A Bipolar Theory of Living Processes

The contrasting results in the two series are shown in Table 19. II. Calomel. To each of three rabbits 2 се. per kgm. of a 0.5 per cent solution of calomel in sodium thiosulphate was given hypodermically. The animals were killed 24 to 30 hours later. Each showed marked diuresis and diarrhea, with some salivation (Table 20 a). A 111. Сајјет. (а) To each of 5 rabbits 4 се. per kgm. of a 1 per cent solution of caffein was given intravenously. Each showed extreme toxic effects and died within 10 to 15 minutes.

(b) To each of four rabbits 1 to 2 ce. per kgm. of the 1 per cent caffein solution was given hypodermically in two successive doses about 10 minutes apart, the interval being determined by the ‘clinical effects. These showed less marked but positive clinical effects terminating in milder convulsions. The animals were killed when the convulsions appeared. (c) To each of five rabbits two or three doses as in the last preceding series were given and the animals kept until the following day, when a final dose was given and the animal killed during the resultant convulsion.

The average effects of the caffein upon the electrical conductivity of the animals in each of these groups is shown in Table 20 b. IV. Sodium bromid. Twelve rabbits were divided into 5 groups and given sodium bromid (3 gm. per kgm.) through a stomach tube in single or repeated doses, as follows: Group 2, 3 rabbits, 2 doses—1 hour apart—killed 1 hour after last dose. Group 4, 2 rabbits, 1 dose on each of two successive days—killed 1 hour after second dose.

Group 5, 2 rabbits, 1 dose on each of 4 successive days—killed 1 hour after last dose. The average effects upon the electric conductivity of the brains of the animals in each group are shown in Table 20 с. V. Cocaine. (a) То each of 4 rabbits 1.2 се. per kgm. of a 5 per cent solution of cocain was injected intravenously. The injection was followed by a mild convulsion followed by complete relaxation. Тһе animals were killed in from one-half to threequarters of an hour after the dose was given.

(b) То each of two rabbits 2 cc. рег kgm. of a 5 per cent solution of cocain was injected intramuscularly, and the animals killed one hour later (Table 20 d). LOGICAL HUMAN TISSUES. In view of the finding of Loeb, Lillie, McClendon and other physical chemists that the permeability of the ovum is increased by fertilization, and the indication of their researches and our own that any alteration in function of the cells is attended by an alteration in their electric conductivity, one would infer that the electric conductivity of tissues in which the cells are in as active a state as in cancerous tissue would be higher than the electric conductivity of normal tissue. We therefore included in our research measurements of the electric conductivity ‚ of malignant and benign tumors and of various precancerous conditions.

In this study we have measured 219 sections from 159 clinical cases. These have included malignant and benign tumors of the breast and of the uterus, ulcer and carcinoma of the stomach, carcinoma of the rectum, malignant and benign tumors of the mouth, jaws, and neck, x-ray burns and various types of goiters—hyperplasia, fetal adenoma, multiple adenoma, toxic adenoma, exophthalmie goiter, simple colloid goiter, thyroiditis. Whenever possible adjacent normal tissue has been measured for comparison. The pathological diagnosis and differentiation of different types of tissue in single specimens were made by the pathologist of the surgical section at Lakeside Hospital.

Among the goiters the highest conductivities were found among the adenomata. Variations in conductivity are well illustrated by the following measurements of a goiter, one portion of which was malignant. Three specimens from this gland gave the following measurements: colloid portion, 0.00124; early degeneration, 0.00159 ; rapidly growing portion, 0.00346. The highest conductivities were found in the degenerating adenomata and the malignant thyroids; the conductivities of the hyperplastic thyroids were lower; and the conductivities of the colloid goiters were the lowest of any of the pathological tissues studied.

In all instances in which comparative measurements were made the conductivity of the malignant growth was higher than that of a normal portion of the same organ, as is illustrated by the following examples: In the light of these comparisons the following measurements of the conductivities of x-ray burns and of the adjacent normal tissues are significant. The outer growing parts of cancers showed a high conductivity in contrast with the conductivity of the central non-growing parts.

