store Division Pharmacist-
Deputy Director and Division Druggist-Deputy Director
109
Statute on the
Optician's Store Druggist-Director . . . . . . . . .
109
Statute on the
Optician's Store Druggist-Deputy Director
111
~ Statute on the
Optician's Store Division Pharmacist-Director
111
Statute on the
Optician's Store Division Druggist-Deputy Director
112
- Statute on the
Medical Equipment Base (Warehouse) Pharmacist-
- Director . .
. . . . . . . . . . . . . . . . . . . . . . . . . . .
113
- Statute on the
Medical Equipment Base (Warehouse) Pharmacist-
o Deputy Director . . . . . . . . . . . . . . . . . . . . . . . . .
114
Statute on the
Medical Equipment Base (Warehouse) Division Druggist-
Director . .
. . . . . . . . . . . . . . . . . . . . . . . . . . .
115
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Statute on the
Medical Base (Warehouse) Division Druggist-
Deputy Director . . . . . . . . . . . . . . . . . . . . . . . . . .
116
Statute on the
Control and Analysis Laboratory Pharmacist-
Director .
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
116
- Statute nn the
Control and Analysis Laboratory Pharmacist-
Deputy Director . . . . . . . . . . . . . . . . . . . . . . . . .
117
Statute on the
Pharmacy and Pharmaceutical Base (Warehouse) Phaxmacist-
Technologist . . . . . . . . . . . . . . . . . . . . . . . . .
118
Statute on the
Pharmacy, Pharmaceutical Base (Warehouse), and
Control a:.d
Analysis Laboratory Pharmacist-Analyst . . . . . . . .
119
Ststute on the
Pharmacy Druggist . . . . . . . . . . . . . . . . . . .
121
Statute on the
Drug Store and Pharmaceutical Base (Warehouse) Druggist
121
Statute on the
Junior Druggist . . . . . . . . . . . . . . . . . . .
122
Statute on the
Packer . . . . . . . . . . . . . . . . . . . . . . . .
123
Statute on tYie
Optician's Store, Pharmacy, Drug Store, and Medical
Equipment Store Salesclerk . . . . . . . . . . . . . . . . . . . .
123
Statute on the
Pharmaceutical Booth Salesclerk . . . . . . . . . . . .
124
Statute on the Control and Analysis Laboratory Technician 124
Statute on the tdedical Equipment Store (Base, Warehouse) Druggist
and Junior Druggist . % . . . . . . . . . . . . . . . . . . . . . . 125
Iiistructions on Maintaining Complaint and Suggestion Books in
- Medtekhnika Pharmaceutical Institutions and Stores Engaged in
Retail Trade of Drugs, Medical Items, and Medical Equipment 126
Measures for Improving the Work of Pharmacies of Therapeutic-Preventive
institutions (Excerpt) . . . . . . . . . . . . . . . . . . . . . . 130
Chapter III.
Phannaceutical Factories (Production Operations) 132
- Requlation of the Names of Pharmaceutical Administration Pharmaceutical
Enterprises . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Statute on the Technical Control Division of Pharmaceutical
- Administration Pharmaceutical Enterprises . . . . . . . . . . . . 134
Approval of Larger Standards for the Number of Engineers, Technicians,
Laborers, and Office Workers Employed, and the Standard Staff
Structure of Pharmaceutical Factories (Production Operations) of
USSR Ministry of Public Health Pharmacy Administrations (Excerpt) . 137
Establishment of the Nomenclature of Galenic and Yharmaceutical
Preparations far Production at Enterprises of the Ministry of
Medical Industry, and at Pharmaceutical Factories (Production
Operations),of Union Republic Ministries of Public Health (Excerpt) 140
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Basic Types (Sample Group Assortment) of Products Produced by the
Pharmaceutical Enterprises of USSR Ministry of Public Health
Pharmaceutical Administrations . . . . . . . . . . . . . . . . . . 140
Measures for Improving the Quality of Drugs Produced by the
Pharmaceutical Factiories (Production Operations) of
_ Pharmaceutical Adm?nistrations (Excerpt) . . . . . . . . . . . . . 141
Statute on Regulations Governing the Production of Drugs Produced
by the Pharmaceutical Factories (Production Operations) of the
USSR Ministry of Public Health's Pharmaceutical Administrations
(Excerpt) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Management of Shop Raw Material Consumption and Finished Product
Accounting Forms . . . . . . . . . . . . . . . . . . . . . . . . . 151
- Enforcement of the Instructians for Planning, Accounting, and
Estimating Production Cost at Phannaceutical Enterprises 160 ~
Instruction on the Order of Raw Material and Material Quality -
Control, Production Control, Acceptance of Finished Products, - and Maintenance of Documents by the Technical Control Divisions
of the Pharmaceutical Factories (Production Operations) of the
- USSR Ministry of Public Health's Pharmaceutical Administrations . 160 _
Chapter IV.
Standards Governing the Development, Planning, Equipment, -
- and Maintenance of Pharmaceutical Institutions 167
Standards Governing Development of Pharmacies and the Principles
of Their Distribution (Excerpt) . . . . . . . . . . . . . . . . . 167
= Construction Norms and Rules. Part II. Planning Norms 173 -
Chapter 60. Planning and Construction of Cities, Towns, and Rural
Population Centers (Excerpt) . . . . . . . . . . . . . . . . . . . 173
_ Chapter 69. Therapeutic-Preventive Institutions (Excerpt) . . . . . 174
Samplellornis of Technical and Business Support to Khozraschet :
Pharmacies . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Sample Norms of Technical and Business Support to Pharmaceutical
_ Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
- Rules of Laying Out and Operating Pharmacies, Safety, and Work
Sanitation in Pharmacies (Excerpt) . . . . . . . . . . . . . . . . 228 -
Standard Fire Safety Rules for Hospitals, Clinics, Polyclinics,
Maternity Homes, Dispensaries, Children's Nurseries, Day
Schools, Sanatoriums, Vacation Homes, Pharmacies, Pharmaceutical
Warehouses, Galenic Production Operatians, and Other Public
Healttz Institutions (Excerpt) . . . . . . . . . . . . . . . . . . 235
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Chapter V.
- Pharmaceutical Inctitution Staffs
242
Methods For Determining the Standard Staff Strength of ASSR, Kray,
= Oblast, and City Pharmaceutical Administrations . . . . . . . . .
242
Nomenclature of Pharmaceutical Worker Posts . . . . . . . . . . . . .
249
Changes in the Names of Posts Given in Presently Effective Staff
Standards . . . . . . . . . . . . . . . . . . . . . . . . . . . .
