18

phylloporphyrin, save that the absorption bands. are displaced somewhat towards the red end. In composition hematoporphyrin is represented by the formula C1H,,N2O3, while phylloporphyrin is represented by CH18N2O. There exists a differenec, therefore, or two atoms of oxygen. According to recent investigations upon the reduction products of hematoporphyrin and their relationship to the chlorophyl derivatives a markedly characteristic pigment, mesoporphyrin, was obtained, having the formula C1HN,O,, and which stands in a certain measure between hematoporphyrin (C16H18N,O,) and phylloporphyrin (C18H1N2O). Both hematoporphyrin and phylloporphyrin, however, on dry distillation yield pyrrol. A close relationship, therefore, exists between chlorophyl and hemoglobin. This suggests that the two substances are constructed from the same mother-substances, and is of greatest biological importance.

16

Physiologically, chlorophyl and hemoglobin have an entirely different and opposite metabolic function to perform, and in their very general action alone could they be said to work similarly. By this I mean that hemoglobin in the red corpuscles of animals deals with a gas of the atmosphere, and is the agent by means of which the large quantity of oxygen makes its way into the system. Chlorophyl is the agent, in the case of plants, by means of which a different gas of the atmosphere, carbon dioxide, makes its way into the plant organism in large quantity. In this respect alone are they alike, for the circumstances under which these gases are taken into the organisms, and their purposes, are entirely different.

We are all familiar with the function of hemoglobin in the blood as the carrier of oxygen from the lungs to the tissues. Whenever blood, or a solution of hemoglobin, is in any way brought into contact with oxygen, a true chemical compound, oxyhemoglobin, is formed. This oxyhemoblobin is not a very firm compound, and if placed in an atmosphere containing oxygen it is dissociated, giving off free oxygen and leaving behind hemoglobin. By a continuation of the process in the normal body, of combining with oxygen to form a loose chemical compound, which in turn can be dissociated easily when the oxygen pressure is lowered, the tissues. receive their large supply of oxygen. This oxygen is then used in the process of katabolism or destructive metabolism. The hemoglobin acts, physiologically, therefore, as a carrier pure and simple.

Chlorophyl in the plants is in no way connected with respiration, which is also carried on by the plant, with the absorption of oxygen and liberation of carbon dioxide. Its function is that of transforming the kinetic energy of the sun's rays into potential chemical energy, which is the great power so characteristic of the vegetable kingdom. It is connected with th eanabolic or constructive metabolic changes, which construct complex chemical substances possessing a great amount of chemical

energy from simple and completely oxidized inorganic substances, as water and carbon dioxide. This power of chlorophyl seems to be entirely dependent upon the sun for its development and the phenomena of building up carbon compounds. As far as can be ascertained, the carbon dioxide of the air, in the presence of sunlight and chlorophyl, is split up into carbon monoxide and oxygen, the oxygen being thrown out of the plant. The chlorophyl is said not to enter into the reaction at all, but to act merely as a catalytic agent, which serves for the transformation of energy. The life of the plant in general, due to the presence of chlorophyl, is synthetic, a reduction process; that of the animal, due to the presence of hemoglobin, is analytic, an oxidation process. The plant converts kinetic into potential energy; the animal converts the potential energy of its food-stuff-the plant-into kinetic energy. This energy, derived from the sun, through the transformation powers of chlorophyl, makes all life more or less dependent upon the existence of this pigment.

Society Proceedings.

TRANSACTIONS OF THE AMERICAN ASSOCIATION OF CLINICAL RESEARCH. First Meeting Held at Boston, Mass., October 27 and 28, 1909.

SESSION OF OCTOBER 28, 1909.

A Detailed Plan of Procedure for Scientific Clinical Research.

James Krauss, M.D., read the following paper on "A Detailed Plan of Procedure for Scientific Clinical Research:"

"Given the opportunity, what shall be the detailed procedure for scientific clinical research?

"At the outset, we must say that the data for clinical research do not differ from the data for ordinary clinical work, but the data must be observed and recorded with greater minuteness and precision; in fact, with all the minuteness and precision that the clinic and the laboratory can give.

