PHENOMENA RESEARCH JOURNAL (Ph.R.J.)
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Editorial board and the proofs of our competencies
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(4)The link to the "Medical Phoenix
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to disscutions in
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Short summary of actual papers
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Texts of papers arranged as in (2)
(1) [a] Editorial board and [b] the proofs of our competencies
[a] Editor in chief: prof. Andrzej Brodziak, M.D., Ph.D., Sc. D. Associate Editors: Damian Kaszuba M.D., Małgorzata Muc-Wierzgoń M.D., Ph. D., Marek Baranowski M.D., Ph.D., Jaycee McPeteren
[b] "PHENOMENA RESEARCH JOURNAL" is directed by the staff of 5-th Department of Internal Diseases of Silesian School of Medicine (Katowice, Poland). The activity and achievement of the Department is presented by http://www.slam.katowice.pl./jednostki/5klinchw/eng5klinchw.html. The superior organisation is: Silesian School of Medicine presented, in all, by http://www.slam.katowice.pl.
(A) Titles and short summary of scientific articles, accesible already now!
4.ATTEMPT TO TREAT EPILEPSY WITH THE APPLICATIONS OF WEAK EXTRA - LOW FREQUENCY ELECTROMAGNETIC FIELDS. Sieczkowska M., Brodziak A.
5.Central injection of morphine: effects on IL-6 and IL-6 receptor mRNAs in the brain, pituitary and adrenal gland. Barbara Zubelewicz*, Derek Renshaw , Ryszard Braczkowski & Michael S. Harbuz
6.Intracerebroventricular injection of
morphine stimulates plasma corticosterone in adjuvant -induced arthritis.
Barbara Zubelewicz*^, Derek Renshaw, Ryszard
Braczkowski*, Michael S.Harbuz
7.Transient increase of plasma
Interleukin-6 after infusion of recombinant Tumour Necrosis Factor a in
advanced cancer patients. Zubelewicz B., Romanowski
W., Braczkowska B.*, Lissoni P.^, Braczkowski R.
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http://www.religioustolerance.org/cults.htm
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(6) Short summary of actual papers
1. The unit of neural networks modelling recall od mental images by oscillations of feedback loops caused by change of set-point signal.
Authors: Andrzej Brodziak, Marianna Rys
From 5th Department of Internal Diseases of Silesian School of Medicine, Poland, Bytom, ul. Zeromskiego 7 http://salve.slam.katowice.pl/eng5klinchw.html
The authors try to find the concrete physical and mathematical meaning to the process of recollection from memory in neuron like-element networks and to the related notion of mental images. They deduce the nature of his process from old concepts of homeostatis and self-control (feed-back loop) and memorization of data by synaptic weights of threshold logic units. Through the composition of outlines, illustrating these concepts, they formulated the most simple, but extendable unit, which can keep equilibrium, memorize data, recognize an image and recall it in the absence of the external object. The functional consistency of this elementary unit, was checked through its simulation on a computer. A simple mathematical analysis is also presented. The defined unit has back-propagating connections, which transmits set-point signal. The authors quote neurophysiological evidences for existance of such "reconstructive" pathways.
The paper was published in English languague in "Postepy Fizyki Medycznej", 1990, 21(1): 30-37.
2. Does epidemiological data support the hypothesis that the pattern of light (Zodiac Sign by Hipparch); assimilated by a pregnant women influences; through pineal gland and gonadothropins; the development of the fetus brain and subsequent psychosomatic features of personality.
Authors: Andrzej Brodziak, Damian Kaszuba, Marianna Rys
From 5th Department of Internal Diseases of Silesian School of Medicine Poland, Bytom, ul. Zeromskiego 7 http://salve.slam.katowice.pl/eng5klinchw.html
Summary of the part I and theoretical basis
We present in the full text of the paper rates of mortality, caused by myocardial infarcts (plus other diseases of circulation system) and cancers among people dead during the calendar year 1994 nd 1995 in Poland, born under different zodiac signs. Data were obtained from Main Statistical Biuro of the Country (Glowny Urzad Statystyczny - Poland).
The discussion about type A of behavior, prone to coronary hearth disease (C.H.D.) (1-6) and typ C predisposing to development of cancers (7-12) is continued in behavioral medicine literature. Recently thy system Enneagram (13) clasifing personality to 9 different types is discused vividly (14). This system, from one side, discern personality types similar to behavior types A (PERFORMER) and C (GIVER), but from other side, personality types similar to known characteristics of person born under different zodiac signs. One of us published considerations on conformability of these two systems of classification of personalities formerly (15).
We assumed that trials of the formulation of personality types, according to so called zodiac sign undertaken since centures constituted the pre-Freud'ian period of the development of the theory of personality (16).
Of course we understand the notion of zodiac signs as Hipparch, who already in the year 125 B.C. divided the ecliptic into 12 equal parts. Zodiac signs in this way denotes, in facts, monthly periods of a callendar year only; and their names by astral constellations are customary and historical only.
We found significant differences in mortality rates by reason of diseases of circulation system and cancers among persons born under the same particular, different zodiac signs and dead before their 60 year of life.
This finding is probably one of first objective arguments that, after all, the relation between so called 'zodiac signs' and a kind of personality, which influences death circumstances, thus an aspect of human destiny really exists.
Our methodological approach should be clarified. Mortality rates were calculated on data concerning 757816 persons. New-born (death during the first year of life) were not taken into account.
Result were listed of different diagrams and many statistal test were performed. The mean time of life (68.0) people born in deffenrent year periods is similar and calculated extreme differences (67.5 for Taurus and 69.4 Sagittarius) are not statistically significant.
The probalbility (frequency) of death by reason of myocardial infarct in relation to other causes is higher among people born under Taurus, Gemini, Cancer and Scorpio.
People born under Virgo, Libra, Sagittarius, Aquarius die more often by reason of cancers. These different proportions, verified by test are significant for groups of people born under Taurus and Aquarius and Scorpio and Aquarius . The c2 value is high for many other comparaisons also, however doesn't exceed the limit for p<0.05.
A periodic year regularity of these rates seems to become noticeable. The mortality rate by reason of infarct for people born (conceived!!) in subsequent zodiacal months increases (Ram, Taurus, Gemini), then decreases (Cancer, Leo, Virgo, Libra) and afterwards again increases (Sagittarius, Capricorn, Pisces and again Ram). The data for Scorpio sign disturbs this regularity.
We formulated a hypothesis, which facilitates the discussion of these results. Our hypothesis assumes that some inborn characterological features (personality type) of a new-born persons are induces by the pathern of day-light, perceived by a pregmant woman. There are many experimental findings supporting this hypothesis. Perceived light, trough visual pathways, nucleus suprachiasmaticus and pineal gland determines circadian rhythm of secretion of melatonin (17,18). Pineal gland acting on hypothalamus determines circadian changes of many hypophyseal hormones and especially gonadothropins (18,19,20).
It is also found already that the photoperiod perceived by females influences many foetal functions 821,22), It is remarkable that female melatonin influences fetal gonadal function (23,24,25,26). The influence of gonadal hormones on the development of embrional and fetal brain is also proved.
Thus, it could be concluded that biological rationale exists for the thesis that the calendar period of pregnancy can be related to some inborn personality characteristics. From other side researchers intersted in clinical psychology and behavioral medicine try to relate some behavioral types to disease, which cause more frequently early death. Therefore it seems to us that scrupulous analysis of mortality rates performed on big files of data, gathered in different countries, especially in southern hemisphere could clarified many questions concerning relation of month of conception to some aspects of lifestyle and behavioral patterns.
Literature:
1. Friedman M., Rosenman R.H.: Overt behaviour pattern in coronary disease - Detection of overt behaviour pattern A in patients with coronary disease by a new psycho-physiological procedure. J. Amer. Med. Ass., 1960, 173, 1320- 1324.
2. Friedman M., Rosenman R.H.: Type A behaviour pattern. Its association with coronary heart disease. Annales of Clin. Res., 1971, 3, 300-306.
3. Friedman M.: Alteration of type A behaviour and reduction in cardiac recurrences in post myocardial infarction patients. Amer. Hearth J., 1984, 108, 237-239.
4. Wright L.: The type A behaviour pattern and coronary artery disease. American Psychologist, 1988, 1, 2-14.
5. Price V.A.: Type A behaviour pattern. A model for research and practice. Academic Pres, New York, 1982.
6. Ruberman W., Weinblatt E., Goldberg J.D., Chaudhary B.S.: Psychosocial influences on mortality after myocardial infarction. N. Engl. J. Med., 1984, 311, 552-559.
7. Bahnson C.B.: Stress and cancer: the state of the art. Psychosomatics, 1980, 21, 975-978.
8. Jenkins D.: Social environment and cancer mortality in men. N. Engl. J. Med., 1984, 48, 395-398.
9. Temoskok L.: Personality, coping style, emotion and cancer. Towards an intergrative model. Cancer Surveys, 1987, 6, 545-567.
10. Hahn R.C., Petitti D.B.: Minnesota Multiphasic Personality Inventory rated depression and the incidence of breast cancer. Cancer, 1988, 61, 845-848.
11. Baltrush H.J.F., Santagostino P.: The type C behaviour pattern - new concept. International J. Psychophysiology, 1989, 7, 126.
12. Baltrush H.J.F., Strangel W., Titze J.: Stress, cancer and immunity. Acta Neurologica, 1991,
13, 315-327. 13. Palmer H.: The Enneagram. The definitive guide to the ancient system for understanding yourself and the others in your life. Harper & Row Publishers, San Francisco - New York, 1988.
14. Wagner J.: Call for paper for "First International Enneagram Conference" - which was led on the Stanford University Campus, August 5-7, 1994.
15. Brodziak A.: Alchemia Twoich Marzeä. Wydawca: Zakad Poligraficzny, Bytom (ul. Wolnoci 37), 1992.
16. Pellegrini R.J.: Birthadate psychology: a new look at some old data. J. Psychol., 1975, 89, 261-265.
17. Tamarkin L., Baird C.J., Almeida O.F.: Melatonin a coordinating signal for mamalian reproduction? Science, 1985, 227, 714-720.
18. Fleming A.S., Scardicchio D.S.: Photoperiodic and pinel effects on food intake, food retrived and weight in femal Syrian hamsters. J. Biol. Rhythms, 1986, 1, 285-301.
19. Martinet L., Allain D.: Role of the pineal gland in the photoperiodic control of reproductive and non-reproductive functions in mink. Ciba Foundation Symposia, 1985, 117, 170-187.
20. Ortavant R., Bocquier F., Pelletier J., Ravault J.P., Thimonier J., Volland Nail P.: Seasonality of reproduction in sheep and its control by photoperiod. Australian J. of Biol. Sci., 1988, 41, 69-85.
21. Weaver D.R., Reppert S.M.: Maternal melatonin communicates daylength to the fetus in Djunfarian hamsters. Endocrinology, 1986, 118, 2861-2863.
22. Elliott J.A., Goldman B.D.: Reception of photoperiodic information by fetal Siberian hamsters: role of the mother's pineal gland. J. Exp. Zol., 1989, 252, 237-244.
23. Jarrige J.F., Tlemcani O., Baucher D.: Gonadal function in male offspring of pinealectomized female rates. Acta Endocrinologica (Copenhagen), 1987, 116, 247-252.
24. Yellom S.M., Longe L.D.: Effect of maternal pinealectomy and reverse photo- period on the circadian melatonin rhythm in the sheep and fetus during the last trimester od prengancy. Biol. Reprod., 1988, 39, 1093-1099.
25. Jarrige J.F., Laurichesse H., Boucher D.: Androgenic activity in 15-day old male rats: role of the maternal pineal gland. Biol. Reprod., 1992, 46, 386-391.
26. Weaver D.R., Keohon J.T., Reppert S.M.: Definition of a prenatal sensitive period for maternal - fetal communication of day length. Am. J. Physiol., 1987, 253, E701-E704.
** Some fragments of this paper and some points of our inference were published already in following articles:
(a) Brodziak A., Romanowski W., Kaszuba D., Zubelewicz B., Braczkowski R.: Not zodiac sing, but seasonal time - dependent light exposure influences the psychosomatic features of new born child. Acta Neurobiol. Experim., 1994, 54, suppl., 177-178.
(b) Brodziak A., Kaszuba D., Romanowski W., Ry M.: Mortality rates caused by myocardial infarct and cancers among people born under different zodiac signs. Psycho-Oncology Letters [5, Philonoes str. Zographou 15773 Athens, Greece, ISSN1105-2643].
3. How biological systems detect and estimate the time-space expansion (E. Hubble'ian) rate?
From 5th Department of Internal Diseases of Silesian School of Medicine Poland, Bytom, ul. Zeromskiego 7 http://salve.slam.katowice.pl/eng5klinchw.html
Key words: time-space, circadian rythm, intra-cellular oscillators, feed-back loop, relativistic physics, evolution
The authors review recent experimental data concerning the molecular basis of circadian rythms and the mechanism of intra-cellular clock which reset by the external astronomical time-giver. They also the discuss the mutations of gene, which form interconnected feedback loops constituting the endogenous intra-cell oscillator. Then they refer to their former papers and show how to connect three simple feed-back loops in a system "memorizing - recognizing - and recalling" of circadian periods (so called equi-me-rec-unit), whicht is necessary to define, working endogenous clock, sensitive to external factors.