252
Staff Standards for Pharmacy Pharmaceutical and Auxiliary Personnel .
253
Supplements to the Staff Standards for Pharmacy Pharmaceutical and
Auxiliary Personnel Approved by Order No 1185 of the USSR Minister
of Public Health, 29 December 1952 . . . . . . . . . . . . . . . .
260 -
Standard Staffs of Pharmacy Administrative-Business Personnel
260
Interim Staff Standards for Pharmaceutiical and Auxiliary Personnel of
Interhospital Pharmacies . . . . . . . . . . . . . . . . . . . . .
261 _
Staff Standards for Medical and Pedagogical Personnel and for Kitchen
Workers of City Hospitals Possessing Polyclinics (Outpatient Clinics),
Clinical Hospitals, and Hospitals Within the Composition of
_
- Medical-Sanitary Units, and of City Hospitals Temporarily Not
Possessing Polyclinics, Tuberculosis and Infection Hospitals,
and City Polyclinics (Outpatient Clinics) Existing Temporarily
as Independent Institutions (Excerpt) . . . . . . . . . . . . . .
263
Staff Standardsfor Medical Personnel and Kitchen Workers of Central
Rayon and Rayon Hospitals, Section Hospitals, Outpatient Clinics,
and Paramedic-Obstetric Points (Excerpt)� . . . . . . . . . . . . .
265
Staff Standards for Medical Personnel and Kitchen Workers of
Section Hospitals (Exce.Lpt) . . . . . . . . . . . . . . . . . . . .
265
Staff Standards for Medical Personnel and Kitchen Workers of Maternity
Homes, Gynecologicai Consultation Offices, Obstetric and Gynecologic
al
Departments (Wards), and Newborn Children's Departments (Wards)
_ (Excerpt) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
266
- Staff Standards for Medical and Pedagogical Personnel and Kitchen
Workers of Tuberculosis Hospitals (Excerpt) . . . . . . . . . . .
266 `
Staff Standards for Medical Personnel and Kitchen Workers of Infection
Hospitals (Excerpt) . . . . . . . . . . . . . . . . . . . . . . .
267
_ Staff Standards for Medical, Pharmaceutical, and Pedagogical
Personnel and Kitchen Workers of Psychiatric Hospitals, Departments,
- and Wards (Excerpt) . . . . . . . . . . . . . . . . . . . . . . .
268
Staff Standards for Medical, Pharmaceutical, and Pedagogical
Personnel and Kitchen Workers of City and Oblast (Kray, Republic)
Psychoneurological Dispensaries, Departments, and Offices (Excerpt)
269 i
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- Staff Standards for Medical, Pharmaceutical, and Pedagogical
Personnel and Kitchen Workers of City and Oblast (Kray,
Republic) Antituberculosis Dispensaries, Departments, and
Offices (excerpt) . . . . . . . . . . . . . . . . . . . . . . . .
. 269
Staff Standards for Medical and Pharntaceutical Personnel and
- Kitchen Workers of City and Oblast (Kray, Republic) Oncological
Dispensaries, Departments, and Offices (Excerpt) . . . . . . . .
. 269 -
Staff StanBards for Medical, Pharmaceutical, and Pedagogical
Personnel and Dining Hall and Kitchen Workers of Hospitals for
~ Disabled Veterans of the Patriotic War (Excerpt) . . . . . . . .
. 270
Staff Standards for Medical and Pharmaceutical Personnel and
- Kitchen Workers of Narcotic Dispensaries, Departments, and
Offices (Excerpt) . . . . . . . . . . . . . . . . . . . . . . . .
. 270
- Staff Standards for Medical and Pharmaceutical Personnel and
Kitchen Workers of City and Oblast (Kray, Republic)
_
Dermatological-Venereological Dispensaries, Departments, and
Offices (Excerpt) . . . . . . . . . . . . . . . . . . . . . . . .
. 271
Staff Standards for Medical Personnel and Dining Hall and Kitchen
Workers of Sanatoriums for Adults (Excerpt) . . . . . . . . . .
. 271
Standard Staffs of Administrative-Managerial Personnel of Control
and Analysis Laboratories of the Union Republic Ministry of
- Public Health Pharmaceutical Administrations . . . . . . . . . .
. 272
Norms for the Work Load of an Analytical Chemist in Control and
Analysis Laboratories of Phaxmaceutical Administrations 272
Instructions on the Order of Computing the Sizes of the Staffs of
Control and Analysis Laboratories of Union Republic Public
Health Ministry Main Pharmaceutical Aclministrations . . . . . . . . 274
Staff Standards for Auxiliary Personnel of Control and Analysis
Laboratories . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
Chapter VI.
Phannaceutical Personnel 280
List of Higher and Secondary Special Educational Institutions
Providing Training and Degrees Entitling tke Bearer to
Engage in Medical and Pharmaceutical Activity (Excerpt) 280
List of Educational Institutions (Courses) Which Entitled Their -
- Graduates, or Persons Taking Courses in Them for a Certain
Period of Time, to Engage in Medical and Pharmaceutical
Activities Prior to 1 October 1972 (Excerpt) . . . . . . . . . . . 282
The Rules of Permitting Persons Who Had Received Medical or
Pharmaceutical Training and Degrees in Appropriate Training
Institutions of Foreign States to Engage in Medical or Pharma-
ceutical Activities in the USSR (Excerpt) . . . . . . . . . . . . . 284
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Statute on Specialization and Improvement of the Professional
_ Knowledge and Skills of Medical and Pharmaceutical
Workers Having a Higher Education (Excerpt) . . . . . . . . . . .
285
List of the Names of Physician and Pharmacist Specialization
and Advanced Training Cycles (Excerpt) . . . . . . . . . . . . . .
267
Measures for Further Improvement of the System of Advanced Training
for Executives in Public Health . . . . . . . . . . . . . . . . . .
290
The Order of Material Support to Pharmaceutical Workers Undergoing
Advanced Training . . . . . . . . . . . . . . . . . . . . . . . .
2 ~2
Improving the I'lanning of Physician and Pharmacist Advanced Training
293
The Status of Secondary Medical Personnel and Measures to Improve
Planning, Training, and Utilization . . . . . . . . . . . . . . .
297
. Statute on Constantly Operating Advanced Training and Specialization
Courses for Secondary Medical and Pharmaceutical Personnel
(Excerpt) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
297
List of Specialties and Time Li.mits for Specialization and Advanced
_
Training of Secondary Medical and Pnarmaceutical Personnel
(Excerpt) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
298
Statute on Certification of Specialized Pharmacists Working in the
Public Health System . . . . . . . . . . . . . . . . . . . . . .