"Every observation and experiment-clinical, physical, chemical, physiological, anatomical, histological, bacteriological, diagnostic, therapeuticmust be noted in writing at the time the observation and the experiment are made and the phenomena must be noted as clearly and distinctly as possible in the order of their appearance.

"The steps here indicated are the same for single or conjoined clinical research. In single work, the data can be accepted only provisionally until they are verified as far as any subsequent verification can go. In conjoined work, every observation and experiment having received instantaneous verification or modification, the records of these data may be confidently subjected to analysis for the discovery of the actual facts and the relationship existing between the facts.

I....

"What data shall such a record show? "First, it shall show the existing condition of the patient: (a) the subjective complaints, the primary source of our information; (b) the general appearance, age, sex, nationality,, weight, occupation, family status, and condition of wife (or husband, as the case may be), and children; (c) all objective evidences of disease-functional and organic, mental, sensory, motor, secretory, thermic, trophic, plastic, neuromuscular, bony, integumentary, ocular, auditory, digestive, respiratory, circulatory, urinary, generative, morphologic, histologic-in short, every macroscopic and microscopic, homologous and heterologous, pathological phenomenon.

"Secondly, the record shall show the previous condition of the patient: (a) the prodromata of the disease; (b) the habits of life-eating, drinking, clothing, housing, bathing, exercise, labor, the vita sexualis, the use of drugs, exposure to wind and weather, travel; (c) the previous diseases of infancy, childhood, puberty and maturity.

"Thirdly, the record shall show the family history: (a) of the parents and near relatives-father, mother, uncles, aunts, brothers, sisters, cousins, nephews, nieces; and (b) of the more distant relatives.

"Fourthly, the record shall show the diagnostic conclusion: (a) as to the pathologic state-defects, deformities, inflammations, degenerations, atrophies, hypertrophies, growths, functional excesses, insufficiencies, perversions, constitutional tendencies; (b) as to the anatomic position-region or organ; (c) as to the etiologic. factor-developmental, traumatic, parasitic, metabolic, toxic.

"Fifthly, the record shall show the therapeutic conclusion: (a) the indications upon which treatment was decided-problematic or fixed, vital or remedial, symptomatic, pathologic, anatomic, etiologic; (b) the method of treatment-expectative, adjustive, curative; (c) the therapeutic applications-hygienic, mechanic, surgical, medicinal; external, internal; technique, dosage, repetition.

"Sixthly, the record shall show the daily condition of the patient-the changes of aggravation, amelioration or other modification, in the order as they have been experienced by the patient and as they have occurred before the eye of the observer. "Seventhly, the record shall show the results: (a) the date of the cessation of the different symptoms; (b) the period of convalescence, if any; (c) the ultimate result-cure, improvement, non-improvement, death.

"Finally, in case of death the record shall give: (a) the phenomena, both mental and bodily, immediately preceding death; (b) the anatomic and histologic changes observed during necropsy.

II.

"From the recorded data, we analyze the actual facts. It is not always easy to discover the true facts contained in observations. Facts are actual occurrences. Observations often are occurrences mixed with preconceived notions. How are these to be separated so that we may be reasonably sure that we are having the actual medical facts?

"We must remember that a fact exists only in

relation to other facts and that every statement of fact involves certain general notions and theories. Thus the facts of medicine cannot be stated except in terms of the conceptions or hypotheses which heretofore have been assumed by medicine.

"For the purpose of clinical analyses, therefore, it is necessary that we apply our knowledge of medicine, not merely the knowledge of present day medicine, but the knowledge of historical medicine. There are those who think that every new discovery invalidates all previous discoveries, that modern medicine invalidates all past medicine; but this is an error, an assumption of the ill-informed. order to be able to recognize a fact, we must know not only something of the subject we analyze but we must know also the possible sources of error, and this requires a knowledge not only of descriptive but of historical medicine.

In

"Observations of a specific character in distinct relationship with other observations of a specific character, corroborated by a conjoined observer, may undoubtedly be accepted as facts.

"First, we analyze the recorded data for the diagnostic facts: the subjective symptoms, the objective signs, the immediate and remote antecedents. The subjective symptoms indicate to a greater degree the pathological process in the flux, the objective signs indicate to a greater degree the anatomical state, and the antecedents indicate the etiological factor.