The authors formulate the hypothesis that biological systems, based on such interconected feed-back loops can detect the relativistic time transformation. It is possible due to specific features of biological clocks, which are always build at the moment of birth (of conception) according to "the ancient genetic pattern", set up 4 billions years ago. The authors argue that the changing time-space curvature causes mutations, which determine the way of biological evolution.
As a conslusion of the inference presented in the paper the authors formulate the Biological postulates to cosmological theories
The biological point of view forces us to discern separate regions in the expanding time-space. The phenomenon of life and consciousness should be taking into account. It seems that living forms exist in the front of expanding time-space only. Probably special shape of the time-space is necessary for arising of consciousness. The physical properties of frontal reagion of the time-space are probably indispensable for the phenomenon of life.
The hypothesis, presented here, states that the changing time-space curvature causes mutations, which point out the way of biological evolution.
We conceived this theory considering recent experimental data concerning the molecular basis of circadian rythm related to the natural mechanisms of genetic mutations (1,2). We try to expain below how the resetting of intra-cellular clock is related to the possibility of the estimation of the time-space expansion stage
Literature:
1. Wosshall L., Price J., Sehgal A., Saez L., Young M.: Specific block in nuclear localization of PERIOD protein by a second clock mutation - type timeless. Science, 1994, 263, 1606-1609.
2. Crosthwaite S.K., Loros J.J., Dunlap J.C.: Ligh-induced resetting of a circadian clock is mediated by a rapid increase in FREQUENCY transcript. Cell, 1995, 81, 1008-1012.
(7) Texts of papers arranged "subsequently" as in (2)
ad.1. The full text and its illustrations are in the course of computerization. It will be available soon.
ad.2. The full text and its illustrations are here
ad.3. . The detailed content of the paper is presented bellow:
How biological systems detect and estimate the time-space expansion (E. Hubble'ian") rate?
Authors: Andrzej Brodziak,Marek Baranowski, Jaycee Mc Peteren,Małgorzata Muc-Wierzgoń, Damian Kaszuba..
From 5th Department of Internal Diseases of Silesian School of Medicine Poland, Bytom, ul. Zeromskiego 7
Key words: time-space, circadian rythm, intra-cellular oscillators, feed-back loop, relativistic physics, evolution
Summary
The authors review recent experimental data concerning the molecular basis of circadian rythms and the mechanism of intra-cellular clock which reset by the external astronomical time-giver. They also discuss the mutations of genes, which constitute interconnected feed-back loops creating the endogenous intra-cell oscillator. Then, they refer to their former papers and show how to connect three simple feed-back loops in a system "memorizing - recognizing - and recalling" circadian periods (so called equi-me-rec-unit), what is necesary to determine, working endogenous clock, sensitive for external influences.
The authors formulate the hypothesis that biological system, based on such interconected feed-back loops can detect the relativistic time transformation. It is possible by reason of special particularity of biological clocks, which are build always again in the time of birth (of conception) according to "the ancient genetic pattern", set up 4 billions years before. The authors argue that the changing time-space curvature determine mutations, which point out the way of biological evolution.
The mechanism of intra-cellular clock resetting by the extermal environmental time-giver
Circadian rythm is settled by so called intra-cellular oscillator, influenced by morning light and sunset light(2). The oscillator is set up by the feed-back loop created by specific genes e.g. "frequency - FRQ" among unicellular organisms Neurospora or "period - PER" among Drosophilla. These genes control synthesis of respective FRQ or PER protein, which in excess inhibits further transcription process. Recently S. Crosthwaite with co-workers have proved that light influences the DNA sequences, constiting the promotors of these genes (2).
The physiological task of FRQ protein is stimulation of biochemical pathways necessary in the day time.. We present on the fig. 1 the simplified scheme of the intra-cellular oscillator,proposed by Susan Crosthwaite (2)
Fig. 1
.
J. Enright and co-workers deduce from the theory of feedback control systems the conclusion that any simple system build as on the fig. 2 can form the oscillating unit (3). However they assume that both elements F1 and F2 of this unit are so called "inertial" elements, characterized by the transmission function, between input and output as illustrated on the fig. 3. Then they assume then that F1 and F2 elements include internal damping feed-back loops. So the scheme of a biological intra-cellular oscillator needs refinement
Fig. 2
Fig.3
The analysis of the mechanism of action of intra-cellular oscillator, made by two independent research teams, working on diffrent uni-cellular and multi-cellular organisms (Neurospora and Drosophila) have shown that such an oscillator, indeed, consists of two feed-back loops sensitive to light intensity changes. In Neurospora organisms the oscillator is composed from FRQ-gene and Clock Controled genes (CCgs) and external system "changing gradually" intensity of the light (2). In Drosophila organisms PERIOD and TIMLESS genes constitue the equivalent units (1).
In our former papers we tried to present how to connect three simple feed-back loops into a system, which will be able to oscillate (4,5). We called this kind of system an "equilibrating-memorizing-recognizing-and-recalling-unit" (for short :"equi-me-rec-unit"). It is illustrated on the fig. 4, taken from our former papers (4,5).
Fig. 4
Oscillators of this kind are characterized by a stable basic rythm, determined by some periods of time necessary for internal transmissions, but which can be tuned by external factors. The elements d1,d3,d4 and d2 on the fig.4 mark delays in the internal transmissions.,.
We have suggested above that intra-cellular oscillator as well as basic neural network (fig.5) have this kind of structure (4.5)
.Fig. 5
Such a structure can memorize the pattern of the day, i.e.time elapsed between, sunrise and sunset. The element d4 on the fig.4 represents the length of a night. It is proved by the fact that particular mutations of PER gene, namely PER5 and PERL, are known to shorten or lengthen periods of circadian Drosophila behavior (1). It is also supported by recent finding that there are two peaks of melatonin secretion related to dusk and dawn (9). R. Wever took into acount "external factors" and put forward sophisticaled mathematical model of intra-cellular oscillator . One of initial statments of his model is the following equation:
were:
y - represents the oscillating variable
y1 and y2 are the first and second time derivates of y
Z - represents the "external, restoring force"
b - is the coefficent of damping
w - is frequency of oscillations
Then R. Wever proved in a mathematical way how an external force "Z" can affect the rythm of intra-cellular oscillator (6). Recently a computer stimulation of this model has been made and unusual sensitivity of the described oscilators to weekly "changes of external force". ^Z has been noticed.
Obviously, intra-cellular oscillators count periods of time. These oscillators are a kind of a clock. It is easy to tune the clock of this kind to another frequency. The set-point signal for such oscillators are the period of time, elapsed between the sunrise and the sunset Two feedback loops of the first layer shown on the fig.4, correspond. to the molecular loops pointed out on the fig.1.The third feedback loop in the case of time counting corresponds to "astronomical time giver" Since it acts peridically it can also be represented by a feedback loop.
Many experimental measurements have shown that cells in cultures, kept in darkness, as well as experimental animals or even people dwelling in darkness set the endogenous rhythm with the basic period parameter of 25 hours.
This difference between "endogenous" basic time period and astronomical circadian period has been discussed many times (3,6). Many explanatory sugestions have been formulated , however, this phenomenon is not undestood well. We are convinced that explanation arising from our initial hypothesis should also be taken into account.
Evolving biological system and the relativistic transformation of time
We propose below the explanation of the permanent difference between the "endogenous" and "astronomical" length of the day by the effect of relativistic physics. Our attempt to explain this phenomenon will show a possible mechanism of a way which can be utilized by biological systems to estimate the time-space expansion stage.
Therefore we should remember that the above described intra-cellular oscillator is build at birth (or better at the time of conception) according to "the ancient genetic pattern". Cellular clocks, based on the above mentioned interconnected feed-back loops, created on the basis of some DNA sequences also exists, also in the most primitive uni-cellular organisms. Discoverers of FRQ gene found it in Neurospora genus (2). A number of other so called homeobox or structural genes where transmitted from primitive genera to the Homo sapiens sapiens species (7). Thus it seems that genes constituting the clock mechanism, like other homeobox genes, have their orgin 4 billions years ego. Intra-cellular clocks which emerged 4 billions years ago have been noticed, the "ancient" period of the length day.After the reconstruction at the birth the difference in the lenght of the day is detected..
Within following 4 billions years the biological systems were translocated in time-space with our whole solar system. This translocation results from the expansion of the time-space. The speed and accelerations of this translocation can be referred to the oldest astrophysical objects, e.g. to quasars. The solar system moved, in relation to these astrophysical objects high, infra-light speed. So, the relativistic effect concerns biological systems, because their development hat been going for last 4 billions years.
Even the most serious manuals of "particular relativistic theory", as Richard P. Feynmann's: "Lectures of physics" (7) deal with so called "relativistic time transformation" and consequent resulting so called "siblings paradox". According to R.P. Feynmann this sibling object, after translocation in time-space, will be younger which "performed accleleration in time". Inside this particular sibling subsystem the time elapses in a "relatively" slower way.
We believe that the retivistic transformation of time can be detected by biological systems due to the fact that the time-clock is built at the time of birth (of conception) according to "the ancient genetic pattern"dating back to 4 billions years ago.
The comparison of indications concerning the length of a day between endogenous ("ancient") clock and astronomical data requires the use of bigger dZ external force value for tuning between endogenous and astronomical day length . A critical dZ value could determine the appropriate time for essential structural mutations.
The increasing dZ force necessary to obtain the consistence between "endogenous rythm " and "astronomical time" is one of possible biological estimations of present ,actual time-space curvature.
Possibilities of the hypothesis falsification
Trials of falsification of our hypothes will occur in the future, when biologists will investigate the intra-cellular clocks of different species espedally old, non evolving species and when physicist and topology mathematicians will precise better the kind of time-space shape in which we are living.
Biological postulates to cosmological theories ,arising from our hypothesis-
speculations.
The biological point of view makes us distingnish separate regions in the expanding time-space. The phenomenon of life and consciousness should be taking into consideration. It seems that living forms exis only in the front of expanding time-space . Probably special shape o the time-space is necessary for arising of consciousness. The physical properties of frontal reagion of the time-space seems to be indispensable to the phenomenon of life.The changing time-space curvature could trigger same mutations,determining the way of biological evolution.This considerations seem to, be important in the era when prominent physicists do research an the possibility of travelling in time-space (10).
Literature
1. Wosshall L., Price J., Sehgal A., Saez L., Young M.: Specific block in nuclear localization of PERIOD protein by a second clock mutation - type timeless. Science, 1994, 263, 1606-1609.
2. Crosthwaite S.K., Loros J.J., Dunlap J.C.: Ligh-induced resetting of a circadian clock is mediated by a rapid increase in FREQUENCY transcript. Cell, 1995, 81, 1008-1012.
3. Enright J.T.: Mutual excitation of damped oscillators and self-sustainment of circadian rythms. In: Mathematical models of the circadian sleep-wake cycle. M.C. Moore-Ede (ed.), Raven Press, New York, 1984.
4. Brodziak A.: Podstawowe mechanizmy regulacji fizjologicznych. [Basic physiological control mechanisms - Introductory chapter to the manual: "Human physiology"]. Rozdzia wst©pny do podr©cznika: "Fizjologia czowieka". PZWL [State Medical Publishing Co.], Warszawa, 1989.
5. Brodziak A., Ry M.: The unit of neural networks modelling recall of mental images by oscillations of feedback loops caused by change of set point signal. Problemy Techniki Medycznej, 1990, nr 1, 30-37.
6. Wever R.A.: Toward a mathematical model of circadian rhythmicity. In: Mathematical models of the circadian sleep-wake cycle. M.C. Moore-Ede (ed.), Raven Press, New York, 1984.
7. Feynmann R.P.: The Feynmanna lectures on physics. Vol. 1. Addison-Wesley Publishing Co., Reading Massachusetts, USA, 1963.
8. Gehing W.J.: De la mouche a l'homme, un m©me supergene pour l'oeil. La Recherche, 1995, 280, 58-64.
9. Wehr T.A., Schwartz P.J., Turner E.H., Feldman N.S., Drake C.L., Rosenthal N.E.: Bimodal patterns of human melatonin secretion consistent with a two-oscillator model of regulation. Neurosci. Lett., 1995, 194, 105-108.
