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in severe cases there is daily fever。 In fact； in Graves' disease we find displayed to an extraordinary degree an exaggeration of the whole action of the kinetic mechanism。
We have stated that in acute Graves' disease there is a tendency to the production of spontaneous fever； and that there is a magnified diurnal variation in temperature which is due to an increased output of energy in even the normal reaction producing consciousness。 In Graves' disease there is； therefore； a state of intensified consciousness； which is associated with low brain thresholds to all stimuliboth to stimuli that cause muscular action and to stimuli that cause fever。 The intensity of the kinetic discharge is seen in the constant fine tremor。 It is evident that the thresholds of the brain have been sensitized。 In this hypersensitization we find the following strong evidence as to the identity of the various mechanisms for the production of fever。 In the state of superlative sensitization which is seen in Graves' disease we find that the stimuli that produce muscular movement； the stimuli that produce emotional phenomena； and the stimuli that produce fever are as nearly as can be ascertained equally effective。 Clinical evidence regarding this point is abundant； for in patients with Graves' disease we find that the three types of conversion of energy resulting from emotional stimulation； from infection stimulation； and from nociceptor stimulation （pain）； are； as nearly as can be judged； equally exaggerated。 In the acute cases of Graves' disease the explosive conversion of latent energy into heat and motion is unexcelled by any other known normal or pathologic phenomenon。 Excessive thyroid secretion； as in thyrotoxicosis from functioning adenomata； and excessive thyroid feeding； cause all the phenomena of Graves' disease except the exophthalmos and the emotional facies （Figs。 15 and 23）。 The ligation of arteries； the division of its nerve supply； or the excision of part of the gland； may reverse the foregoing picture and restore the normal condition。 The patient notes the effect on the second day and often within a week is relatively quiescent。 On the contrary； if there is thyroid deficiency there results the opposite state； a reptilian sluggishness。
At will； then； through diminished； normal； or excessive administration of thyroid secretion； we may produce an adynamic； a normal； or an excessively dynamic state。 By the thyroid influence； the brain thresholds are lowered and life becomes exquisite； without its influence the brain becomes a globe of relatively inert substance。 Excessive doses of iodin alone cause most of the symptoms of Graves' disease。 As we have stated； the active constituent of the thyroid is iodin in a special protein combination which is stored in the colloidal spaces。 Hence one would not expect to find changes in the cells of the thyroid gland as a result of increased activity unless it be prolonged。
We have thus far considered the normal roles played by the brain； the adrenals the liver； the muscles； and the thyroid in transforming latent into kinetic energy in the form of heat and motion as an adaptive response to environmental stimuli。
The argument may be strengthened； however； by the discussion of the effect of the impairment of any of these links in the kinetic chain upon the conversion of latent into kinetic energy。
Effect Upon the Output of Energy of Impaired or Lost Function of Each of the Several Links in the Kinetic Chain
（1） _The Brain_。In cerebral softening we may find all the organs of the body comparatively healthy excepting the brain。 As the brain is physically impaired it cannot normally stimulate other organs to the conversion of latent energy into heat or into motion； but； on the contrary； in these cases we find feeble muscular and intellectual power。 I believe also that in patients with cerebral softening； infections such as pneumonia show a lower temperature range than in patients whose brains are normal。
（2） _The Adrenals_。In such destructive lesions of the adrenals as Addison's disease one of the cardinal symptoms is a subnormal temperature and impaired muscular power。 Animals upon whom double adrenalectomy has been performed show a striking fall in temperature； muscular weakness；after adrenalectomy the animal may not be able to stand even；and progressive chromatolysis。
（3） _The Liver_。When the function of the liver is impaired by tumors； cirrhosis； or degeneration of the liver itself； then the entire energy of the body is correspondingly diminished。 This diminution of energy is evidenced by muscular and mental weakness； by diminished response and by gradual loss of efficiency which finally reaches the state of asthenia。
（4） _The Muscles_。It has been observed clinically that if the muscles are impaired by long disuse； or by a disease such as myasthenia gravis； then the range of production of both heat and motion is below normal。 This is in agreement with the experimental findings that anesthetics； curare； or any break in the muscle…brain connection causes diminished muscular and heat production。
（5） _The Thyroid_。In myxedema one of the cardinal symptoms is a persistently subnormal temperature and； though prone to infection； subjects of myxedema show but feeble febrile response and readily succumb。 This clinical observation is strikingly confirmed by laboratory observations； normal rabbits subjected to fear showed a rise in temperature of from one to three degrees； while two rabbits whose thyroids had been previously removed and who had then been subjected to fright showed much less febrile response。 Myxedema subjects show a loss of physical and mental energy which is proportional to the lack of thyroid。 Deficiency in any of the organs of the kinetic chain causes alike loss of heat； loss of muscular and emotional action； of mental power； and of the power of combating infectionsthe negative evidence thus strongly supports the positive。 By accumulating all the evidence we believe we are justified in associating the brain； the adrenals； the thyroid； the muscles； and the liver as vital links in the kinetic chain。 Other organs play a role undoubtedly； though a minor one。
Studies in Hydrogen Ion Concentration in Activation of the Kinetic System
Having established the identity of some； at least； of the organs which constitute the kinetic chain； we endeavored to secure still further evidence regarding the energy…transforming function of these organs by making studies of the H…ion concentration of the blood； as one would expect； _prima facie_； that the normal reaction would be altered by kinetic activation。＇*＇
＇*＇ The H…ion observations were made in my laboratory by Dr。 M。 L。 Menten。
H…ion concentration tests were made after the application of the adequate stimuli by which the function of the kinetic organs had been determined； and we studied also the effect upon the acidity of the blood of strychnin convulsions after destruction of the medulla； of deep narcotization with morphin before anesthesia； of deep narcotization with morphin after the H…ion concentration had already been increased by fear； by anger； by exertion； by injury under anesthesia； or by anesthesia alone。
The complete data of these experiments will be later reported in a monograph； here it is sufficient to state that anger； fear； injury； muscular exertion； inhalation anesthesia； strychnin； alcohol； in fact； all the stimuli which we had already found to produce histologic changes in the brain； the adrenals； and the liver…excepting bacterial toxinscaused increased H…ion concentration。 Of striking significance is the fact that morphin alone caused no change in the H…ion concentration； while if administered before the application of a stimulus which by itself produced increased H…ion concentration； the action of that stimulus was neutralized or postponed。 If； however； morphin was administered after increased acidity had been produced by any stimulus； or by inhalation anesthesia； then the time required for the restoration of the normal alkalinity was much prolonged； and in some instances the power of acid neutralization was permanently lost。
After excision of the liver； the normal H…ion concentration was maintained for periods varying from one to several hours； after which the concentration （acidity） began to increase as the vitality of the animal began to decline； the concentration （acidity） increasing rapidly until death。 After excision of the adrenals the blood remained normal for from four to six hours； when the H…ion concentration increased rather suddenly； the increase being synchronous with the incidence of the phenomena which immediately preceded death。
In none of these cases was it determined whether the increased H…ion concentration was due to other causes of death or whether death was due to the increased acidity。
It is also significant that after the application of each of the adequate stimuli which increased the H…ion concentration of the blood in other parts of the body the blood from the adrenal vein showed a slight diminution in acidity； as； in most instances； did the blood from the hepatic vein also。
In fact； the H…ion concentration of the blood in the adrenal vein was less tha