(a) The subjective symptoms, when facts, appear and reappear with more or less regularity within certain limits, and there ought to be no conflict in the records of conjoined observers in this respect. If the symptoms are specific and specifically stated in the original wording of the patient, not as an answer to leading questions, but as a spontaneous description of a complaint for which relief is sought, and if the symptoms appear and reappear at the same locality, in a given sequence, under characteristic circumstances, there can hardly be a doubt that the symptoms are expressive of subjective facts. When the objective symptoms bear out the subjective symptoms in that both point alike to the same pathological process, there can be no doubt that the subjective symptoms express clinical facts.

(b) The objective signs are naturally clinical facts, and if there is here an apparent conflict between two observers of an identical subject, it may be due (1) to error in observation; (2) to incomplete observation; (3) to difference in statement. Just as the objective sign is the corrective of the subjective symptom, so is the subjective symptom the corrective of the objective sign. Reliance on one clinical element to the exclusion of other clinical elements is not a safe method to reach true conclusions. The reported objective symptoms should harmonize with the recorded subjective symptoms. If they do not harmonize, and the objective signs are clear and distinct, described minutely and comprehensively or brought within ocular demonstration by tests, specimens or photographs, they are to be accepted as clinical facts, even if they do not harmonize with the recorded subjective symptoms. On the other hand, if the objective signs are not distinct and clear, they have either not reached full development, or they have not been observed accu

rately and comprehensively. In two conflicting records on identical observations, that which gives the objective signs clearly and distinctly and in harmony with the subjective signs may be accepted as presenting the facts as against that record which gives the objective signs loosely, incompletely, and in problematic harmony with the subjective symptoms. The signs harmonizing with actual knowledge may, ipso facto, be accepted as facts. However, if there appear to be differences between the signs recorded and the knowledge hitherto possessed of those signs, such differences need not militate against the signs to be taken as facts, for clinical research has nothing to do with such exhibition as took place at the late International Congress at. Washington when delegates seemed more concerned in getting Koch to admit that he was in error than in ascertaining the truth as to the convertibility of bovine into human tubercle bacilli. Objective signs may be clinical facts, even though they may not harmonize with our individual knowledge.

(c) The antecedents are to be recognized as clinical facts, when they are in distinct causal relationship with the subjective symptoms and the objective signs of the disease. We must distinguish between necessary antecedents and accidental antecedents, between the cause and the occasion. This is easier said than done and yet it is not very difficult and certainly not impossible. The objective and subjective symptoms combined will decide whether the antecedents are relevant. Sometimes, however, several diseases may be clinically associated which are pathologically and anatomically distinct, or which are consecutive, one following another. We must distinguish between the cause of a particular symptom or consecutive disease and the cause of a series of symptoms constituting primary disease. There would be no difficulty if we had to deal with single antecedents and single sequents. The single sequent of a single antecedent is always a consequent. But we are dealing usually with several antecedents. To decide which of these antecedents has a causative relationship with the symptoms and signs in question, we must know the effects that these antecedents are capable of producing. If an antecedent is sufficient of itself to produce and will invariably reproduce the disease in question, it is the cause of the disease. If the antecedent, however, cannot produce the disease, but only prepares certain conditions of predisposition for the production of the disease, it is the occasion, not the cause of the disease. If neither cause nor occasion, the antecedent is accidental and of no consequence. We exclude or eliminate from the given antecedents what does not appear to have been concerned in the production of the disease, and thus determine the occasion and the cause that did enter into the production of the disease.