10. Lawrence M.Krauss.:The physics of Star-Trek. Harper Collins Inc, 1995
The unit of neural networks modelling recall od mental images
by oscillations of feedback loops caused by
change of set-point signal
Authors: Andrzej Brodziak, Marianna Ry
From 5th Department of Internal Diseases of Silesian School of Medicine, Poland, Bytom, ul. żeromskiego 7
http://www.slam.katowice.pl/~klin5chw
The authors try to find the concrete physical and mathematical meaning to the
process of recollection from memory in neuron like-element networks and to the related
notion of mental images. They deduce the nature of his process from old concepts of
homeostatis and self-control (feed-back loop) and memorization of data by synaptic weights
of threshold logic units. Through the composition of outlines, illustrating these
concepts, they formulated the most simple, but extendable unit, which can keep
equilibrium, memorize data, recognize an image and recall it in the absence of the
external object. The functional consistency of this elementary unit, was checked through
its simulation on a computer. A simple mathematical analysis is also presented. The
defined unit has back-propagating connections, which transmits set-point signal. The
authors quote neurophysiological evidences for existance of such
"reconstructive" pathways.
Kohonen asks "Is there any place for mental images in neural computing?". His answer is yes, but physical nature and information processing underlying this phenomenon is not yet precised. Recall from memory is a very basic process, which is probably related directly to yet more primary concepts explaining the phenomena of self - control. Therefore here we try to combine the basic concepts of biological homeostasis and self-control with the oldest concepts of a memorizing unit, meaning the threshold logic unit.
Comparison of the outline if the feedback loop (fig.2) and anther, old known notion of the threshold logic unit (fig.1) reveal that they are related to each other. However both original outlines are incomplete in some sense because the first doesn't precise the source if the set-point signal and the second doesn't say what signifies the mysterious element - wn+1 in the formula describing its action.
It seems that both concepts are fragments of a larger, more natural system, which are able to keep equilibrium, memorize data, recognize the image and recall it. We propose in figure 3a the outline of such a larger equilibrating-memorizing-recognizing and recalling unit (in short the equi-me-rec unit). Essentially it is composed of two layers of interconnected feedback loops. External influences or external stimuli: x1, x2, ..., xi , ..., xn, act on lower level elements, which are "under control".
The output signals of these elements y1, y2 ... act as "influences" (or stimuli) on the element of the higher level loop.
The output signals are checked here with the thresholds T1A, T1B, ... It is realized by parts "originating" from the threshold logic units. Similarly, the resistance's or weights of inputs of stimuli can be insereted here also on the basis of our initial intention to make an exhaustive assemblage of two old concepts. The control theory forsees also that the output signal, which is directed back to the input, can be transformed in a different way in "k" or "l". So the signal, returning to the lower subunits can be transformed in a similar way in t and/or p. The most simple transformation of cause is change of the sing f(s)=-s. Thus it can be that: e = f(s)-f(y) = -s-f(y) = -e = s+f(y) (1).
The element under the control can be supplied by a stable level of energy and after the change of the error signal, changes of the output signal in time can have intertial or oscillatory character.
The essential feature of the equi-me-rec unit is its ability to fall into oscillations as the result of the change of the set-point signal. If we will roughly discern two values of the set-point signal coming from a higher level (s): a lower one: s = 0 and a higher one: s = 1, where 1 will be near to the threshold value, and the unit will transform the output signal according to the formula (1), then even in the absence of stimuli x1 ... xn, setting s = 1 will cause that e = s+f(y) = 1+0 = 1, so it will take a relatiavely big value and the threshold can be surpassed. The upper subunit will be restimulated. Restimulation will cause oscillations. Of course, in the situation that s = 0, appropriate amount(or appropriate set) of stimuli x1 ... xn can give the same result. Thus the equi-me-rec unit can be activated by two ways: 1) by external stimuli or 2) by change of the set-point signal to a big value.
The system, presented in fig. 3a, could be simulated in different, sophisticated ways, assuming binary or continuous - nonlinear character of its components. We conceived however a very simple method, which aims only to check the functional consistency of the concept of the equi-me-rec unit.
For this purpose it is sufficient to simulate subunits of the system by procedures of one of the object oriented programming languages and using discrete recycling. Such simulation also resembles principles of action of the so called cellular computers characterized by parallel actions of all subunits (7). We used co called "systolic architecture" of the program. The program illustrates the performed communications among procedures and resulting states of the system by a dynamic outline presented on the screen.
Connections among subunits (neuron-like elements) and values of "synaptic weights", as well as values of elements: wn+1 were changed during experiments. We verified some versions of possible organisation of the equi-me-rec unit. Finally we found that a consistent, working structure of the unit can be obtained when: external; "associative" signal is given trough the input (s'') and the imposed set-point signal decreases in a stepwise manner during subsequent cycles of actions. In this case the procedure, reproducing the action the superior neuron-like-element, has the following form:
TO NEROUN 'LIKE ELEMENT' 2C
IF s'' = 0 [yn+1=0] (2)
IF s'' = 1 [yn+1= * g] (3)
IF s'' = 2 [yn+1=1] (4)
n
I = yi * vi (5)
i=1
R = yn+1 * vn+1 (6)
E = I + R (7)
IF E > T2C [S=1] [S=0] (8)
IF R > T2C [S=2] (9)
y1 ... y2 ... yn = 0 (10)
s1 ... s2 ... sn =
0
(11)
END
Procedures, equivalent to the lower-level neuron-like element input y1 = 0 or 1 and in the case: IF R>T1AV1B yi = 2, what is an equivalent to the double frequency of output (firing at high frequency). We searched during our experiments for the solution, which would satisfy the main requirement that equi-me-rec unit has recurrent features, it means that is could be expanded to a much larger system by the simple addition of next layers. We search for the structure of a subunit of the equi-me-rec unit which could always be the same.
The reader should remember here also that the changed set-point signal can come not only from upper layers but, as we call here through "an associative" connection, what means that it come from other part of the network, which can memorize symbols of considered patterns. To emphasise the need of symbols it is useful to remember here the biological analogy of "the separate area pf the brain cortex" which memorized words (Brock's and Wernicke's areas) denoting objects (its mental images).
The conclusion from our experiments is as follows: the organisation of the equi-me-rec unit can be depicted in the form of the fig. 3a, where elements A, B, C have characteristics to the equations (2-11). Coefficient "g" in the equations (3) should be rather small (e.g. 5/6) and the value of threshold T lower then vn+1 (e.g.: 2/3 * vn+1).
Oscillations of the unit can be induced through the change of the (s'') signal, but not through the possible input "q". Elements S1, ... Si ... S' should have memorizing characters
1A 1B
and, as in other inputs, the immanent for subunits values: wn+1 , w, vd+1 should be discerned
1A 1B 2C
from the value xn+1, xd+1, yn+1 which change during subsequent cycles. It appears that con esistent working structure of the equi-me-rec unit should assume two levels of "internal energy" (arousel of neuron - like-element), what is represented in equation (7) by a value of "E". Also two levels of positive output (at least two frequences of "firing") should be assumed. Thus, to the "recognition" of the pattern its "imagination" is attached (equations 6,7) and it causes the double energy ("arousel") of the system. The activation of the system through "associative" connection (through the increase of the set-point values") cause the similar action of the network, but at lower level of "arousel". We coun'd find other working, consistent structure avoiding double level of "internal energg" to realize changes of weights during learning periods, according to the principle of Heeb (8). It was not however the aim of our experiment.
Mathematical interpretation of our finding can be formulated in terms of multidimentional geometrical model of the pattern recognition. The activation of the threshold logic unit is equivalent to the recognition of multidimentional geometrical model of the pattern recognition. The training, of the threshold element consists of adjustments of weights: w1 ... wn . A set of values x1 ... xn determines a point in a multidimentional space and also a vector X. Often the similarity of images is expressed by the Euclidean distance among its representing points. A clase of similar objects is often represented by the so called mean pattern Pj, it means also a vector, in the same space. It is known, from the geometrical properties of Euclidean space, that the distance between a given point X and a point Pj is expressed by the formula:
________________
|X - Pj| = (X - Pj) * (X - Pj) (12)
The same classification is obtained comparing the square of the expression for the distance:
|X - Pj|2 = (X - Pj) * (X - Pj) = X*X - 2X * Pj + Pj * Pj (13)
The fragment X * X doesn't change the classification either, so it can be omitted and we can compare finally only the expressions
X * Pj - 1/2 Pj * Pj (14)
After the learning procedure, elements pij = wij : the elements of vector Pj are equal to so called "weights of resistances" for input signals. As we remember, the vector Pj denotes the learned pattern image. But from the other side, it can be written that:
wn+1 = - 1/2 * Pj * Pj
The last expression signifies that the value (wn+1) is determined well by elements of this particular mean pattern, which is recognized by a given threshold element. We have argued above that a high value of the set-point signal is an equivalent of the element (-wn+1) and it can replace external signals (it means the value X * Pj) and causes the transgression of the threshold, which will induce oscillations of the equi-me-rec unit. But as we have demonstrated, a high value of the set-point signal in an equi-me-rec unit denotes the memorized mean pattern of this particular unit. So we can say, that by means of the change of the set-point signal we induce the "home", immanent pattern, which specifies the unit.
Biological analogy of the defined circuits exists. Some histological (cytoarchitectonic), neurophysiological and clinical data indicate, that so called recurrent axons, and more generally, recurrent pathways, are essential for the process of recalling of mental images and subsequent imaginative information processing (9,10,11). Taking into account their existence, the basic way of connections among neurons can be outlined by this fig. 3b. Neurosurgical experiments and the concepts of Mishkin and Martinez support the idea that corticothalomo-hippocampal circuits are essential to the process of learning and memory (12,13,14). Interneurons with manifest "long term potentiation" phenomenon (symbolized on fig. 3b by "D") induce features of neural circuits, analogous to the described equi-me-rec units. Interneurons can change "the sign" and the amplification of "signals". Thus, sets of neurons interconnected in the way presented in fig. 3b (which is analogous to the equi-me-rec unit) can manifest high inclination for reverberating oscillatory flows of impulses.
R. Shephard researcher of internal representations of objects and imaginative
information processing, found the metaphor of "resonant systems" or
"resonance phenomenon" very useful (15). However he doesn't consider the
physical structures of such circuits. Rumelhart, presenting his concept of "back
propagating errors" doesn't consider problems of recollection or mental images (16).
Thus, it seems to us important to try to determine structural systems, modelling neural
circuits, which have the intrinsic nature to fall into a resonant oscillations, with
non-linear changes of states of subunits. It is especially important in
the era of "connectionism", when some people want to try to reproduce in
electronic circuits the recall of mental images.
We present the figures nr 1, 2, 3a, 3b bellow.

fig.2

fig3b.
Literature
1. Kohenen T.: An introduction to neural computing. Neural Networks, 1988, 1, 3-6.
2. Cannon W.: The wisdom of the body. London, Trubner and Co., 1932.
3. Wiener N.: Cybernetics or control and communication in the animal and the machine. New York, John Wiley and Sons, 1948.
4. Mc Culloch W.S., Pitts W.A.: A logical calculus of the ideas immanent in neurous activity. Bull. Math. Biophysics, 1943, 5, 115-133.
5. Nillson N.J.: Learning machines. New York, Mc Graw Hill Inc., 1965.
6. Grossberg S.: Nonlinear neural networks. Principles mechanisms, and architectures. Neural Networks, 1988, 1, 17-61.
7. Greussay P.: L'ordinateur celluiaire. La Recherche, 1988, 19, 1320-1330.
8. Hebb D.O.: The organization of the behavior. New York, John Wiley and Sons, 1949.
9. Brodziak A.: [Psychonika. Theory of structures and information processing of human central nervous systems and its application in informatics]. Katowice (Poland), Publishing House of Polish Academy of Sciences (in Polish language), 1974.
10. Brodziak A., Amanowicz K., Pasternak R.: Pamiêæ neuronalna i istota wyobrażeń [Neural memory and the nature of recalling.]. Pol. Tyg. Lek. [Polish Medical Journal], 1986, 41, 771-774.
11. Brodziak A., Pasternak R.: Istota percepcji bólu [The nature of pain perception.]. Wiadomoci Lekarskie [Medical News], 1988, 41, 195-208.
12. Mishkin M.: A memory system in the monkey. Philos. Trans. Royal Soc. London (Biol.), 1982, 293B, 85-92.
13. Mishkin M., Appenzeller T.: The anatomy of memory. Scientific American, 1987, 256, 61-71.
14. Martinez J.L.: Learning and Memory. San Diego - New York, Academic Press, 1986.
15. Shepard R.N.: Ecological constraints on internal representation: resonant kinematics of perceiving, imagining, thinking and dreaming. Psycholog. Rev., 1984, 91, 417-447.
16. Rumelhart D.E., Hinion G.E., Wiliams R.J.: Learning representations by back-propagation errors. Nature, 1986, 323, 533-536.
Its is the program simulating so called EQUIMEREC unit, written in, LOGO language.See letters to the Omega point mailing list.