Carcinoma of the thyroid: Center ок отоор аа Бозе 0.00101 пета Рот ELAS E ын E зыр EET 0.00528 Carcinoma of the uterus: 1. In an attempt to determine the specific electric conductivity of various normal animal tissues and whether or not variations in function are accompanied by measurable changes in their electric conductivity, 4,764 sections from 455 rabbits and 219 sections of pathological human tissues have been measured. 2. The specific normal conductivity of the cerebrum, cerebellum and liver can be estimated within a narrow range; while the nor-

mal conductivity of other tissues can be estimated within a sufficiently narrow range to determine the order of their relative conductivities. 3. The spinal fluid has the highest conductivity of any of the tissues studied, the lung and the liver the lowest. 4, The order of the conductivities of the following tissues was unchanged in all the animals studied with the exception noted in (6); viz., spinal fluid, bile, blood, voluntary muscle, cerebrum, cerebellum, liver, lung. In a limited number of observations the conductivity of the heart fell between that of the cerebellum and the liver, but on account of the wide range of the individual measurements, this cannot be considered as established.

5. The conductivity of normal tissues appears to vary according to the season and the general environment. 6. In every normal adult animal studied the conductivity of the cerebrum was higher than the conductivity of the cerebellum. In fetuses and in very young rabbits this relation was reversed—the conductivity of the cerebellum being higher than the conductivity of the cerebrum until about the time when the young rabbit left the nest and began voluntary activities, when the normal adult conductivity relation of the cerebrum and the cerebellum appeared to be established. A most significant corollary to this observation was found in the post-mortem examination of the brains of two patients, one of whom died after days of unconsciousness resulting from a brain tumor, while the other who died from carcinoma of the stomach, was conscious to the end. In the patient who had been unconscious, the conductivity of the cerebellum was higher than that of the cerebrum. In the other patient, as in all our normal animals, the conductivity of the cerebrum was higher than that of the cerebellum.

7. The conductivity of the gray matter of the brain is higher than that of the white matter. 8. Exhaustion from any cause—-surgical shock, insomnia, emotion (fright), infection, еёс.—1ѕ marked by a diminished conductivity of the brain and an increased conductivity of the liver. 9. The immediate effect of activation appears to be an increased conductivity of the brain, tending later to decrease as the stage of exhanstion approaches. This has been shown to be an immediate effect of physical injury; an early effect of the injection of diphtheria toxin; an immediate effect of the injection of adrenalin.

10. Thyroid feeding in large doses over a prolonged period produces the typical symptoms of hyperthyroidism with ultimate exhaustion accompanied by the changes in the conductivity of the brain typical of exhaustion from any other cause; 1.е., the conductivity of the cerebrum and cerebellum is decreased. 11. Thyroid feeding in moderate doses until the symptoms of hyperthyroidism appear but not to the stage of exhaustion produces conductivity changes in the brain typical of the stage of stimulation produced by other agents; i.e., increased conductivity of the brain and decreased conductivity of the liver. These changes were diminished or reversed by the administration of adrenalin.

12. lodoform increases the conductivity of the brain and of the liver. These changes are reversed by adrenalin. 13. The injection of hydrochloric acid produced diminished conductivity of the cerebellum and cerebrum and increased conductivity of the liver. The injection of sodium bicarbonate produced increased conductivity of the cerebellum and cerebrum and decreased conductivity of the liver. 14. Rabbits were kept awake continuously for 96 hours. At the end of this period a number were killed and conductivity measurements made; others were allowed a brief period of rest of from four days to a week. At the end of the insomnia period the conductivity of the brain was decreased and the conductivity of the liver was increased; at the end of the short period of rest, the conductivity of the brain and of the liver was but little changed, if at all; at the end of the longer periods of rest, the brain was again approaching its normal conductivity.