298
List of Specialized Pharmacists in Individual Specialties
Subject to Certification . . . . . . . . . . . . . . . . . . . . .
302
Instructions on the Procedures for Certifying Specialized
Pharmacists . . . . . . . . . . . . . . . . . . . . . . . . . . .
302
Statute on Certification of Druggists . . . . . . . . . . . . . . . .
306
Instructions on the Procedures for Certifying Druggists
309
Methodoloqical Recommendations on Determining the Need for
Pharmaceutical Personnel and Planning Their Training (Excerpt)
310
Instructions on Organizing and Conducting Training and Production
Practice for Students of Medical (Pharmaceutical) Institutes
and Medical Schools of USSR Universities (Excerpt) . . . . . . . .
313
Instructions on Application of the "Statute on Production Practice
_ for Students of Secondary Special Educational Institutions of
the USSR" in Relation to Secondary Medical and Pharmaceutical
Educational Institutions (Excerpt) . . . . . . . . . . . . . . . .
320
Statute on the Practical Training Base of Medical and Pharmaceutical
Schools . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
322
Instructions on the Order of Awarding the "Outstanding Public
Health Worker" Badge and Issuing the Badges . . . . . . . . . . .
323
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Chapter VII.
_
= Organization of the Supply and Marketing
of Medicines and Medical Articles
325
Determininq the Need for Medicines and Medical Articles in 1979
and Subsequent Years, and Filling Out the Orders (Excerpt)
325
Instructions on Filling Out an Order for Medical Products (Excerpt).
327
The Procedures for Filling Out Orders for and Distributing and
Dispensing Antidiabetic Drugs . . .
. . . . . . . . . . . . . . .
329
Special Conditions Governing Medical Product Supply . . . . . . . . .
331
Instructions on the Order for Quality Acceptance of Technical
Production Equipment and Consumer Goods . . . . . . . . . . . . .
336
Instructions on the Order af Quantity Acceptance of Technical
Production Equipment and Consumer Goods . . . . . . . . . . . . .
346
Instructions on the Order of Establishing Contract Relationships
for the Delivery of Products and Goods Through the Receipt of
Orders for Services by Suppliers and Purchasers
354
Statute on the Order of Submitting and Examining Complaints by
- Enterprises, Organizations, and Institutions, and af Arbitrating
Disagreements Concerning Business Contracts . . . . . . . . . . .
358 -
Statutes of Limitations for Exercising Rights Concerning Exaction of
Fines, Penalties, and Foxfeitures, and the Time Limits for
Complying with Decisions Made in Regard to Disputes Between State
Institutions, Enterprises, and Cooperative and Public Organizations
363
Improvement of the Drug Supply to the Public and to Therapeutic
Institutions . . . .
. . . . . . . . . . . . . . . . . . . . . . .
363
Material Liability of Freight Dispatchers, Freight Receivers, and
Transportation Organizations for Improper Use of Containers in
Freight Shipment . . . .
. . . . . . . . . . . . . . . . . . . . .
364
Instructions on Centralized Computer Accounting of Surpluses of
Medicines and Their Redistribution in Response to Requests by
Pharmaceutical Administrations . . . . . . . . . . . . . . . . . .
365
Interim Minimum Mandatory Assortment of Medicines Carried by
Category I-VI Khozraschet Pharmacies . . . . . . . . . . . . . . .
367
" List of Perfumes and Personal Hygiene Articles Included in the
Assortment Carried by Group I Retail Pharmacies, Drug Stores,
- Pharmaceutical Sales Booths, and Pharmaceutical Points
385 _
Improvement of Drug Information . . . . . . . . . . . . . . . . . . 385
Standard Statute on the Office of Pharmaceutical Information 388
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Chapter VIII.
The Order of Storing, Accounting, and
Issuing Drugs at Pharmaceutical Institutions 395 _
The Order of Writing Prescriptions for Ambulatory Patients, and of
Issuing Medicines on Their Basis . . . . . . . . . . . . . . . . . 395
The Order of Storing, Accounting, Prescribing, Issuing, and Using
Poisonous, Narcotic, and Potent Drugs . . . . . . . . . . . . . . . 415
Instructions on Detoxifying and Destroying Potent Poisonous '
Substances (Excerpt) . . . - � � � � � � � � � � � � � � � � - . . 434
- Instructions on II�contaminatinq Potent Toxic Compound Packaging -
Materials (Excerpt) . . . . . . . . . . . . . . . . . . . . . . . . 436 -
Additional Measures for Intensifying the Fight Against Addiction 438
Publication of a List of Addictive Narcotics . . . . . . . . . . . . . 440
List of Narcotics and Narcotic Drugs . . . . . . . . . . . . . . . . . 441
Standards for the Use of Ethyl Alcohol by Medical Institutions, and the Order of Prescribing, Issuing, and Accounting for _
Ethyl Alcohol in Therapeutic-Preventive Institutions an3
Pharmacies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
List of Prescription Infusions, Extracts, and-Alcohol-Containing
Solutions and Mixtures Issued by Pharmacies . . . . . . . . . . . 452
The Order of Employing References to Part II of the Standards for
the Use of Ethyl Alcohol by Medical Institutions, Approved by
Order No 675 of the USSR Minister of Health, 16 September 1969 453
The Order of Applying Paragraph 9 of Order of 675 of the USSR Minister
of Public Health, 16 Sentember 1969 . . . . . . . . . . . . . . . . 454
Order of Issue of Ethyl Alcohol by DOSAAF Therapeutic-Preventive
Institutions . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
Assortment of Prepackaged Over-The-Counter Drugs and Medicinal _
Plants Issued by Pharmacies, Pnarmaceutical Points, and
Drug Stores . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
The Order of Issuing Medicines to Retired Individuals 460
List of Categories of Patients Receivir,g Free Medicines During
_ Ambulatory Treatment . . . . . . . . . . . . . . . . . . . . . . . 460
The Order of Issuing Medicinal Herbs, Ethyl Alcohol (To Patients "
- With Sugar Diabetes) and Mineral Waters to Disabled Veterans of
- the Patriotic War . . . . . . . . . . . . . . . . . . . . . . . . . 462
Instructions on the Order of Organizing and Accounting Free Issue of
Medicines to Some Categories of Patients Undergoing Ambulatory -
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
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Supplying Medical Insitutions and The Public With Antitumor
Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . 464
Free Treatment of Sugar Diabetes Patients With Peroral
Sulfanilamide Preparations . . . . . . . . . . . . . . . . . . 465
List of Medicines Recommended for Dysentery Patients Undergoing
- Ambulatory Treatment . . . . . . . . . . . . . . . . . . . . . . 465
List of Medical Preparations to be Issued Free to Patients With
Hypophyseal Dwarfism to Compensate for Endocrine Insufficiency . 465
Supplemental List of Medicines Given Free to Patients With Hypo-
physeal Dwarfism to Compensate for Endocrine Insufficiency 466
List of Medical Preparations to be Given Free to Patients
Suffering Addison's Disease to Compensate for Endocrine
Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . 466
The Order of Furnishing X-Ray Films and Barium Sulfate for
_ Radioscopy of Patients Undergoing Inpatient and Ambulatory
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . 467
List of Medicines Issued Free to Patients Who Have Undergone a
Kidney Transplant Operation . . . . . . . . . . . . . . . . . . 467
Unified Rules for Labeling Medicines Prepared in Pharmacies 467
Chapter IX.