PPROP ".SYSTEM "BURY "TRUE TO GIVE'PATTERN IF :REPLY = [A] [PATTERN'CHAR]
IF :REPLY = [B] [PATTERN'UN'CHAR] IF :REPLY = [C] [IF :IMPULS = 0 [MAKE "S' 2 MAKE
"IMPULS 1] [MAKE "S' 0]] IF :REPLY = [D] [MAKE "S' 2] IF :REPLY = [E]
[PATTERN] IF :REPLY = [F] [STOP] REMOVE2'TEXT WAIT 20 ACTION IF KEYP [SETCURSOR [22 0]
REPEAT 35 [TYPE CHAR 32] SETCURSOR [17 0] PR [WE BEGIN THE RUN FOR THE SYSTEM AGAIN.] WAIT
50 SYMULATION STOP] GIVE'PATTERN END
TO PATTERN'CHAR MAKE "X1 1 MAKE "X2 1 MAKE "X3 1 MAKE "X5 1 MAKE "X6 1 MAKE "X7 1 MAKE "X9 1 MAKE "X10 1 MAKE "X11 1 PATTERN'FIG END
TO PATTERN'UN'CHAR MAKE "X1 0 MAKE "X2 0 MAKE "X3 1 MAKE "X5 1 MAKE "X6 0 MAKE "X7 0 MAKE "X9 0 MAKE "X10 0 MAKE "X11 0 PATTERN'FIG END
TO PATTERN MAKE "DATA :DATA + 1 IF :DATA > 1 [MAKE "X1 ITEM 1 :PATTERN MAKE "X2 ITEM 2 :PATTERN MAKE "X3 ITEM 3 :PATTERN MAKE "X5 ITEM 4 :PATTERN MAKE "X6 ITEM 5 :PATTERN MAKE "X7 ITEM 6 :PATTERN MAKE "X9 ITEM 7 :PATTERN MAKE "X10 ITEM 8 :PATTERN MAKE "X11 ITEM 9 :PATTERN PATTERN'FIG STOP] SETCURSOR [17 0] PR [GIVE THE CHOSEN PATTERN !] MAKE "X1 FIRST RL SETCURSOR [1 0] PR :X1 REMOVE'TEXT MAKE "X2 FIRST RL SETCURSOR [2 0] PR :X2 REMOVE'TEXT MAKE "X3 FIRST RL SETCURSOR [3 0] PR :X3 REMOVE'TEXT MAKE "X5 FIRST RL SETCURSOR [6 0] PR :X5 REMOVE'TEXT MAKE "X6 FIRST RL SETCURSOR [7 0] PR :X6 REMOVE'TEXT MAKE "X7 FIRST RL SETCURSOR [8 0] PR :X7 REMOVE'TEXT MAKE "X9 FIRST RL SETCURSOR [11 0] PR :X9 REMOVE'TEXT MAKE "X10 FIRST RL SETCURSOR [12 0] PR :X10 REMOVE'TEXT MAKE "X11 FIRST RL SETCURSOR [13 0] PR :X11 SETCURSOR [17 0] MAKE "PATTERN (SE :X1 :X2 :X3 :X5 :X6 :X7 :X9 :X10 :X11) END
TO REMOVE2'TEXT SETCURSOR [17 0] REPEAT 4 [REPEAT 35 [(TYPE CHAR 32)] PR []] SETCURSOR [17 0] END
TO ACTION CHANGE'FIG'3 NEURON'A NEURON'B NEURON'C REMOVE1'TEXT CHANGE'FIG'1 NEURON'2A CHANGE'FIG'2 END
TO PATTERN'FIG SETCURSOR [1 0] PR :X1 SETCURSOR [2 0] PR :X2 SETCURSOR [3 0] PR :X3 SETCURSOR [6 0] PR :X5 SETCURSOR [7 0] PR :X6 SETCURSOR [8 0] PR :X7 SETCURSOR [11 0] PR :X9 SETCURSOR [12 0] PR :X10 SETCURSOR [13 0] PR :X11 SETCURSOR [17 0] END
TO REMOVE'TEXT SETCURSOR [18 0] REPEAT 5 [(TYPE CHAR 32)] SETCURSOR [18 0] END
TO CHANGE'FIG'3 SETCURSOR [11 24] PR CHAR 32 SETTC [1 0] SETCURSOR [11 24] IF :S' = 2 [PR 1] [PR 0] SETTC [7 0] SETCURSOR [17 0] END
TO NEURON'A IF :S1 = 0 [MAKE "X4 0] IF :S1 = 1 [MAKE "X4 :X4 * :K] IF :S1 = 2 [MAKE "X4 1] MAKE "W1 0.9 MAKE "W2 0.9 MAKE "W3 0.2 MAKE "W4 1.6 MAKE "T1 1.1 MAKE "I :W1 * :X1 + :W2 * :X2 + :W3 * :X3 MAKE "R :W4 * :X4 MAKE "E :I + :R IF :E > :T1 [MAKE "Y1 1] [MAKE "Y1 0] IF :R > :T1 [MAKE "Y1 2] MAKE "X1 0 MAKE "X2 0 MAKE "X3 0 END
TO NEURON'B IF :S2 = 0 [MAKE "X8 0] IF :S2 = 1 [MAKE "X8 :X8 * :K] IF :S2 = 2 [MAKE "X8 1] MAKE "W5 0.9 MAKE "W6 0.9 MAKE "W7 0.2 MAKE "W8 1.6 MAKE "T2 1.1 MAKE "I :W5 * :X5 + :W6 * :X6 + :W7 * :X7 MAKE "R :W8 * :X8 MAKE "E :I + :R IF :E > :T2 [MAKE "Y2 1] [MAKE "Y2 0] IF :R > :T2 [MAKE "Y2 2] MAKE "X5 0 MAKE "X6 0 MAKE "X7 0 END
TO NEURON'C IF :S3 = 0 [MAKE "X12 0] IF :S3 = 1 [MAKE "X12 :X12 * :K] IF :S3 = 2 [MAKE "X12 1] MAKE "W9 0.9 MAKE "W10 0.9 MAKE "W11 0.2 MAKE "W12 1.6 MAKE "T3 1.1 MAKE "I :W9 * :X9 + :W10 * :X10 + :W11 * :X11 MAKE "R :W12 * :X12 MAKE "E :I + :R IF :E > :T3 [MAKE "Y3 1] [MAKE "Y3 0] IF :R > :T3 [MAKE "Y3 2] MAKE "X9 0 MAKE "X10 0 MAKE "X11 0 END
TO REMOVE1'TEXT SETCURSOR [1 0] PR CHAR 32 SETCURSOR [2 0] PR CHAR 32 SETCURSOR [3 0] PR CHAR 32 SETCURSOR [6 0] PR CHAR 32 SETCURSOR [7 0] PR CHAR 32 SETCURSOR [8 0] PR CHAR 32 SETCURSOR [11 0] PR CHAR 32 SETCURSOR [12 0] PR CHAR 32 SETCURSOR [13 0] PR CHAR 32 SETCURSOR [17 0] END
TO CHANGE'FIG'1 SETTC [1 0] SETCURSOR [6 27] PR 0 SETCURSOR [3 9] PR 0 SETCURSOR [8 9] PR 0 SETCURSOR [13 9] PR 0 SETTC [7 0] SETPC 2 IF OR :Y1 = 2 :Y1 = 1 [PU SETPOS [-80 102] PD SETPOS [-16 89] SETCURSOR [2 16] PR [1] WAIT 20 PU SETPOS [-80 102] PE SETPOS [-16 89]] [SETCURSOR [2 16] PR [0]] IF OR :Y2 = 2 :Y2 = 1 [PU SETPOS [-80 52] PD SETPOS [-16 74] SETCURSOR [4 16] PR [1] WAIT 20 PU SETPOS [-80 52] PE SETPOS [-16 74]] [SETCURSOR [4 16] PR [0]] IF OR :Y3 = 2 :Y3 = 1 [PU SETPOS [-80 2] PD SETPOS [-16 59] SETCURSOR [6 16] PR [1] WAIT 20 PU SETPOS [-80 2] PE SETPOS [-16 59]] [SETCURSOR [6 16] PR [0]] END
TO NEURON'2A IF :S' = 0 [MAKE "Y4 0] IF :S' = 1 [MAKE "Y4 :Y4 * :K] IF :S' = 2 [MAKE "Y4 1] MAKE "V1 0.9 MAKE "V2 0.9 MAKE "V3 0.2 MAKE "V4 1.6 MAKE "T 1.1 MAKE "I :V1 * :Y1 + :V2 * :Y2 + :V3 * :Y3 MAKE "R :V4 * :Y4 MAKE "E :I + :R IF :E > :T [MAKE "S 1] [MAKE "S 0] IF :R > :T [MAKE "S 2] MAKE "Y1 0 MAKE "Y2 0 MAKE "Y3 0 MAKE "S1 :S MAKE "S2 :S MAKE "S3 :S END
TO CHANGE'FIG'2 SETCURSOR [2 16] PR 0 SETCURSOR [4 16] PR 0 SETCURSOR [6 16] PR 0 SETCURSOR [11 24] PR CHAR 32 SETTC [1 0] SETCURSOR [11 24] PR 0 IF :S = 0 [SETCURSOR [3 26] PR 0 SETCURSOR [6 27] PR 0 SETCURSOR [3 9] PR 0 SETCURSOR [8 9] PR 0 SETCURSOR [13 9] PR 0 SETTC [7 0] STOP] PU SETPOS [40 77] SETH 90 PD FD 30 SETCURSOR [3 26] PR 1 SETPC 3 RESULT PU SETCURSOR [6 27] PR 1 PU SETPOS [40 77] SETH 90 PE FD 30 SETCURSOR [3 26] PR 0 SETPC 2 PU SETPOS [57 75] PD SETH 225 REPEAT 84 [RT 0.3 FD 2] SETCURSOR [13 9] PR 1 PU SETPOS [-11 21] PD SETPOS [-90 34] SETCURSOR [8 9] PR 1 PU SETPOS [-1 29] PD SETPOS [-90 81] SETCURSOR [3 9] PR 1 WAIT 20 SETCURSOR [6 27] PR 0 PU SETPOS [57 75] SETH 225 PE REPEAT 84 [RT 0.3 FD 2] PU SETPOS [-11 21] PE SETPOS [-90 34] PU SETPOS [-1 29] PE SETPOS [-90 81] SETTC [7 0] END
TO RESULT PU SETPOS [90 95] PD SETH 270 REPEAT 12 [LT 30 FD 8] WAIT 20 PU SETPOS [90 95] PE SETH 270 REPEAT 12 [LT 30 FD 8] END
TO HELP MAKE "HELP 0 SETCURSOR [22 0] PR [] SETTC [7 5] TYPE [F] SETTC [1 3] TYPE [orward..] SETTC [7 5] TYPE [N] SETTC [1 3] TYPE [ew run..] SETTC [7 5] TYPE [Q] SETTC [1 3] TYPE [-DOS..] SETTC [7 5] TYPE [S] SETTC [1 3] TYPE [top..] MAKE "REPLY1 RC SETTC [7 0] SETCURSOR [22 0] PR [] REPEAT 35 [TYPE CHAR 32] IF :REPLY1 = "N [TS CT SETCURSOR [5 0] PR [WE BEGIN THE RUN FOR THE SYSTEM AGAIN.] WAIT 100 SYMULATION] IF :REPLY1 = "Q [TS CT SETCURSOR [5 0] PR [WE RETURN TO DOS.] PR [TO START SYSTEM AGAIN :] PR [1 / LOGO] PR [2 / LOAD "STYMULATION] PR [3 / STYMULATION] WAIT 100 .DOS] IF :REPLY1 = "S [TS CT SETCURSOR [5 0] PR [THE FINISH OF THE SYSTEM] MAKE "HELP 1] END
TO FIGURE CLEAN TS CT HT LOADPIC "DISIGN SETTC [1 0] SETCURSOR [3 9] PR [0] SETCURSOR [8 9] PR [0] SETCURSOR [13 9] PR [0] SETTC [3 0] SETCURSOR [2 16] PR 0 SETCURSOR [4 16] PR [0] SETCURSOR [6 16] PR [0] SETCURSOR [3 26] PR [0] SETTC [1 0] SETCURSOR [6 27] PR [0] SETTC [1 0] SETCURSOR [11 24] PR [0] SETTC [7 0] SETPC 3 SETCURSOR [17 0] SETCURSOR [22 0] PR [TO INTERUPT STRICKE 'BLANK - BARR '] END
TO SYMULATION TS CT (SETWIDTH 80) MAKE "K 5 / 6 MAKE "IMPULS 0 MAKE "DATA 0 MAKE "S1 0 MAKE "S2 0 MAKE "S3 0 MAKE "S 0 MAKE "S' 0 MAKE "X1 0 MAKE "X2 0 MAKE "X3 0 MAKE "X4 0 MAKE "X5 0 MAKE "X6 0 MAKE "X7 0 MAKE "X8 0 MAKE "X9 0 MAKE "X10 0 MAKE "X11 0 MAKE "X12 0 MAKE "Y1 0 MAKE "Y2 0 MAKE "Y3 0 MAKE "Y4 0 PR [] PR [DETERMINE THE KIND OF EXPERIMENT. GIVE ONE OF FOLLOWING SYMBOLS :] PR [] PR [] (TYPE [A - HANDLING OF THE] CHAR 32 CHAR 32 [C H A R A K T E R I S T I C] CHAR 32 CHAR 32 [PATTERN ( IMAGE )]) PR [] (TYPE CHAR 32 CHAR 32 CHAR 32 CHAR 32 [FOR ANY CYCLE ( THE MODEL OF " P E R C E P T I O N "\)]) PR [] PR [] (TYPE [B - HAMDLING OF] CHAR 32 CHAR 32 [U N] CHAR 32 [C H A R A K T E R I C T I C] CHAR 32 CHAR 32 [PATTERN]) PR [] (TYPE CHAR 32 CHAR 32 CHAR 32 CHAR 32 [FOR ANY CYCLE ( THE MODEL OF UNKNOWN IMAGE )]) PR [] PR [] PR [C - ONE "ASSOCIATIVE" IMPULSE ( BIG SET'POINT VALUE FOR UPPER] (TYPE CHAR 32 CHAR 32 CHAR 32 CHAR 32 [SUBUNIT THE MODEL OF "MOMENTARY IMAGINATION" )]) PR [] PR [] PR [D - HANDLING OF "ASSOCIATIVE IMPULSES" FOR ANY CYCLE ( THE MODEL] (TYPE CHAR 32 CHAR 32 CHAR 32 CHAR 32 [OF A LONG IMAGINATION )]) PR [] PR [] PR [E - INPUT FROM YHE KEYBOARD OF THE PATTERN AND ITS HANDLING] (TYPE CHAR 32 CHAR 32 CHAR 32 CHAR 32 [FOR ONY CYCLE OF THE ACTION OF THE EQUI - ME - REC UMIT]) PR [] PR [] PR [F - FINISH] PR [] PR [] MAKE "REPLY RL SETWIDTH 40 FIGURE GIVE'PATTERN CT TS SETCURSOR [5 0] PR [WE RETURNED TO LOGO.] PR [] PR [TO START THE SYSTEM AGAIN WRITE :] PR [SYMULATION] END
The planetary imprinting- some arguments.
