partly with the absence of the essential carbohydrate or other food stuff, and partly with the presence of -oxybutyric acid. It is probable that future research will add still others to the class of fatigue substances, especially to those which are accompaniments of disease. Fatigue is one of the most common features of disease, and especially of diseases that are characterized by an upset of the chemical balance of the body. In such cases a considerable increase in the quantity of some intermediate metabolic product may conceivably lead to fatigue phenomena.
A few years ago, in studying experimentally the action of fatigue substances on muscle, I came upon an unexpected result. Fatigue substances in small quantity have a physiological action which is exactly the reverse of that of the same substances in larger quantity—instead of depressing or fatiguing protoplasm, they act so as to augment its activity. In other words, they increase its irritability, so that a given stimulus is capable of eliciting a greater response than it could elicit without the aid of the fatigue substances. Graphic records of the contractions of muscles under the influence of very small quantities of carbon dioxide, lactic acid or other fatigue substances, show how potent this augmenting action may be (Fig. 5). I believe that in this action we have the long-sought explanation of the treppe. In the early stages of muscular work the fatigue substances are present in small quantity, in later stages in large quantity. Correspondingly in the early stages there is augmentation or treppe; in the later stages there is depression or fatigue.
Thus far I have confined myself largely to a consideration of fatigue as exhibited by muscles, where the phenomena are best known and can be studied most accurately. There is every reason to believe, however, that the main principles of muscular fatigue are demonstrable in the other tissues and organs of the body—that in them also fatigue is characterized, physically, by a diminution in working power and, chemically, by both the destruction of energy-yielding substances and the appearance of toxic metabolic products. Diminution of working power is manifested in very different ways by diverse tissues. Glands in fatigue seem to secrete less than when fresh, and it may be that the action of digestive juices is diminished. The kidneys may be deranged, so that their epithelium is unable wholly to prevent the passage of albumin from the blood to the urine. A fatigued heart is dilated, its beats are quickened and may become irregular, and its diastole, or resting period, may become abbreviated. Fatigue often results in an abnormally high bodily temperature, constituting a fatigue fever. The •chemical phenomena of fatigue in the various organs and tissues, apart from the muscles, is almost wholly unstudied, and there is great need of a careful analysis of the entire subject.
The fatigue of the nervous system is of great general interest, yet