Medicine Quality Control 471
Instructions on Medicine Quality Control, and the Basic
Requirements on Preparation of Medicines in Pharmacies 471
Storage Life of Some Concentrated Solutions and Aromatic Waters
in a Pharmacy . . . . . . . . . . . . . . . . . . . . . . . . . 482
Shelf (Storage) Life of Vitamin-Enriched Eyedrops Prepared in a
Pharmacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
Shelf (Storage) Life of Sterile Solutions Prepared in Pharmacies and
Contained in Neutral Glass Botitles Capped With Rubber Stoppers . 484
Shelf (Storage) Life of Eyedrops Made in Pharmacies and Contained
in Neutral Glass Bottles Capped With Rubber Stoppers 488
Approval of Interim Standards for the Maximum Permissible
Concentration of Nonpathogenic Microorganisms in Medicinal
Reagents Used by Pharmacies . . . . . . . . . . . . . . . . . . 490
Instructions on Evaluating the Quality of Medicines Prepared in
Pharmacies, and the Norms of Permissible Deviations in
Medicine Preparation . . . . . . . . . . . . . . . . . . . . . . 495
Instructions on Sanitary Conditions in Pharmacies . . . . . . . . . 498
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Instructions on Bacteriological Control Over Maintenance of
Sanitary Conditions in Pharmacies . . . . . . . . . . . . . . . . 502
Instructions on the Order of State Quality Control of_ Drugs
, Produced by Industrial Enterprises (Excerpt) . . . . . . . . . . 506
Addition of Supplements to the Instructions on the Order of State
Quality Control of Drugs Produced by Industrial Enterprises,
Approved by Order No 860 of the USSR Minister of Public Health,
30 December 1970 . . . . . . . . . . . . . . . . . . . . . . . . 508
Interim Instructions on Controlling Prepared Medicinal Agents,
Taking the Form of Eyedrops in Bottles, for Absence of
Mechanicai Impurities . . . . . . . . . . . . . . . . . . . . . . 511
The Order of Quality Control of Drugs Delivered to Pharmaceutical
- Administration Warehouses by Industrial Enterprises . . . . . . . 514
Instructions on the Order of Quality Control of Imported Drugs
(Excerpt) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
Instructions on Bacteriological Control oi Chemical Phannaceutical
Preparations Intended for Injections (Excerpts) . . . . . . . . . 516
Repeat Control of Medicinal Preparations . . . . . . . . . . . . . 517
Chapter X.
Planning, Accounting, Accountability
519
Specific Features of Applying the Statute on the Socialist
State Production Enterprise to Organizations Belonging to the
Pharmaceutical Network of a Union Republic Ministry of Public
Health, and to Trade Organizations Within the Union Republic
Medtekhnika System . . . . . . . . . . . . . . . . . . . . . . .
519
Statute on Centz�alized Accounting Offices o� Pharmacies, Drug
Stores, Enterprises, and Business Organizations of the Main
Pharmaceutical Administrations of the U5SR Ministry of Public
Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
522
. Economic-Financiarl Fictivity Indicators for 197_ . . . . . . . . . .
528
Instructions on Maintaining Initial Accounts and Compiling Reports
in Pharmacies Operating Under a Centralized Accounting System
533
Instructions on the Order of Maintaining Accounts and Cempiling
Reports on Medicines Issued by Khozraschet Pharmacies
573
Instructions on Accounting for Medicines, Bandaging Materials, and
Medical Articles in Therapeutic-Preventive and Other Public Health
Institutions Operating on the Basis of the USSR State Budget
- (EXcerpt) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
575
Instructions on the Order of Conducting an Inventory of Stock on Hand,
Material Valuables, Money, and Bills in Institutions (Enterprises)
and Organizations of the Union Republic Ministry of Public Health
Main Pharmaceutical Administrations (Excerpt) . . . . . . . . .
592
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Intensification of Control Over the Sales of Medical Goods, and
Over Compliance With State Retail Prices in Khozraschet
- Pharmaceutical Institutions . . . . . . . . . . . . . . . . . . . 619
Statute on Material Liability flf Laborers and Office Workers For
Losses Suffered by an Enterprise, Institution, or Organization .
623
List of Posts and Jobs Filled or Performed by Workers With Whom an
Enterprise, Institution, or Organization May Sign Written
. Agreements on Complete Material Liability for Failure to Take Care
of Valuables Entrusted to Them for Storage, Processing, Sale
(Issue), Shipment, or Use in the Course of Production (Excerpt) .
626
Standard Agreement on Complete Individual Material Liability
627
Instructions on the Order of Compensating for Losses From Writing
-
Off Drugs With Expired Shelf Life in Khozraschet Pharmaceutical
' Institutions . . . . . . . . . . . . . . . . . . . . . . . . . .
629
- Uniform Reflection of Write-Off Expenditures Stemming From Natural
Loss of Medicines in the Books of Pharmaceutical Institutions .
631
- The Order of Reflecting, in the Books of Pharmaceutical Insti-
tutions, the Issue.of Drugs to Fatients Gratis and With a
Discount . . . . . . . . . . . . . . . . . . . . . . . . . . . .
632
' Norms of Natural Loss of Medicines and Cotton in Pharmacies
632 -
- Instructions on Applying the Norms of Natural Loss of Medicines and
Cotton in Pharmacies . . . . . . . . . . . . . . . . . . . . . .