Damian Kaszuba, Andrzej Brodziak
The period of an itrauterine development is the most susceptible to harmful, biophysical factors of the environment. The best known is the influence of these factors on a period of organogenesis. The exposition to those factors may result in a formation of polydysplasia. Harmful biophysical conditions of the environment can cause other changes of the human body, which are originally indefinable. They can predispose a foetus to different diseases in adult life.
Biophysical factors of the environment always display a periodic characteristic.
A date of birth is determined by a time of conception and allows to estimate the probable time of every crucial stage of an intrauterine development of a foetus. Those facts help to investigate the biophysical environmental factors, which may interfere with an embryogenesis or organogenesis, at a particular season of the year.
In according to above-mentioned guidelines, I decided to investigate relationship between season of birth and death rate of adult human for some diseases.
Necessary data were obtained from Central Statistical Office and Government Centre of Computing Pesel. The research was conducted on the total population of Poland in 1994, which was between 18 and 55 years of age. It means that there were included subjects which had been born from 1939 to 1976 (20 419 528 persons). A retrospective observation of the death rates (130 761 cases) concerned two years: 1994 and 1995.
A statistical analysis, using chi-square test, showed the correlation between month of birth and rates of death in examined group. It was statistically significant for the whole distribution of death, for such cause of death as: all neoplasms, malignant neoplasm of lung, larynx, all diseases of cardiovascular system, ischaemic heart disease, and hypertensive disease.
I also compared mortality of each month of birth with the other. In a such way, I found months of birth rising a risk of death for different diseases. Among months rising a risk of death there are: January (all neoplasms {graph 1}, malignant neoplasm of lung, larynx, all diseases of cardiovascular system, ischaemic heart disease, diabetes ), February (malignant neoplasm of brain, ischaemic heart disease), March (all neoplasms), April (malignant neoplasm of colon {graph 2}, hypertensive disease). Months of birth reducing a risk of death are: May (malignant neoplasm of larynx ), September (diabetes), November (asthma), December (all neoplasms, malignant neoplasm of lung, larynx, all diseases of cardiovascular system, ischaemic heart disease, and hypertensive disease).
The most surprising fact is the presence of similar tendency for the most diseases. People born in initial months of year, die of different diseases more frequently then those, who were born in final months (graph 1).
Graph 1. Months of birth rising a risk of death - all neoplasms.

On the other hand, the distribution of death by months of birth for malignant neoplasm of colon and brain is accidental except for a one peak corresponding to Februar (neoplasm of brain) and April (neoplasm of colon {graph 2}).
Graph 2. Months of birth rising a risk of death - neoplasm of colon.

A statistically significant trend in death rate for hypertension, asthma and diabetes is much more clearly expressed for the date of birth in a particular season of the year then for a month of birth. There are groups of months elevating the risk of death. A numbers of death is higher for such period of the year as: January- March (diabetes), March- May (asthma), April- June (hypertensive disease). The same number of deaths is relatively lower for the following periods: September- October (diabetes), October- December (asthma, hypertensive disease).
There are no correlation between month of birth and mortality for malignant neoplasms of stomach and oesophagus.
In conclusion, further observations are required in different population. In this way scientists may identify harmful, biophysical factors of the environment inducing such relationship.
ATTEMPT TO TREAT EPILEPSY WITH THE APPLICATIONS OF WEAK EXTRA - LOW FREQUENCY ELECTROMAGNETIC FIELDS
Małgorzata Sieczkowska, Andrzej Brodziak
V Department of Internal Medicine, Silesian Medical Academy
7 Żeromski Street, Bytom and Municipal Neurological Outpatient Department in Bytom
Abstract: In a group 35 patients with epilepsy the effect of extra-low frequency electromagnetic field upon the brain bioelectric activity was studied. Application of weak low frequency magnetic field has been found to compensate abnormal profile of electroencephalographic changes in patients suffering from epilepsy.
Key words: Epilepsy - Electroencephalography - Extra-low frequency elrctromagnetic field (ELF-EM).
Introduction
The latest developments in routinely applied magnetotherapy and in neurophysiology and medical biophysics encouraged us to start clinical trials on therapeutic application of weak extra - low frequency electromegnetic fields in patients with epilepsy.
The so called magnetotherapy ie. application of variable electro- magnetic field of 1 - 50 miliTesli (mT) intensity and 3 -100Hz frequency has already been applied in post traumatic rehabilitation (6, 25, 26).
Theoretical and experimental results (12, 13, 28) induced medical team of V Department of Internal Medicine at SMA to undertake examinations on the possibilities of immunity stimulation processes in patients with neoplasms by ELF - EM application. The experiments have proved that ELF field application generally leads to mental relaxation, phisical relaxation, improves mood and helps falling asleep (5, 11).
Some earlier papers from several research centers, especially those from Sandyks experimental group showed favourable effect of ELF-EM application in patients with neurological diseases as Parkinsons disease (14, 16, 18, 19, 23) and multiple sclerosis (8, 15, 17, 22, 24).
So far the attempts to apply magnetic field in epilepsy treatment have been undertaken by Aninos, Tsagas, Sandyk and Steinhoff ( 1, 2, 21, 27). They applied the equipment for magnetoencephalography. These authors claimed that neurons of epilepsy focus in cerebral cortex are the source of fairly strong magnetic fields. These fields may be registered extracranially by magnetoencephalography (MEG) and differ from magnetic fields emitted by the groups of neurons that do not show attacks. According to these authors application of external magnetic field of some higher intensity may again balance abnormal magnetic field profile caused by epilepsy focus.
Glial cells have been established to change their function under the influence of extra-low frequency electromagnetic field. Among the epileptogenic pathogenetic mechanisms there have been lately glial cells functioning disorders often enumerated. Among them they have been deficient astrocytes absorption of
K ions secreted excessively to intercellular space by active neurons and ability to eliminate glutaminic acid from this space. Deficiency of the above mentioned functions leads to increased extracellular space conduction evoking coupled synchronic depolarization of numerous neurons which has been known to be the cause of epilepsy seizure.
Favourable effects of extra-low frequency electromagnetic field might be employed in epilepsy treatment in theoretic model of ELF-EM effect in patients with epliepsy could offered or if there were know the exact characteristics of EM field leading to reduction of that increased extracellular space conduction to reduce the tendency towards synchronic depolarization of many neurons at the same time.
The aim of the research was:
1. To determine the effect of extra-low frequency electromagnetic field of 0.63
mT induction and of 7 and 42 Hz frequency upon the bioelectric activity upon epileptic patients brain.
2. To look for the possibility of introducing into clinical practice knowledge aboutelectroencephalographic changes due to extra-low frequency electromagnetic field in patients with epilepsy.
Materials and methods
35 patients with epilepsy (20with generalized epileptic seizure and 15 with partial epileptic seizure) were hospitalized at the Neurologic Ward of Municipal Specialist Hospital No 1 and followed up at the Outpatient Neurological Department in Bytom.
Extra-low frequency electromagnetic field of 0.63 mT introduction was produced by the EM field amplificator (Amplifier 50W-2) designed by electronic engineers and physicists from Computer Physics Department at the Jagiellonian University of Cracow. It emitted vibrations of 7 and 42 frequency. Bioelectric activity of brain was recorded with the equipment containing : 1. a pair of electrodes situated on both sides of mesiotemporal area of the head, 2. preamplifier, 3. analog to digital converter, 4. computer with the software. Photograph 1 illustrates the equipment.
There were two computer programmes used to visualise the records and electroencephalographic changes in patients before and after magnetic field application:
[2] Programme is based upon Gaussian curve in which Gaussian profil is adjusted to each negative spike and negative sharp wave and its width shows spike and wave duration.
The programme counts in two-minute record the amount of negative spikes and sharp waves at peaks if their amplitude exceeds 60 uV, and their duration is shorter than 80 ms (spikes) or ranges from 80-200 ms ( sharp waves).
The analysis of brain bioeletric activity with the application of the above mentioned equipment and software was carried out in each patients and computer EEG records were estimated both prior to and after simulated exposure and before and after magnetotherapy.
Effects of magnetic field with simulated exposure, 7 and 42Hz field activity as well as field effect upon brain bioelectric activity in the groups of patients with generalized and partial seizures were compared.
Wilcox-Wheit test was applied to statistical analysis of parameter changes called here amplitude sum before and after field application, while chi-square test was applied to compare reactions on field activity in the respective groups. Standard computer programmes were used for statistical evaluation.
Results:
Pictures 1 and 2 illustrate the results obtained by the application of the above mentioned equipment. They can be summarized in the following way:
Discussion
The EEG changes in at least one area of the brain in the group of 19 healthy volunteers have been shown by Bell and Chesson who applied 0.2 and 0.4 Gauss induction field (0.02 and 0.04mT) and 1.5-10Hz vibration frequency. The changes caused inhibition of EEG inhibition at the given frequency equal to stimulation frequency (4). The authors also noticed non-linear dependancy between the induction of the applied field and the response.
Bell et al. noted the reduction of bioelectric activity in occipital lobe on EEG record of healthy people when 1 gauss (0.1mT) and 10Hz magnetic field was applied (3).
Lyscov et al. observed increase in alpha wave activity and decrease in delta wave activity in all EEG leads as well as increase in beta wave activity in case of frontal leads when 1.26mT an 45Hz magnetic field is applied in healthy controls (9).
Sandyk and co. described the effect of pico-Tesli magnetic fields on bioelectric activity of the patients with Parkinsons disease demonstrated by the increase of alpha and beta activity on EEG (20).EEG changes coexisted with the decrease of tremor and increase of luteinizing hormone (LH) and prolacitin in patients blood.
The effect of 4.5mT and 40Hz magnetic field upon EEG activity in patients post cerebral stroke showing increase in amplitude frequency and alpha wave index has been described (7).
Steinhoff applied 1.5 T and 0.3Hz magnetic field in 19 patients with foci epilepsy to observe in some of them reduction of epilepsy activity on EEG; in none of the patients there were increase epilepsy activity on EEG record (27).
The patients who suffer from so called partial, complex temporal epileptic seizure have been known to have these fits often in increased geomagnetic activity period.
Increased geomagnetic activity appears on the days of so called geomagnetic storms. Instability of geomagnetic field is induced by the so called magnetospheric micropulsations and causess so called W.O. Schumanns resonance excess. The strongest Schummans basic resonance component is the 7.8Hz frequency vibration.
Physical model of differences in some brain areas stimulation by different, low frequency magnetic field was presented by prof. Micek from Physics Institute at the Jagiellonian University in Cracow (10). According to the basic thesis of the work, EM field induces electric disorders in brain tissue which behaves like the wave undergoing absorption, reflexion and refraction. These effects appear as
a result of the presence of the areas characterized with different propagation speed and their different absorption as well as naturally limitted areas like cranium. In this model the haed is treated as resonance system for electric courses. Electric wave is refracted or reflected. Thus prof. Micek assumes that standing wave appears in the system when the brain is surrounded by cranium.