15. A limited number of observations indicate that the changes produced by infection are minimized provided the infection is applied in the presence of morphin: that is, excessive infection alone decreases the conductivity of the brain and increases the conductivity of the liver; in this limited series of observations the conductivity of the brain remained practically unchanged when diphtheria toxin was administered in a morphinized animal, and the conductivity of the liver was but slightly altered.

16. A limited series of observations of the influence upon the electric conductivity of the brains of animals of various agents, which produce marked clinical effects, indicate that the progress of alteration in function produced by any agent is coincident with changes in electric conductivity. 17. In the pathological specimens studied, active malignant growths had a high conductivity in comparison with adjacent normal tissue and the inactive portions of the same growth, and with growths of a non-malignant type.

1. Influences which affect the general physical condition of the organism produce changes in electric conductivity in the dominating reactive tissues, these changes being uniformly and measurably manifested in the brain and the liver. Apparently these changes in conductivity appear more promptly than any gross clinical alteration. 2. Apparently the liver is more promptly and more markedly affected than any other tissue, as animals showing either no or very slight changes in the cerebrum and cerebellum will often show a marked alteration in the conductivity of the liver. On account of the wide variation in liver measurements and the apparent susceptibility of this organ to seasonal and environmental changes, the effects of applied agents are best determined by measurements of the cerebrum and cerebellum.

3. A study of the individual measurements from which the averages have been computed seems to indicate that the variations represent slightly different stages in a process that varies in rate in different animals and in the different organs of the same animal. 4. In view of the above indication and the direct evidence of the measurements we feel justified in the assumption that the first effect of stimulation within the organism is a slight decrease of the conductivity of the liver followed by a rapid continuous rise to above the normal as the state of exhaustion approaches; a slight and prompt increase in the conductivity of the cerebellum followed by a gradual continuous fall; a relatively slower increase in the conductivity of the cerebrum followed by a gradual continuous decrease.

5. These studies indicate that electric conductivity measurements provide a means whereby to further the interpretation of the normal operation of the organism, and whereby to measure the progress of pathological processes within the various organs and tissues. 6. From our findings to date, it would appear that the intracellular changes in exhaustion and shock which are revealed by the microscope are paralleled by alterations in electric conductivity, and that both the histologic and the electric changes bear a direct relation to the vitality of the organ.

. LOEB. Journ. Biol. Chem., 1916, xxviii, 175; The Organism as a Whole from a Physico-chemical Viewpoint, New York, By GEORGE W. CRILE, HELEN В. HOSMER AND Amy Е. ROWLAND From the American Journal of Physiology, Vol. 62, No. 2, October, 1922 In previous publications? we have demonstrated that the intracellular changes in excitation and exhaustion which in certain organs and tissues—notably the brain—are revealed by the microscope, are manifested also by alterations in electrical conductivity.

Histologie studies and measurements of electrical conductivity must be prosecuted after the death of the animal, although, as noted in a preceding report,” with proper precautions it is reasonable to believe that the changes noted at least parallel the progress of processes in the living animal. However, to determine finally whether or not the variations in the histologic picture and in the electric conductivity are parts of one and the same process as that manifested by changes in functional activity, it was necessary to devise some method by which the functional changes in the cells might be measured in the living animal. Only by such a measure could it be ascertained whether or not changes in electric conductivity indicate changes in functional activity. Clinical evidence would appear to demonstrate that this is the case, but clinical evidence cannot be accurately measured, nor does it identify without question the organs which are principally concerned. Some accurate index that could be applied to the organ itself in the living animal was essential.

Variations in functional activity indicate variations in oxidation; variations in oxidation are manifested by variations in heat production. If heat is a constant product of functional activity, then, if we could measure the progressive changes in the temperature of the various tissues and organs during the various phases of excitation and exhaustion under conditions identical with those formerly studied, we not only should be able to check our findings in the previous researches but should be able finally to link those findings with the clinical evidence.