633
Introduction of Norms for Natural I,oss of Ethyl-Alcohol During Its
- Storaqe, Movement, and Transportation, and Introduction of
an Interim Norm for Loss of Ethyl Alcohol During the
Unpackaging of Large Quantities (Excerpt) . . . . . . . . . . . .
634
Norms for Natural Loss of Natural and Synthetic Perfumes and Ester
Oils During Warehouse Storage and Handling . . . . . . . . . . .
638
Norms for Natural Loss of Pharmaceutical Ltensils in Pharmaceutical
Warehouses and Galena Packing Enterprises . . . . . . . . . . . .
638
Norms for Expenditu,re of Laboratory Utensils During Warehouse Storage 638
Interim Norms for Natural Loss of Medicines During Issue of Goods
From Pharmaceutical Warehouses . . . . . . . . . . . . . . . . . 639
Norms for Natural Loss ef Medicinal Leeches During Their -
Transportation and Storage . . . . . . . . . . . . . . . . . . 640
Norms for Natural Losses of Perfumes, Cosmetirs, and Mineral Water . 640
Interim Norms for Expenditure of Auxiliary Materials in Pharmacies
During Preparation and Tssue of Medicines, and During Packaging 641
Index of the Principal Orders on the Pharmaceutical Service
Publishea by the USSR Ministry of Public Health 643
[166-11004]
COPYRIGHT: Izdatel'stvo "Meditsina", Moscow, 1979
11004 _
CSO: 1840 FOR OFFICIAL 46
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vnc 002.6
FRAGNIENT INFORMATION SUBSYSTEM IN PHYSIOLOGY AND MEDICINE
Moscow VESTNIK AKADEMII NAUK SSSR in Russian No 10, 1979 PP 52-54
LArticle by Candidate of Pedagogical Sciences D. I. Blyumenau, Candidate
of Medical Sciences K. F. Britikova, and Candidate of Biological Sciences
7
S. I. Nudman and I. V. Sorokina
LTex~j The steady increase in the role oi scientific information connected
with the progress of science and technology requires a seaxch for more re-
Pined forms of providing scientific reseaxch with information. Integral
information systems, by means oP which a combination of such services as a
aelective dissemination of information, reference service, preparation of
- ebstract and bibliographic publications, circulation of local information
- retrieval systems and so forth is performed, appear as some of the means
creating the possibility of raising the level of software.
, The idea of a one-time input of informa.tion (one-time processing of input
documents), which forms the basis for integral information systeme, has
gained wide recognition among specialists in information services and its
development is continuing. The overwhelming number of currently operating
integral information systems function primarily as documentary service sys-
tems, that is, they ensure in a certain mode the issue in the final anal-
ysis of primary documents to the consumer, who hes to extract the neces-
sary inPormation from them by himself. The importance of the development
of such systems for improving the efficiency and quality of service for
- laxge groups of specielists is indisputable. However, they do not fully
solve one of the most serious problems of information service--the issue of
- relevant information, that is, corresponding to the consumer's needs in a
volume in which an zndividual specialist can assimilate it.
The study performed by the authors of this article at the Institute of
Physiology imeni I. P. Pavlov of the USSR Academy of Sciences was based on
the hypothesis on the possibility for such a Porm of information service in -
which a certain spectrum of standard information needs of certain groups
and categories of specialists would be met not by the full text of the prim- .
ary source, but by its standard fragments with an independent information
mesning outside the document context. The axray of such standaxd fragnenta -
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singled out at the stage of one-time input of documents into integral in-
forms,tion systems through their formal and meaningful analysis should form
an independent subsystem, which we call the Fragment subsystem. The de-
velopment of such a subsystem should eliminate in large measure the nega-
tive aspecta of the excesa of documentary flow.
A atandard independent fragment of a text implies a meaningfully closed
context of a document, in a particular case in the form of a table, diag-
ram, formula a.nd so forth, understood outside the text of the entire doc-
ument and capable of ineeting, without turning to the primary source as a
whole, the standard information need, that is, the need characteristic of
certain stages in the creative e.ctivity of certain categories and groups
of specialists in certain fields of knowle@ge. For example, S. L. Kruglov
believes that st andard needs are dictated by the conditions of a specific
- problem. It can be assumed that in primary documents a c:ertain set of
standard information needs connected with the performance of certain stand-
ard tasks can be met by certain types of text fragnents sufficiently in-
_ formative and independent to satisfy these needs. In this case the system
in answer to a need standard in form should issue, for example, not a cer-
- tain number of documents, in which the availability of relevant information
is atill hypothetical, but directly the text fragments containing releva.nt
information.
Postulating the hypothesis on the possibility of a formalized extraction
from documents of fragnents of independent importance, we assume a priori
that such fragnents cannot meet all the needs, even standard needs. There-
fore, in many cases an entire document will be necessary and in others, the
level of a fragment's conversion, that is, of its information content, can
prove to be unacceptable. Therefore, the main object of the studies dis-
- cussed was limited to the clarification of the futtdemental possibility for
the establishm.ent of similar types of integral information systems for phys-
iological and medical subjects.
When the problem of the independent importance of a certain fragment was
solved, two conditions were laid down: a) the text had to be comprehen-
sible without the use of information from the other parts of the document
(with the exception of the title; every fragment is accompanied by a bib-
liographic description of the article); b) the text should correspond to
the standaxd information need. The degren oP independer.ce of the singled
out fragnents was evaluated by four experts--specialists in the field of
pY~ysiology and medicine.
Thp experiment was conducted on two files of documents. The content of 220
articles published in FIZIOLOGICHESKIY ZHURNAL SSSR imeni I. M. Sechenov
in 1978 and 60 articles from the journal NEYROFIZIOLOGIYA of the same year
- were studied initially (survey articles were not used, bec ,ase in their
- atructure they did not lend themselves to fragimenting corresponding to the
task set). An examinatior of the structure oP articles published in these
journals showed its identity. Tn particulax, in these articles it is -
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possible to single out fragments for such subjects as the "state of the
~ problem," "method of research,'t "research results't and "discussion of the
results obtained." It is very important that, basically, these fragments
are noted in articles by the appropriate titles and singling them out does
not preaent special diff{culties. As s result of the work on fragrnenting
_ articles from both journals, we obtained the dats presented in the follow-
ing table.