Standing wave is the result of the interference (superposition) of two waves of identical frequency radiating in opposite directions (direct and refracted wave). It produces arrows and knots within the area. The arrrows are characterized with maximal vibration amplitude and knots with the lack of variable magnetic field.
According to computer simulation evaluation of the model, low frequency 7Hz EM field stimulates temporal lobes areas and 42Hz frequency field stimulates numerous areas around the brain.
In this physical model, although low frequency magnetic field stimulates the whole brain there are, however, some areas with the bigger stimulation. Thus with 7Hz frequency temporal lobes are stimulated while at 42Hz frequency all brain area is stimulated. It is illustrated in picture 3.
Since in case of generalized seizures the discharges spread around all brain area and in partial seizures involve one area only at the beginning, we conclude that changes of the brain bioelectric activity are significantly more frequent after 42Hz field application than after 7Hz field in patients with generalized seizures.
The above discussion allows the following conclusions:
Conclusions:
1. Anninos P.A., Tsagas N.: Localisation and cure of epileptic foci with the use of MEG measurements. Int. J. Neurosci. 1989, 46, 235-242.
2. Anninos P.A., Tsagas N., Sandyk R.: Magnetic stimulation in the treatment of partial seizures. Int J. Neurosci. 1991, 60, 141-171
3. Bell G.B., Marino A.A., Chesson A.L: Frequency specific blocking in the human brain caused by electromagnetic fields. Neuroreport. 1994, 5(4):
510-512.
4. Bell G.B., Marino A.A., Chesson A.L: Frequency specyfic responses in the human brain caused by electromagnetic fields. J. Neurol Sci. 1994, 123(1-2): 26-32.
5. Brodziak A., Muc-Wierzgoń M., Ziółko E., Baranowski M.: About the possibilities of geophysical remotelly-controlled response upon nervous and hormonal system of a man during sleep. Art of Treatment 1996, 1: 77-84.
6. Chvojka J.: Pulsing magnetic fields and their effect on the healing fractures and pseudoathroses. Acta Chir Orthop. Traumatol. Cech. 1985, 52: 36-46.
7. Janoszka Grabarczyk B., Chromy M., Szeliga Cetnarska M. et al.: Magnetic field impact on the electroencephalogram record (an initial report). Progresses of Rehabilitation 1995, 9: 63-71.
9. Lyscov E.B., Juutilainen J.: Effects of 45Hz magnetic fields on the functional state of the human brain. Bioelectromagnetics 1993, 14(2): 87-95.
10. Micek S.: Modelled stimulation of some brain areas with low frequency magnetic field. Internal report, September 1996. Physics Institute at the Jagiellonian University in Cracow, 1996.
11. Okoń Z., Brodziak A., Muc-Wierzgoń M.: The therapeutic effect of magnetic field upon central nervous system. Art. of Treatment, 1996, 2, 105-108.
12. Persinger M.A.: Out-of-body-like experiences are more probable on people with elevated complex partial epileptic-like syndrome during periods of
enhaced geomagnetic activity: a nonlinear effect. Percept. Mot. Skills., 1995, 80, 563.
13. Persinger M.A., Psych C.: Sudden enexpected death in epileptics following sudden, intense increases in geomagnetic activity. Int. J. Biometeorol., 1995, 38, 180.
14. Sandyk R.: A drug naive parkinsonian patient successfully treated with weak electromagnetic fields. Int. J. Neurosci. 1994, 79(1-2): 99-110.
15. Sandyk R.: Chronic relapsing multiple sclerosis: a case of rapid recovery by application of weak electromagnetic fields. Int. J. Neurosci. 1995, 82(3-4): 223-242.
16. Sandyk R.: Improvement in word-fluency performance in Parkinsons disease by administration of electromagnetic fields. Int. J. Neurosci 1994, 77(1-2): 23-46
17. Sandyk R.: Imrovement in word-fluency performace in patients with multiple sclerosis by magnetic fields. Int. J. Neurosci. 1994, 79(1-2): 75-90.
18. Sandyk R.: Inprovement of body image perception in Parkinsons disease by treatment with weak electromagnetic fields. Int. J. Neurosci. 1995, 82(3-4): 269-283.
19. Sandyk R.: Reversal of visuospatial deficit on the Clock Drawing Test in Parkinsons disease by treatment with weak electromagnetic fields. Int. J. Neurosci. 1995, 82(3-4): 255-268.
20. Sandyk R.: The effects of external picoTesla range magnetic fields on the EEG in Parkinsons disease. Int. J. Neurosci. 1993, 70(1-2): 85-96.
21. Sandyk R., Anninos P.A.: Attenuation of eplepsy with application of external magnetic fields: a case report. Int. J. Neurosci. 1992, 66(1-2): 75-85.
22. Sandyk R., Jacono R.P.: Improvement by picoTesla range magnetic fields of perceptual- motor performance and visual memory in a patient with chronic progressive multiple sclerosis. Int. J. Neurosci. 1994, 78(1-2): 53-66.
23. Sandyk R., Jacono R.P.: Rapid improvement of visuoperative functions by picoTesla range magnetic fields in patients with Parkinsons disease. Int. J. Neurosci. 1993, 70(3-4): 233-254.
24. Sandyk R., Jacono R.P.: Resolution of longstanding symptoms of multiple sclerosis by application picoTesla range magnetic fields. Int. J. Neurosci. 1993, 70(3-4): 255-269.
25. Sieroń A.: Soft magnetotherapy and laserotherapy. Silesian Medical Academy, Katowice 1993.
26. Sieroń A., Cielar G., Radelli J., Żmudziński J.: Post traumatic ophthtalmoplegia treated with low frequency magnetic field. Ann. Acad. Med. Siles. 1992, 25, 82-88.
27. Steihoff B.J., Stodieck S.R., Zivcec Z. et al. .: Transcranial magnetic stimulation (TMS) of the brain in patients with mesiotemporal epileptic foci. Clin. Electroencephalogr. 1993, 24(1): 1-5.
28. Stoupel E., Marttel J., Rotenberg Z.: Admissions of patients with epileptic seizures (E) and dizzines (D) related to geomagnetic and solar activity levels: differences in female and male patients. Med. Hypotheses. 1991, 36(4): 384-388.

time [ms]
Fragment of record of a patient with partial seizures before application of EM field 7Hz.

frequency [Hz]
Transform Fourier analysis of above mentioned fragment of EEG record before application of EM field 7Hz. Red colour ilustrates theta waves range. Their amplitude sum is 21632.

Figure 1 - Fragment of EEG record of a patient with generalized seizures before application of EM field 42Hz. Visible discharge of setsof sharp wave with free wave.

The equipment used to perform the described experiment.
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Central injection of morphine: effects on IL-6 and IL-6 receptor mRNAs in the brain, pituitary and adrenal gland.
Barbara Zubelewicz*, Derek Renshaw , Ryszard Braczkowski & Michael S. Harbuz
Division of Medicine, University of Bristol, BRI, Marlborough St, Bristol, BS2 8HW,UK
*5th Department of Internal Medicine, Silesian Medical University, Zeromskiego St.7,
41-902 Bytom, Poland
This paper has already been published in
Central European Journal of Immunology 1998,23,50-54
Summary.
There is a growing interests for connections between the central nervous system and immune/inflammatory response. Morphine (MF) has been shown to increase circulating concentration of interleukin (IL)-6 through centrally mediated mechanisms. Rats with AA have elevated levels of circulating IL-6. We have investigated the role of central MF injection on the induction of IL-6 mRNA and IL-6R(receptor) mRNA in brain, pituitary and adrenals.
IL-6 and IL-6R mRNA were not detected in the brain in any of the groups. IL-6 and IL-6R mRNA were increased in the anterior pituitary of AA rats given morphine compared with saline treated AA rats. In the adrenal cortex, IL-6 mRNA was unaltered and IL-6 receptor mRNA was significantly decreased under these same conditions.
Introduction.
There is a growing interest for connections between the central nervous system and immune/inflammatory response. Adjuvant arthritis (AA) is a chronic immunologically mediated disease which runs with chronic activation of hypothalamo-pituitary-adrenal (HPA) axis [1]. In addition, AA is associated with activation of cell-mediated immunity, resulting in increased secretion of inflammatory cytokines, such as Interleukin (IL)-1b ,
Tumour Necrosis Factor a (TNF a ) [2,3] and IL-6 [2].
IL-6 exerts multiple action on the growth, differentiation and function of lymphoid and non-lymphoid cells and regulates various aspects of the immune response and its production during injury or infection [4]. Plasma levels of IL-6 appear to mirror the changes in inflammation seen in AA [5]. IL-6 is an important immune mediator co-ordinating the activity of different immune cells with an important role in acute phase response [3]. While IL-6 is generally considered to be a pro-inflammatory cytokine, Mihara and colleagues noted that administration of IL-6 was able to suppress the development of AA suggesting a protective role [7].
Plasma concentration of IL-6 can be elevated by acute stress [8 ], and acute administration of IL-1 or endotoxin [9]. Injection of IL-1 or LPS into the lateral ventricle will increase plasma IL-6 [ 10,11 ] an effect which can be blocked by prior icv injection of IL-1 receptor antagonist suggesting a central mechanism.
Opiates such morphine have been reported to increase IL-6 through a centrally mediated, receptor dependent mechanism [10,11 ].
IL-6 and IL-6 receptor (IL-6R) mRNAs have been identified in brain, pituitary and adrenal gland [12,13 ].
In present study we have administered morphine centrally in control and AA rats. The purpose of this study was to investigate alterations in IL-6 and IL-6R mRNAs in the brain, pituitary and adrenal gland to determine if these tissue might be involved in the increase in circulating IL-6 which is a feature of AA.
Methods.
Adult male PVG rats ( 60 days of age;250+ 20g) kept in a 12h light:12h dark cycle (lights on at 07.00 hours) under heat and humidity controlled conditions were used for the experiment. Animals were allowed laboratory chow and tap water ad libidum and were housed six to a cage.
Treatments:
AA was induced by a single intradermal injection of 0.1 ml of a 10mg/ml suspension of ground, heat-killed Mycobacterium butyricum in parrafin oil into the tail base under light halothane anaesthesia. Control animals were injected with vehicle alone. In these
model inflammation is usually apparent 12-13 days after induction, clearly visible by day 14 and reaches peak severity at day 21 [14]. Ten days after adjuvant injection a guide cannula was inserted into the right lateral ventricle. Following development of hind-paw inflammation, saline or MF (10 m g in 4m l) was administered into the lateral ventricle over 1 minute. Rats were subsequently decapitated after 2 hours. Brains, pituitaries and adrenal glands were removed and rapidly frozen on dry-ice and stored at-80 oC until in situ hybridization.
In situ hybridization:
12 m m sections were taken through adrenal, pituitaries and brains and and riboprobes were used for in situ hybridization to examine IL-6 and IL-6r mRNAs in these tissues.
3 end of IL-6 and IL-6r probes were labelled with 35S-a dATP
Section were fixed in 4% paraformaldehyde, washed in 1xPBS and acetylated in a solution of 0.25% acetic anhydride, 1.4% triethanolamine in 0.6% sterile saline. After dehydration, delipidation and partial rehydration, section were allowed to air dry and sections were hybridised to probe overnight at 37 degrees. Slides were then washed 4 times over 1 hour period in 1x SSC , incubated twice in1xSSC at room temperature for 15 min x2. Finally, they were diped briefly in water x2 to remove salt deposits prior to drying and then dried complete in a warm air stream. Hybridized sections were exposed to autoradiography film for 3 weeks and the resulting images were analysed using a computer assisted image analysis system ( Image 1.22 developed by Wayne Rasband, NIH, Bethesda, MD,USA) and run on an Apple MacIICi. Results are presented as the mean percentage change from control ± standard erroe about the mean..
Statistical comparisons were made using Fisher PLSD test following one-way ANOVA.
A p< 0.05 was considered significant.
Results.
Effect on IL-6 and IL-6R mRNA in brain sections.
No message for either IL-6 or IL-6R mRNAs was detected in brain sections containing hippocampal subfields after 3 weeks exposure both in control and AA animals (data not shown).
Effect on IL-6 and IL-6R mRNA in pituitary and adrenals.
At the pituitary level , IL-6 and IL-6R mRNAs were present in the anterior pituitary but not the posterior pituitary. Acute icv morphine administration or AA alone did not significantly alter IL-6 mRNA (fig.1). However, there was a significant (p< 0.01) increase in IL-6 mRNA comparing the AA+ morphine with AA+ saline group. The decrease in AA+ saline pituitaries was not significantly different from the control +saline group. There were no significant changes in IL-6R mRNA in the morphine or AA animals but IL-6R mRNA was significantly increased in the AA rats injected with morphine (fig.2).