As the first means to this end we decided to use the method of measurement employed by physicists for the measurement of minute temperature variations, that is, to employ thermocouples so constructed that they could be applied to the brain, liver, muscle or other tissue of the living animal. This method of measuring variations in the temperature of living tissues was first utilized, as far as we have been able to discover, by Becquerel and Breschet? in 1835, when they used thermocouples to determine variations in temperature in different parts of the body in different pathological conditions. They inserted thermocouples into various muscles of the arm, the thigh and the leg, into the abdomen and into different portions of tumorous growths. They even inserted the couples into the auricles of the heart to determine the difference between the temperature of arterial and venous blood. Their reasons for undertaking this research are significant. In their Premier Memoire sur la Chaleur Animale, they state in brief that this research was suggested as the result of certain other attempts to answer the following questions: “Ате the vital forces of an electrical or chemical nature? Has the organism its own peculiar mode of action ?”

In 1869 and 1870 Schiff* published the results of an extensive research undertaken in the hope of answering the following questions: Is the stimulation of the nerves of sensation necessarily transmitted to the cerebral hemispheres, or is the direct transmission of the stimulation in the normal animal arrested at the spine or in the pons Varoli? Furthermore, is the transmission to the brain in ас- cordance with the fundamental laws governing transmission along the nerves? Is the formation of a perception in the brain accompanied by phenomena which the means of investigation at our command will not permit us to regard as subject to the general laws of material movement?

In Schiff’s research thermocouples were employed which were applied directly to exposed nerves or inserted into different parts of the brain. The author felt that he had established the following points: 1. That the irritation of the nerve increased its temperature. 2. That successive irritations produced diminished response of the nerve. 3. That every peripheral irritation gave a response in the brain manifested by increased temperature. 4, That the temperature was always higher in the right hemisphere of the cerebrum.

6. That no response to peripheral irritation was noted in the brains of animals under morphin. “These preparations (of opium) especially of morphin do not permit any manifestation to an appreciable degree of the effect of sensory irritation on the temperature of the brain.” 7. That not only tactile sensation but stimulation of all the organs of special sense produced an increase in the temperature of the cerebrum. 8. That repeated excitation of the special senses—sight, hearing —produced progressively lessening effects as manifested by temperature changes in the brain. “It is seen, consequently, that this last series of experiments is perhaps the most important for our conclusions.”

9. That psychic excitation, independent of the sensations which produced it, was accompanied by a production of heat in the nerve centers, which was quantitatively greater than the heat engendered by less complex sensations. The author believed that his observations definitely excluded the possibility that the temperature changes noted were due to circulatory changes; and that his experiments were sufficient “фо establish, with all the desirable precision, that the production of heat which we have observed is really the result of excitation which is peculiar to and an intrinsic part of the nerve elements.”

In 1868 Rosetti (5) recorded an attempt to construct thermocouples for the measurement of body temperature and reported one practical application. Also in 1868, Lombard (6) described a thermopile devised by him for the study of external temperature changes. In particular he studied the relation of heat to mental work as manifested by temperature changes of the outside of the head, which he believed could be referred to changes in the temperature of the brain. Albutt (7) in 1875 employed similar apparatus to that of Lombard in an attempt to discover the relation between internal and external heat.

From that time the literature records the occasional use of thermo-electric apparatus for the measurement of changes in bodily heat, but no especially noteworthy researches are recorded until within recent years. A bibliography of these intermediate studies is offered by Benedict and Snell (8) in their description of a resistance thermometer devised by them for the observation of variations in the rectal temperature of subjects in a calorimeter chamber.

In 1909 Gamgee (9) devised a clinical apparatus in which thermocouples were employed for the continued measurement and registration of diurnal variations in temperature, and following his lead, Sims, Woodhead and Varrier-Jones (10) produced a thermo-electrie apparatus which could be used consecutively for 24 hours or more without disturbing the patient. In 1911, A. V. Hill (11) utilized the thermo-electric method in an investigation to determine the presence or absence of temperature changes during the transmission of a nervous impulse. Не concludes that