Results of Fragmenting Articles From Pt~ysiological Journal.s
Number.of Number of SinglEd Out Fragments (Aspects) _
.
scanned ' State of
Name of journal srticleQ the problem" "Method" "Results" "Discussion"
FIZIOLOGICHESKIY 220 220 220 148 148
ZHURNAL SSSR
- NEYROFIZIOLOGIYA 60 60 60 50 50
As can be seen from the table, individual fragments the "state of the prob-
lem" and "method of research" were singled out in all the 220 articles of
FIZIOLOGICHESKIY ZHURNAL SSSR, but the fragments "results" anci "discussion"
could be singled out only in 148 axticles, because in 72 articles these
sections were organically interconnected and were read as a single whole
(the subtitles in these articles were called "results of experiments and
their discussion"). Thus, of the 220 articles studied in this journal 736
individual fragments were singled out. In the journal NEYROFIZIOLOGIYA in
10 axticles the sections "research results" and "discussion" did not lend
themselves to fragmenting. Therefore, in 60 articles 220 independent frag-
_ ments were singled out.
Subsequently, an analysis of articles from clinical journa.ls was made. In
paxticular, 77 articles from the jow.�nal KHIRURGIYA were subjected to frag-
menting. A total of 44 articles lent themselves to fragmenting.l Of them
110 indeperldent fragrneiics on 18 aspects were singled out, in particular
the "state of the problem," "etiology," "pathological anatomy," "clinical
differential diagnosis,f~ treatment, remote results of treat-
picture,n n n n n n
ment," "postoperative complications, prevention of diseases and so forth.
Fragments of such aspects as "treatment" (21+), "clinical picture" (14),
"etiology" (11), "remr'ce results" (10) and "differential diagnosis" (9)
proved to be the most frequent.
The use of formal text signs--maxkers and indicators identifying various
sense aspects (fragments) of documents--facilitates the procedure of ex-
- traction of independent fragments (fragrnenting of texts). For exsmple,
such markers as "picture," "symptoms," "clinical aspects" and "complaints"
l. Among the 33 articles that did not lend themselves to fragnenting it
was not advisable to single out fragments from 13 axticles of the general
type "brief reports," and fragments from 20 articles would not have been
' understandable outside the context.
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can serve as identifiers Por the aspect "clinical picture;" "cauaes," "on-
set," "consequence" and so forth, for the aspect "etiology." The list of
such indicators is given in a special dictionary, where both the equiva-
lence ot' formal signs and the poseible paradigmatic relations among them,
for example, "operation-intervention-resection," are taken into account.
The experts and specialists chosen for an evaluation of the independence
of the fragnente acknowledgedthat they met the requiremente. Only one
fragment from the journal HIiIRURGIYA wa,s rejected as not independent.
The data obtained attest to the furdamental posaibility of singling out
individusl fra.grnents of articles published in pY~ysiological and medical
_ journals and of developing on t1his basis the so-called Fragment subsystem
- within the framework of a,n integral information system. -
_ Such a subsystem can be used not only by scientific workers, but a.lso clin-
- icians, for whom, obviously, this is especially important when there is a -
need for an emergency solution of certain problems connected with treating
people. -
COPYRIGHT: Izdatel'stvo "Nauka", "Vestnik Akademii nauk SSSR", 1979 . 11,439
~ Cso: 1840
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I
UDC 577.391+519.95
- PRINCIP:,ES OF FUNCTIONAL ORGANIZATION OF TISSUE SYSTEMS
Pushchino PRINTSIPY FUNKTSIONAL'NOY ORGANIZATI"'II TKANEVYKH SISTEM
_ in Russian 1976 pp 2-17
[Preprint of article by V. G. Tyazhelova and I. G. Akoyev, USSR Academy of
Sciences Scientific Center of Biological Research, Tnstitute of Biological
Physics]
[Text] Analysis of the postradiation kinetics of prolifer-
ative systems in the body showed that they can be de-
scribed rather campletely if consideration is given to
the average time that cells remain within the system's
proliferating, maturing, and functional pools. The
- ratio taken by these times is a characteristic of the
tissue. It is demonstrated that the integral body
contains tissues for which the time constants differ
by one order of magnitude. Research on systems con-
taining a large quantity of units reveals that in the
norm, different body systems are weakly associated
with one another. Within a complex system, control
functions are applied to one of the units, and they
ananifest themselves in the unit with minimum time
constants. Control may be exercised over different
systems exhibiting the same change in the feedback
coefficient.
The research presezted here would be of interest to
radiobiologists and mathematicians dealing with
- biological problems. The material of this preprint
_ will be discussed in the book "Regulyatsiya
_ protsessov vosstanovleniya" [Regul.ation of Resto-
- ration Processes] (Moscow, Izdatel'stvo Nauka)
The mammalian body is a complex multisystem set (1,2,5). Numerous attempts -
have been made to date to describe the behavior of the body as a whole
and its individual systems using the methods of cybernetics. This resear.ch
direction has received a special name--"biocybernetics" (3), which is now
51
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- developing intensively in entirely different aspects. Ii, the present
paper cybernetic methods are used to analyze ttie unique featu,.:s of the `
_ structure of body tissues, mainly proliferative cell systems. Analysis
of the restoration of tissue systems following disturbance of their
equilibrium by radiation made it possible to reveal the fundamental
principles of tissue system organization and control.
When subjected to destructive effects of internal and external origin, the
mammalian body as a whole and its individual systems are able to maintain v
their homeostasis throuqh a large number of compensatory and regulatory
reactions that proceed at different levels of biological organization (4,5).
The laws governing organization and work of regulatory systems is the
province of the theory of automatic regulation (TAR). If we are to apply
it correctly, we must isolate--within the phenomenon under examination--
the system subject to regulation, the regulator, and the principle of regulation. This task--defining the units named above--is the object of
the first phase of the research--analysis of the biological phenomena. -
This is followed by mathematical description of the units, the solution
process itself, the p::ediction of system behavior implied by this
solution, and the generai conclusions.
1. Universal Three-Unit Model of Tissue Functional Organization
The nature of restoration processes is defined in many ways by the inertial _
characteristics of the pouZs making them up. Inertial characteristics can
be defined as the average time cells remain within the system's dividing, -
maturing, and functional pools (6-8).
_ Before we can categorize the diversity of cell forms typical of, as an
example, different primordia in bone marrow, into these three pools, we
would need to distinguish all of the rather basic phenomena associate3
with development of blood elements, reducing their number to a minimum
in this case. This approach of subdividing cells into pools does not
differ from the commonly accepted one of the literature (9).
- The objective of our research was to study the functional organization of
- tissue systen;s, as it is related to functional stability following
disruption of a steady-state condition by radiation, and the precision
with which a new steady state is achieved.