In the adrenal gland, IL-6 and IL-6R mRNAs was located principally in the adrenal cortex. There was a slight IL-6 signal detectable in adrenal medulla. IL-6 mRNA was not altered by any of the treatment (Fig.3). IL-6R mRNA (fig.4) was significantly decreased in the AA +morphine group compared with either the control +morphine (p< 00.1) or the AA +saline (p< 0.05).
Discussion.
The present data show that central injection of opiate agonist Morphine produces significant increase in plasma corticosterone in both control and arthritic rats, and enhances IL-6 and IL-6R mRNA expression in pituitary, while decreases IL-6R mRNA in adrenals.
The inability to detect IL-6 or IL-6R mRNA in the brain of control rats under basal conditions is in agreement with the number of previous studies using Northern blot analysis and the more sensitive technique of RT-PCR [15,16,17 ]. In contrast, however, other workers have detected substantial IL-6 mRNA signal in the CNS of the control animals [12,18 ]. The reason for this discrepancy is unclear. Despite the lack of signal under basal conditions, IL-6 mRNA can be induced in a number of brain areas following both peripheral and central injection of LPS, restrained stress and brain injury [17,18].The patterns of activation can differ depending on the stimulus and the areas investigated. In the mid-brain 4h restrained stress induced an increase in IL-6 mRNA together with decrease in IL-6R mRNA, while in hypothalamus the same stimulus decreased IL-6R mRNA but did not alter IL-6 mRNA [17 ]. In the present study, following morphine infusion mRNAs for IL-6 and IL-6 R remain below detectable limits and it is likely that more sensitive techniques would be required to elucidate the possible effects of morphine treatment within the brain.
At the level of the anterior pituitary both IL-6 and IL-6 receptor mRNAs were detectable in control rats as noted previously [12,16,19 ]. Morphine treatment in the AA rats produced significant increases in both mRNAs compared with levels in AA rats injected with saline. In contrast to previous study [ 20] we were unable to find an increase in IL-6 mRNA associated with AA.
At the adrenal gland, both IL-6 and IL-6 receptor mRNAs were detectable in both adrenal cortex and adrenal medulla confirming previous reports [12,16,21]. Central infusion of morphine or AA did not alter IL-6 mRNA levels in the adrenal cortex. In contrast IL-6 receptor m.RNA levels were reduced in the AA+ morphine group compared with the AA+ saline infused animals. The situation at the level of the adrenal gland is similar to that reported by Shizuya and co-workers following acute stress in the hypothalamus i.e. a decrease in IL-6 receptor mRNA with no change in IL-6 mRNA [17].
From these data it is clear that acute stimuli are able to exert actions on cytokine mRNAs in tissues of the HPA axis. The same stimulus is able to exert different actions which may increase both receptor and ligand mRNAs, decrease the receptor mRNA without affecting the other, or decrease the receptor mRNA while increasing IL-6mRNA. These observations suggest multiple control mechanisms underlying these changes in different tissues.
* Recipient of a scholarship from Foundation for Polish Science.
References.
and the development of adjuvant arthritis. Eur J Immunol 1991,21,2327-2331
J Exp Med. 1990,5,171,1773-1778
adrenal gland and spleen. Endocrinol 1993,133,2574-2578
expression of mRNAs for IL-6 and IL-6R in the hypothalamus and midbrain of the rat. Life Sci 1997,61
19. Valkeniers B., Vergani P., Trouillas J et al.: Regulation of the genes encoding IL-6,its
Receptor, gp 130 in the rat brain in response to the immune activator lipopolysaccharide and the pro-inflammatory cytokine IL-1 beta. J Neurochem 1997,69,1668-1683
inflammatory stress upon anterior pituitary IL-6 mRNA expression in the rat. Brit. J. Rheumatol., 1993,32,653-657
Legend to figures:
Fig.1 IL-6 mRNA expression level in pituitary gland before and after Morphine administration (% change from control). Data are expressed as mean ± SEM. **p.=0.001
Fig.2. IL-6 receptor mRNA expression level in pituitary gland before and after Morphine administration (% change from control). Data are expressed as in fig.1.
* p.=0.01 Control/Saline vs Arthritic/Morphine
** p.=0.001 Arthritic/Saline vs Arthritic/Morphine
Fig.3. IL-6 mRNA expression level in adrenal gland before and after Morphine administration (% change from control). Data are expressed as in fig.1
Fig.4. IL-6 receptor mRNA expression level in adrenal gland before and after Morphine administration (% change from control). Data are expressed as in fig.1 * p.=0.001
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Intracerebroventricular injection of morphine stimulates plasma corticosterone in adjuvant -induced arthritis.
Barbara Zubelewicz*^, Derek Renshaw, Ryszard Braczkowski*, Michael S.Harbuz
*5th Department of Internal Medicine, Silesian Medical University, ul. Zeromskiego 7,
41-902 Bytom, Poland
Division of Medicine, University of Bristol, BRI, Marlborough St. Bristol, BS 2 8HW, UK
corresponding author: B. Zubelewicz, 5th Dept. of Internal Medicine, Silesian Medical University, Żeromskiego St. 7, 41-902 Bytom, Poland.
Abstract.
Adjuvant-induced arthritis (AA) in the rat is a T-cell mediated , chronic inflammatory stress.
In addition, there are profound neuroendocrine changes associated with the development of hind-paw inflammation which have major implications for the ability of the rat to respond to stress. In present study we have determined the effects of a single injection of morphine into the lateral ventricle of control and AA animals on plasma corticosterone levels. AA rats were unable to mount corticosterone response to acute stress but were able to respond to acute stimulation with e.g. LPS. In the present study we found a sustained increase in plasma corticosterone in control animals which was still significantly elevated 2 hours following morphine injection , with a further significant increase in AA rats. These data suggest that alternative systems distinct from those activated in response to acute stress are activated by morphine in the AA animals. We conclude that central opiates may be involved in mediating the HPA axis response to inflammatory (LPS) stress.
key words: adjuvant - induced arthritis -chronic inflammation-
corticosterone - morphine
Introduction.
There is a growing interest in the connections between the central nervous system and immune response. Activation of the hypothalamo-pituitary-adrenal (HPA) axis in response to an acute stressors or acute immune challenge is characterised by an increase in ACTH release from the anterior pituitary which stimulates corticosterone release from the adrenal cortex.
Adjuvant -induced arthritis (AA) is a chronic, immunologically mediated disease which is associated with chronic activation of the HPA axis [ 1,2,3 ]. In contrast to normal animals, rats with AA are unable to mount a significant response to acute stressors such ip. Hypertonic saline, restraint or noise [4,5,6 ]. We have previously demonstrated that despite the chronic activation of pituitary-adrenal axis seen in AA, CRF peptide release into the hypophysial portal blood are paradoxically decreased[ 2,6 ]. In contrast to the lack of response seen with acute physical and psychological stressors, the corticosterone reponse to acute immune stimulation using lipopolysaccharide (LPS) remains intact [ 7 ]. These data suggest alternative signalling mechanisms associated with acute stress and acute immune stimuli.
In present study we have administered morphine centrally in control and AA rats. The purpose of this study was to determine the effect of centrally administered morphine on the activation of the HPA axis by measuring plasma corticosterone.
Methods.
Adult male PVG rats ( Bantin & Kingman, UK; 7-8 weeks of age) were kept under heat and humidity controlled conditions in a 12h light: 12h dark cycle (lights on at 07.00h). Animals were allowed laboratory chow and tap water ad libidum.
AA was induced by a single intradermal injection of 0.1 ml of a 10mg/ml suspension of ground, heat-killed Mycobacterium butyricum in paraffin oil administered under light halothane anaesthesia. Control animals were injected with vehicle alone. In this model hind-paw inflammation is usually apparent 12-13 days after induction , clearly visible by day 14 and reached peak severity at day 21 [ 1 ].
Ten days after adjuvant injection a guide cannula was inserted into the right lateral ventricle and a cannula inserted into the jugular vein for the removal of blood samples. Following development of hind-paw inflammation a pre-injection blood sample (0.5ml) was removed. Saline or morphine (10 m g in 4 m l ) was infused into the lateral ventricle over 1 minute. A further blood sample ( 0.5 ml) was withdrawn after 2 hours.
Trunk blood was taken for plasma corticosterone measurements, in triplicate, by radioimmunoassay using antiserum supplied by Dr G. Makara (Institute of Experimental Medicine, Budapest, Hungary).
The tracer was 125I- corticosterone (INC Biomedicals, CA, USA) with a specific activity of 2-3 mCi/m g. The sensitivity of the assay was 25 ng/ml. The intraassay coefficient of variation was less than 12%.
Statistical comparisions were made using Fisher PLSD test following one-way ANOVA.
A p< 0.05 was considered significant.
Results.
Adjuvant- injected animals which did not exhibit hind-paw inflammation were excludede from the experiment. As reported previously, basal corticosterone levels were significantly
( p< 0.05) elevated in AA rats with hind-paw inflammation (fig.1) compared with non-arthritic controls. In the control rats two hours following morphine injection ( 10 m g in 4 m l icv), there was a significant (p< 0.01) increase in plasma corticosterone compared with the pre-injection levels. Morphine was also able to evoke a highly significant (p< 0.001) increase in circulating corticosterone in AA animals.
These levels were also highly significantly elevated (p< 0.001) over levels in morphine-treated control rats.
Discussion.
The present data confirm that central injection of the opiate agonist morphine stimulates significant increases in plasma corticosterone in both control and AA rats. Furthermore, in the AA animals we have noted a further significant increase in plasma corticosterone following morphine injection compared to control animals receiving morphine. This sustained release was still evident 2 hours following the injection.
We have previously demonstrated that animals with AA are unable to mount a significant CRF mRNA or corticosterone response to the acute stressors of ip hypertonic saline ( a mixed physical and psychological stressors ) [ 1 ], restrained ( a predominantly psychological stressors ) [ 4 ]) or noise stress [ 5 ]. We have been unable to evoke either a corticosterone or CRF mRNA response to these stressors. These findings have suggested that associated with the development of the chronic inflammatory stress of AA there is an inhibition of the control mechanisms normally activated in response to stress. A similar situation is also found in patients with rheumatoid arthritis who, unlike non-arthritic patients, are unable to mount a cortisol response to the stress of surgery [7]. However, it is not that the system is refractory to stimulation as we have been able to demonstrate a significant corticosterone response to acute injection of the immune modulator LPS [ 8 ]. These data suggest a selective adaptation of the HPA axis where, in response to an acute stressors, there is no further activation of HPA axis.
However, in response to an acute immune stimulus, which in the absence of a suitable glucocorticoid response might prove life threatening [9 ], this inhibition can be over-ridden or an alternative pathway activated to elicit the response. This sustained release of plasma corticosterone demonstrated in response to morphine in the present study is similar to the sustained release noted in response to immune mediators. It remains to be determined if opiates activate similar systems to LPS or indeed if endogenous opiates mediate the activation of the HPA axis evoked by acute immune activation.
Centrally administered morphine has previously been shown to reduce acute paw oedema following carageenin injection [ 10 ]. In AA repeated subcutaneous injections of morphine, but not infusion of morphine, has been reported to attenuate inflammation [ 11 ]. These effects were antagonized by naloxone suggesting a receptor mediated mechanism. Our own findings extend these previous observations to suggest that a possible mechanisms underlying the reported anti-inflammatory effects of central morphine may be due to an activation of HPA axis resulting in the release of anti-inflammatory glucocorticoids. In contrast to these findings, one group has reported a proinflammatory effect of morphine in AA following subcutaneous infusion [ 12 ]. This discrepancy is intriguing, as is the observation that centrally-injected, high dose naloxone is also anti-inflammatory [ 13 ].
A possible explanation of these data concerns the mode of administration of morphine. The central or peripheral injection of a bolus of morphine may have been sufficient to reach the threshold limit, activate the HPA axis and hence exert a potent anti-inflammatory effect. In contrast, a slow infusion of the same amount of morphine may not have reached the necessary threshold. The reported proinflammatory actions of morphine are intriguing and may reflect the previously reported dose-dependent, biphasic effects of the opiates on immune function
[ 4 ,13 ].
The similarities between our observations of the sustained increase in plasma corticosterone following central injection of morphine, and those reported following acute injection of immune modulators such as LPS, suggest that similar activation of HPA axis and the role of central opiate activation in mediating acute immune activation of HPA axis and the role of endogenous opiates in the chronic immune stimulated model of AA requires further experimentation.
* ^ Barbara Zubelewicz MD., PhD is a scholar of the Foundation for Polish Science and this work is a part of her postdoctoral thesis.
References.
Paradoxical response of hypothalamic CRF mRNA and CRF-41 peptide and adenophyseal POMC mRNA during chronic inflammatory stress. Endocrinol 1992,130:1394-1400
Legends.
Fig.1 Plasma corticosterone levels before (basal) and 2 hours following morphine (4 m g, icv) administration. Values represent mean ± SEM. ** p< 0.001 CT/SAL vs CT/MF and AA/SAL vs AA/MF.