This paper generalizes, from these positions, the results of modeling
- proliferating body tissues, such as the crypt-villus cell system and the
- hemopoiesis-periPheral blood system, performed earlier with real
radiobiological mat:erial (6-8).
The cell populations of proliferating tissues are restored through re-
population, which begins at the moment mitotic activity recovers. The
end of the mi'cotic inhibition phase and presence of a sufficient quantity
_ of cells in the different pool systems are the initial conditions of
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- repopulation. These initial conditions predefine the concrete source of
restoration, particularly the minimums of cell numbers in the functional
pool--for example in peripheral blood, which is so important to radiation
sickneas. However, these initial conditions do not predetermine the type
of behavior exhibited by the cell system under examination.
Our models were baseci on the hypothesis that a controlling signal that
regulates restoration of a cell system arises in response to this system's
failure to perform its function. If we assume that all cells of a
functional pool have the same capability for performing their function,
_ we may presume that the body reacts to a below-normal number of cells in _
the functional pool.
In nonproliferating cell systems, the capability for intensifying a
= function or compensating for its deficiency is achieved through hypertrophy
- of the intracellular apparatus. The three-unit model of tissue functional
organization developed below is also valid in relation to this approach. .
_ It should apply to the turnover of functional protein (secretions) or to
the quantity of energy produced (volume and number of mitochondria).
- A discrepancy signal is received and transmitted by the body's control
systems (nervous and endocrine), and it is through this act that negative
feedback occurs in the system. ~
In the first part of the paper we will not dwell on the details of system
control. We will assume that the feedback coefficient, k, reflects the
presence and effectiveness of certain hormones in the tissue, and that
it may vary somewhat depending on various conditions. The rate of cell
production is presumed to be proportional to the product of the dis-
crepancy and the size of the feedback coefficient.
Thus the functional pool is the regulated variable, and the proliferating
pool i.s the regulator. T;.: principle of regulation may be stated as
control based on the deviation from the required number of cells in the
functional pool. We should note that in clinical practice, a normal cell
- number is defined as the limit toward which the system tends, but one
which it does not achieve. Owing to this we have a discrepancy between
the actual number of cells and the norm, which is what we need if we are
to control the constant activity of the proliferating pool. In order
that this state of equilibrium would be maintained, cells must be con-
_ stantly produced by the system's active element, this process de�ining
the level of mitotic activity of tissues in their normal state.
- Basing ourselves on the discussion above, we can rather fully describe
; the kinetics of the restoration of proliferating tissues by means of a
_ three-unit model involving the following system of equations:
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-~--1- a k (IVj Ta T1
~t
dna . : n= - n3
d t Tt Tp ' dt T~ ~ T3
(1)
Here nl, n2, ng are the number of cells in the proliferating, maturing,
and functional pools, T1, T2, Tg are time constants corresponding to
equal times of presence of the cells in the indicat ed pools, Tp is the
time of cell generation in the proliferating pool, k is the feedback
coefficient, t is current time, and Ng is the required number of cells
in the functional pool. Figure 1 is a block diagram of the rel.ationships
between the variables.
f
N3
ft 3
Figure 1. Block Diagram of the Mutual Relationship of Variables
in a Three-Unit Model
This is a linear variant of the model, it yields to analytical examination,
and it permits us to conceptualize the biological content of its indivi-
dual components,and evaluate the interaction occurring between different
_ pools of the tissue system.
It should be noted that each pool has its own self-regulation loops, for
example the cell contact inhibition system in the proliferating pool, and
- so on, examination of which would best proceed with isolated cell popula-
_ tions. They will not be examined in this communication, inasmuch as this
paper emphasizes control by the body. In the model examined here, cells
undergo real movement in the feed-forward circuit as they transform out
of proliferating cells into maturing cells and then into functional cells,
while real cell movement does not occur in the feedback circuit. It is
assumed that the feedback circuit is put into play remotely (from afar) by
neurohumoral effectors.
Equation (1) is typical of tracking based on an error--a deviation from a
- given value (14). The transfer functions for nl, n2, n3 are presented
below.
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IY3T (9+ pT )(1 + pT,)
n~ 6 T3(10 r,/kr,)� f(p)
N3 T( P ~'3 J
n~ T3 (1+To/kT3)�~'lP~
N3
n3 TI * To /k 73 ) � ~ (p~
~)�1+p T'�T2�p~.TotP~TT+T,T~+TT3Tc~P3T~TT~. ~3)
~ P ro . 4T3 To + kT3 , To + kr
3
Introduction of the transfer functions is a formal procedure in which the
derivative symbol in equation system (1) is substituted by the symbol p
(that is, the functions are subjected to a Laplace transformation). Thus
the system of differential equations is substitute' '.y a system of
algebraic equations, and the available TAR apparatus permits us to analyze
a number of properties of such a system.
- When t--> ---that is, when p-} 0, we can obtain stable values for the
variables under examination. Their respective values are:
NT NT N
7iI s T+ T T/k 3 . ng ' 37~' Tj /kT . n 3 ~.J ,j, Q ~g � (4)
_ It follows from these expressions that the feedback coefficient, k,
def.ines the stable values of the variab].es in the system after thE
transient proGess ends. A transient process is one in which a system
returns to a stable (steady) state following deviation from it. This
deviation of the stable value from the one required is what is referred
to in the TAR literature as the dynamic error, or dynamic precision.
_ Usually solution of technical problems requires attainment of rather high
precision--that is, minimum error or discrepancy. Formulas (4) illustrate
' that the precision rises as Tp/T1 approaches zero--that is, when the
feedback coefficient is sufficiently large. As an example were we to
- limit the precision to 10 percent, then we would need to satisfy the
, condition k= 9�Tp/Z'3. It might be concluded at first glance from the
formulas for nl and n2 that the model is imperfect, inasmuch as even in
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the limiting case the variables under examination here do not tend toward
their required value. Let us return to the initial equations. In a steady
_ state, the rate of transition from one pool into another must be equal,
and in view of this the following conditions must be satisfied:
_ Nl ^ Nz Na , (19)
T~ TZ T~
Using (5), we transfonn the formulas for nl and n2 into the form
N? Nj
1 f To/kT3 I ` o kT3 .
(s)
We can see from (6) that the values for nl and n2 are detennined with the
same precision as that of ng, and they depend on the length of life of
the functional elements, cell proliferation time, and the size of ths
feedback coefficient. Relationships (5), despite their apparent simplicity,
are extremely important. Possessing data on the time cells remain in
different pools, we could use relationships (5) to estimate the average
number of cells in the different pools and, on the other hand, were we to
- possess data on the latter, we could determine the time cells remain in
the different pools. These relationships are valid, for example, in
relation to the red blood system, for which they equal 106 cells/24 days =
= 106 cells/24 days = 5�106 cells/120 days (3). Similar relation-
ships are satisfied for the crypt-villus cell system as well: 500 cells/
- /10 hr = 500 cells/10 hr = 200 cells/40 hr. The scatter of the values
of these parameters is significantly greater for myeloid cells in the
_ white blood system. It can be assumed that the time of presence in the
proliferating, matur_ing, and functional pools is 8, 6.5, and 9.25 days
for human white blood, and that the number of ce11s in these pools is,
respectively, 2�106, 1.6�106, and 7�103 (10-13), for which relationship (5)
would be satisfied. Such data are absent in the literature for other
tissues in view of the complexities of estimating the relationships
- between the functional, maturing, and proliferating pools, and therefore
_ we did not make the corxesponding estimates. It was assumed that the
number of cells per unit volume of bone marrow reflects the total number
of marrow cells, and that the number of marrow cells reflects the
functional potential of the bone marrow. These assumptions are valid
- after a long postradiation period, and they may be made in steady-state
research.
= If we agree to the validity of relationship (5), which can be written in
general foxm as a/b = c/d = e/ f, then a:c:e = b:d:f is valid as well.
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_ It follows from the latter that the ratic of the numbers of cells in the
p�roliferating, maturing, and functional pools, or the ratio of their
average times of presence in these pools, may be assumed to be a character-
istic of the tissue. Returning to the actively proliferating tissues for
which we were able to make this evaluation, we should note that for red
blood this ratio is 0.2:0.2:1, both for the number of cells and the time
constants of the proliferating, maturing, and functional pools. This ratio
is 0.25:0.25:1 for the crypt-villus cell system, and 30:30:1 for white
blood. We suggest that these ratios are a significantly meaningful
characteristic of the tissue, one which could be used as the basis for
computing, with the assistance of the proposed model, the basic ckiaracter-
istics of restoration following a damaging effect.
It is usually difficult to estimate, in experimental analysis of t"Lssues,
the proportional content of cells in the proliferating, maturing, and
functional pools. It is much simpler to determine the times of presence
of cells in the divisions of tissue types, using formula (5) and the
transient times of the individual pools of the tissues under examination.
For the tissues enumerated above, we found that the first two figures of
both of the parameters examined are close. This permitted us to reduce the
entire set of tissue characteristics to a single quantitative parameter,
a step which turned out to be useful to subsequent analytical examination
and analysis of the graphical dependencies. It is entirely possible that
the noted law is not universal (we will assess its universality later,
after accumulating enough experimental materia7.); however, the found ratios
were discovered to be valid in our analysis of actively proliferating
tissues. We designated this parameter Q, and we will use it subsequently.
As an example, for red blood Q= 0.2, and for white blood Q= 30.
_ Equation (1) may be :ransfornied into a dimensionless form to study the
relative quantity of -'ells in the different pools:
M. 0 OF ~
n, c~l n, nz ,~2 n2
r. k~'(1 - n~ n= - _
T~, dt - T 3 (7)
Variables marked with an asterisk are transformed values related to the
quantity of cells typical for normal conditions:
"f 0 na a ns
7J,t p N~ ; 'r'~~ p!z ; ft J
and change in time occurs in relative units of the duration of the
functional pool , t* = t/T3. This transformation a'lso changes the values
of the time constants and the feedback coefficient. C'apitalizing on the
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fact that the tissues are characterized by approximately equal values of
T1 and T2, and N1 and N2, and that the ratio of these parameters to
T3 and N3 is our parameter Q, we can represent equation system (7) in
the following form:
_ Q17j~ - W - 7'13 ) - 77I dri2 = 72i72= . ~h3 a n ?Z ,
~8)
cl t Q ' PCt Q ' alt z '
The asterisk symbol is dropped from this system. Our subsequent
investigation pertains to the dimensionless variant. In this case we
adopt the average time of presence of cells in the functional pool as
the unit of time. As follows from (8), there is only one variable
parameter in such a dimensionless variant for the examined tissue (given
a fixed Q)--the feedback coefficient k. This makes it possible, on
comparing the restoration process observed experimentally and that ob-
- tained by niodeling, to determine the strength'of the feedback and the
degree of its variability in the presence of different pathological
situations, using the developed model description of the kinetics.
= A digital computer was used to derive the restoration process experienced
by c3ifferent tissues, which will subsequently be referred to as the
transient process. We studied recovery of cell composition following a
50 percent reduction of the quaiLtity of cells in the proliferating pool.
It follows from expressions (2-3) that in this case the quantity of cells
in the functional pool is defined by a third-order differential equation.
Depending on the concrete values of the parameters involved, its solution
- may be the product of three aperiodic units (three first-order systems),
or the product of an aperiodic unit and an oscillating unit. Change in
- the coordinates with time can be described by superimposing the solutions
for each of the units. In the first case
~ x;f)t.f, 0(930
- and in the second case
cos tut).
Parameters tl, T2, Tg, T41 T5, w are determined from the roots of the
equations corresponding to the transfer function (3): When the time
constants of the different components differ by a factor of 5 or 10, the
process with the lower time constant may be ignored, since it attenuates
much faster than do the other components (14).
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Thus to analyze the system we must find the roots of the equation defined by the transfer function, after which it would be easy to reveal the type
of transient process involved--that is, the relationship between the -
oscillatory and aperiodic solutions. To obtain the rootsof the complete _
cubic equation, we can use an iteration procedure which would allow us
to find the roots quickly, with a small number of iterations (14). The .
following system may be reconnended for determining the roots of the -
equation alp3 + a~p2 + agp + 1= 0, which may be placed in the form
(1 +pT) (1 + b2p + blp~ ) = o; i = al/ (a2-B) ; O=T (ag-T) . After determining T, we
can compute the parameters of the oscillating unit using the formulas -
b1=a1/i, b2=a3-T. Considering that the oscillating unit may be more
obvious when presented in the form 1+ 2~pT + p2T2, where T= 21r/W, we get
formulas of the iollowing form for parameters T and E:
Figure 2 shows the results of computing E for different values of parameter
k. For the sake of visuality, the figure also shows the system precision
achieved with the given values of the parameters. As was noted above, the
size of ~ reflects the tendency to oscillate. The general solution for
the oscillatory unit can be represented in the form
_ t
~ cas cv t.
When E