Transient increase of plasma Interleukin-6 after infusion of recombinant Tumour Necrosis Factor a in advanced cancer patients.
Zubelewicz B., Romanowski W., Braczkowska B.*, Lissoni P.^, Braczkowski R.
Department of Internal Medicine, Silesian Medical Univeristy Bytom, Poland
*Department of Epidemiology and Hygiene, Silesian Medical University Katowice, Poland
^ Division of Radiation Oncology, Ospedale San Gerardo Monza, Italy
To whom correspondence should be addressed: Barbara Zubelewicz
5th Department of Internal Medicine Silesian University School of Medicine
Zeromskiego str.7 41-902 Bytom, Poland
fax/tel 00 48 32 81 21 22
fax 00 48 32 2837483
This paper has already been published in
Journal of Experimental and Clinical Cancer Research 1998,17;4,449-452
Shortened title: Tumor Necrosis Factor a influence on Interleukin-6 .
Key words: advanced cancer, Interleukin-6, Tumour Necrosis Factor a
Summary.
Tumour Necrosis Factor a administered in a therapy of an advanced cancer influences certain hormones and cytokines secretion. In turn, these also modulate the biological activity of Tumour Necrosis Factor a . It has been shown in several studies that the cytokine Interleukin -6 (IL)-6 is produced in response to various hormones and other cytokines eg. Tumour Necrosis Factor ( TNF a ). In our study we focused on the Interleukin-6 (IL-6) secretion in response to TNF a administration in 12 patients undergoing TNF a biotherapy due to advanced neoplastic disease. Plasma IL-6 was estimated prior and at various time points ( 2,3,5 and 12 hours) after TNF a intravenous infusion. IL-6 level was estimated with ELISA method.
In conclusion, we suggest the stimulating influence of hrec TNF a administered as therapy of advanced cancer on IL-6 secretion.
Introduction.
Interleukin-6 ( IL)-6 is a potent immunomodulatory cytokine that may have pathogenic significances in several diseases. IL-6 is produced in a variety of tissue of immune and non immune origin and has a multitude of immunoregulatory actions (1). IL-6 can be found in blood in complexes of molecular weight 25-35, 150-200 and 400-500 kDa in association with its binding proteins (2). Increased production of IL-6 is associated with disturbances of homeostasis, such as trauma (3), sepsis (4) and inflammatory diseases (5). Additionally, endotoxemia and tissue injury are also known as reasons of an increase of IL-6 production (4).High levels of circulating IL-6 have also been described in neoplastic diseases and it has been suggested that this elevation could be associated with a poor prognosis of cancer (2,5,6).On the basis of in vitro studies it has been suggested that IL-6-m-RNA can be induced in response to Tumour Necrosis Factor a (7,8). In that case, the levels of IL-6 have been described as correlated with those of hrec TNF a , implying that either both are released as a result of a common stimuli or that circulating IL-6 is produced in response to endogenous TNF a elevation. On the basis of in vitro studies Fong et al. suggested that administration of TNF a antibodies could prevent subsequent IL-6 elevation.
Tumour Necrosis Factor a immunotherapy represent one of the possible biotherapies in human neoplasms(9,10,11). The anti- neoplastic action of TNF a is mainly dependent on cytotoxic action against tumour cells (9,11,12). The major source of TNF are macrophages/monocytes, T cells, B cells and NK cells. TNF a itself exerts a wide variety of biological effects, including the modulation of neutrophils (6,19), lymphocytes (6,15) and endothelial cell function (8) and the possible influence on certain hormones and cytokines secretion (9).Although our understanding of the consequences of hrec TNF a administration has increased, the mechanism responsible for response or non response in individual patients remain unclear. Described up today results are based mainly on in vitro studies and in vivo, during chronic inflammation, but here is not many known about the influence of hrec TNF a administration on several cytokines in that number IL-6 secretion in patients with advanced neoplastic disease.
In our study we focused on the influence of hrec TNF a administration on IL-6 serum levels in an advanced cancer patients.
Patients and methods.
The study included 12 locally advanced or metastatic solid tumour patients (M/F:12/9 median age: 57 years, range 38-65 ) in similar clinical status for whom no other standard therapy was available. All patients had been previously treated with chemotherapy. The experimental protocol was explained to all patients and written consent was obtained. Tumour histotypes were as follows: colorectal adenocarcinoma-6, pancreatic adenocarcinoma-4, gastric adenocarcinoma-2.
Distant organ metastases were present in 8 patients, whilst 4 had a locally advanced disease; the dominant metastatic sites were as follows: liver-5, lung-2, brain-1.
Treatment protocol.
Human recombinant TNF a was supplied by Institute of Molecular Biology and Microbiology Polish Academy of Science-Lodz Poland. The hrec TNF a was a lyophilised powder containing less than 1 ng per mg of protein with the specific activity of 2x105 units x mg -1 was reconstituted using sterile phosphate buffered saline (PBS) and stored at 4 0 C.TNF a was administered in the morning by a 20 minute intravenous infusion at a dose of 75 m g/day for 5 consecutive days corresponding to one cycle. In the absence of progression ,two further cycles of TNF a administration occurred at 14 day intervals during which the dose was increased by 50 m g/day i.e. 2nd cycle (5 days)-100 m g/day, 3rd cycle (5 days)-150 m g/day. All patients in the study were treated at the Department of Internal Medicine, Silesian Medical University in Bytom, Poland or at San Gerardo Hospital in Monza ( Ital;y ) and all administration occurred at the respective hospitals. Patients were considered in the study, when they received at least one therapy with hrec TNF a . No serious side effects were observed, although fatigue, chills, rigor, rush and/or hypotension was observed in 9 patients. The remaining 3 patients received100 mg hydrocortisone (HCT) iv. during TNF a infusion in order to reduce immediate side effects ( chills, fever ).
Blood samples for IL-6 estimation were obtained immediately prior to therapy and at various time points i.e.1,2,3,5 and 12 hours afterwards. Peripheral blood was taken into endotoxin free heparinized tubes. The blood was centrifuged at 600g for 5 min and separated plasma was stored at -20 0 C until assayed. IL-6 was assayed with an ELISA method ( R&D System) with a sensitivity of 10 ng/l.
The statistical analysis was based upon measurements which were evaluated at 1 time point; to the first intravenous infusion and at 5 time points after infusion. Serum levels of IL-6 were additionally evaluated in 10 healthy controls. Independently, the value of erythrocytes, leukocytes, neutrophils and plateles as well as lymphocyte total number and lymphocyte subtypes have been evaluated.
Results.
The toxicity of TNF a was mild in all patients. All of them showed fever greater than 38 0 C which was associated with chills, rigor and fatigue. However, in 9 patients all symptoms disappeared within a few hours of TNF a infusion. The 3 patients that received HCT infusion during TNF a administration were excluded from the study as treatment with steroids is associated with decrease or/and normalisation of IL-6 level (7). An objective clinical response to hrec TNF a after 3 cycles of biotherapy was noted in 5 (41%) of the patients evaluated. Partial response was observed in 3 (25% ) patients, stable disease in 2 (17%) patients and 2 (17%) progressed during the time of observation.
As far as changes in blood cell mean number were concerned, erythrocytes, leukocytes, neutrophils and platelets decreased after TNF a infusion but in not significant manner with respect to these values observed before TNF a treatment. Total lymphocyte number does not present any significant changes in total number. Regarding lymphocyte subtypes a slight increase has been observed as far as T lymphocyte subsets are concerned.
Mean serum levels of IL-6 in patients with cancer before hrec TNF a administration were 70,75 ng/l ( minimum 57,3, maximum-84,2 ng/) in 9 patients and in normal controls were 0,5 ng/l (minimum 0, maximum 2,1 ng/l) .The hrec TNF a intravenous infusion caused an increase in IL-6 levels (Table 1). Mean serum IL-6 levels after hrec TNF a were 100,48 ng/l (minimum- 58,7 ng/l , maximum 237,9 ng/l) .The maximum level of IL-6 was observed 3 hours after infusion-234,3 ng/l, at 5 hours after the infusion the IL-6 serum levels were still significantly higher then prior the therapy, but generally lower then at 3 hours after and then slightly decreased reaching the level of 51.8 ng/l at 12 hours after infusion, a value which is similar to pre-treatment values (Figure 1). In the 3 cases in which patients received HCT injection, the levels of plasma IL-6 after hrec TNF a infusion tended to be lower ( mean 22 ng/l; range 20-25 ng/l, although the numbers in each case are too small for this data to be regarded as significant. This total recurrence of the dynamism effect shows clear significance. Considering the natural disordered oscillations ( the influence of different accidental factors ) there can be seen the natural fluctuations of IL-6 level. The is a probability, that even without the TNF a influence it will be observed the elevation and decline of IL-6 concentration. This probability equals 0,5 for single patient. Concluding, the probability that observed elevations in IL-6 concentration are accidental is very low i.e.0,5
We did not observe any correlation between IL-6 level and clinical response for hrec TNF a therapy.
Discussion.
Neoplastic disease itself has been proposed to increase IL-6 production (18) . In our study, administration of hrec TNF a , which is one of the possible treatment of advanced cancer, up -modulates already increased ( by the disease itself) IL-6 secretion. IL-6 levels were significantly higher in these patients when compare with corresponding IL-6 level before TNF a infusion. IL-6 reached a maximum at 3 hours after the TNFa administration. It is compatible with the observation that TNF a stimulates IL-6 output in patients with chronic hepatitis. This effect has been described by Sheron et al, but the conclusion was drawn on the group of 5 patients Furthermore, the plasma IL-6 level was detected at 20 min, 2 and finally, 3 hours after the hrec TNF a administration without any information about IL-6 response later then 3 hours . We widen previous observation with the data at 12 hours after the infusion, when we observed the return of IL-6 level to pre treatment values. In our observation levels of IL-6 after TNF a administration are considerably lower than
these, described by Wong et al. and based on group of patients with different diseases proceeded with elevation of endogenous TNFa ( e.g. meningoccoceal septic shock). In this case, the possible explanation of the discrepancy is ,that bacterial toxins may alter directly IL-6 production .Wong et al described also another additional factors which can potentially induce IL-6 secretion, in that number IL-1 (1) .The present study suggest also, that TNF a biotherapy is not associated with an increase in number of circulating lymphocytes, which could be explained with an inhibitory effect of TNF a on the progenitors of the hemolymphoietic cells (19)
We hypothesise that TNF a could have stimulating effect on IL-6 secretion probably by direct activation of the IL-6 receptors and/or indirectly by modulating other cytokines ( e.g. IL-2 ) secretion, which consequently stimulate IL-6 release. It is also possible that both of above mentioned mechanisms could be acting simultaneously to result in the observed effect . Described by us elevation of IL-6 level correspond with TNF a increase, described by Fong et al, when described administration of anti-TNF a antibody inhibited IL-6 elevation. From the other hand, as we mentioned in introduction, high level of IL-6 could be bad prognostic factor. It is very difficult to finally conclude, if high level of IL-6 after hrec TNF a administration is one of the post TNF a treatment complications or post-treatment advantages.
Although the single cancer immunotherapy after a period of exhalation has been given up today, the knowledge about reciprocal interactions between cytokines could help in final explanation of their biological action and clinical efficacy.
References.
1. Wong G.W., Clark S.C.: Multiple effects of interleukin-6 within
the cytokine network. Immunol Today 1988,9,37-39
gland in the control of macrophage function and its possible implication in cancer: a
study of interaction between TNF a and hormone melatonin. J Biol Reg Homeost Ag
1994,7-9,8,4,126-129
14 .Braczkowski R., Zubelewicz B., Romanowski W., Lissoni P., Barni S.: Modulation of
TNF a toxicity by the pineal hormone melatonin in metastatic solid tumours patients .
Ann NY Ac Sc 1995,768,334-336
Rosenberg S.A.: IL-6, IFN b as a circulating hormone induction by cytokine
administration in humans. J Immunol 1989,142,1542-1545
16. Sheron N., Lau J.N., Hofmann J., Wiliams R., AlexanderG.J.M..: Dose dependent
increase in plasma IL-6 after recombinant Tumour Necrosis Factor infusion in
humans. J Clin Exp Immunol 1990,127,4,1770-1785
17. Charnay P., Maniatis T. Transcriptional regulation of globin gene expression in
human erythroid cell line K 562.Science 1983,220,1281-1285
18. Boyano MD., Garcia-Vazquez MD., Gardeazabal J.et al. Serum soluble IL-2
receptor and IL-6 levels in patients with melanoma. Oncology 1997,9-10;54(5):400-6
19. Schwarzmeier J.D.:The role of cytokines in haematopoiesis. Eur J Haematol
1996,57,S60,69-74
20.Tempfer C., Zeisler H., Sliutz G., Haeusler G., Hanzal E., Kainz C.: Serum evaluation of IL-6 in ovarian cancer patients. Gynecol Oncol 1997,7,66(1):27-30
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