Secondly, we analyze the data for the therapeutic facts the methods pursued and their comparative value. Analysis will disclose that all therapeutic measures, even those empirically applied, rest on certain methods, and the comparative value of these methods naturally rests on the therapeutic indications and results:

(a) The indications for treatment are the diagnostic facts—the subjective symptoms, the objective

signs, the necessary antecedents; and the indications for the selection of particular therapeutic measures are the known effects of the therapeutic applications. The empiricist knows the effects of his remedies from previous experience, personal or other individual experience. The rationalist knows the effects of his remedies from previous experimentation, personal or other experimentation. Both infer their knowledge of the applicability of their remedies to a case in question from previous information, whether this information was accepted as a matter of belief or justified by conclusive proof. For analysis, it will be necessary to determine whether and what physiological justification there was for the use of the remedies in question, and, furthermore, with physiological justification as the basis, what method of procedure is represented in the application. The diagnostic facts give us not only the disease but the route, the course of the disease. The therapeutic facts, the indications taken for treatment, will disclose whether the therapeutic agent was intended to follow the pathological route, break in upon the point, go round about, or merely serve to adjust disarranged physiological elements.

(b) The therapeutic results demonstrate the value of the therapeutic agents in the method of their employment. Doubt has been cast as to whether any therapeutic agent can enter into what is known as cure of a patient. Because a person improves or gets well, it does not follow, we are told, that he improves or gets well because of the treatment. To a certain extent this is true. Recoveries take place under various forms of treatment, under no treatment, under treatment not indicated or even obviously contraindicated. Spontaneous adjustments of disarranged physiological elements continually occur before our eyes. But when such adjustments cannot be expected to take place or cannot be expected to take place as readily without treatment, shall it be said, or can it be said, that that treatment did not bring on the favorable result? Recovery is a biological process and many elements enter into the production of both. There is, at least, one internal element concerned in disease, the human element; and one external element, the disease-producing element. There is, at least, one internal element concerned in recovery from disease, the human element, the physiological organization in a state of reaction or reactibility; and when the natural state of reaction is insufficient, perverted, or in abeyance, there must also be an external element concerned in recovery from disease, an element that can add or impart to organic reaction and reactibility the necessary power for automatic permanency. Can it be said, then, that a therapeutic agent bringing about such a result has not accomplished the cure, but that, nevertheless, the organism has cured itself? The question really is not: Did or did not the patient cure himself? The question is: What cured the patient when the patient evidently could not cure himself? If the natural healing power of the organism, upon which these contentions rest, were altogether sufficient, there would be no disease whatever in the world. Disease would be stifled before it could show itself. In fact, it could never come to the point of disease, for if the healing power is supreme within the organism there could be only health and

no disease. We treat patients in order to make them well. Our object is to cure our patients when they cannot cure themselves, and when they can cure themselves, to put them in such a condition that they do cure themselves. For the purpose of analyzing therapeutic facts it is only necessary to determine (1) what measures were taken for treatment; (2) what measures of treatment were instituted; (3) what is experimentally known of the physiological effect of those measures; (4) whether those measures represented the introduction of a new extraneous element into the body or merely a physio-. logical adjustment of organic elements that had been disarranged. It is evident that where no new extraneous element is introduced into the body, recov ery must depend on the healing power of the organism, improvement on that healing power in a lesser degree, non-improvement and death on the healing insufficiency of the organism; but where a new, extraneous element is introduced into the body, recovery, improvement, non-improvement, death must depend on the sufficiency or the insufficiency of the effects of that element on the organism. On this basis, the validity of therapeutic measures and the relative position of therapeutic methods can be established.

Thirdly, we analyze the diagnostic and therapeutic facts to determine the general facts of medicine. Without general facts, there can be no science, and certainly no growth of science. The science of medicine consists not only of particular, but also of general facts. It is these general facts that give the stamp of rational empiricism as against ordinary loose empiricism, that disclose the availability of therapeutic methods and principles.

(a) We determine the differences and resemblances among the facts, arrange the similar facts in the order of their importance and relevancy, and draw such generalizations as they warrant. When we know the antecedents which must precede certain consequents, we have the basis for a general fact, which expresses with greater or less generality the uniformity of particular occurrences. We thus ascertain the methods and principles of medicine.

(b) We determine the validity of the general facts by the particular facts. If there is an apparent conflict in judgment, we have to find out whether there is any error in the clinical facts; that is, the diagnostic and therapeutic facts, and, if not, then the error must be logical, an error in reasoning. As long as there is agreement as to the particular facts, logical errors are easily avoided or corrected.

III.

While it is desirable to have a uniform plan for pursuing the clinical observations, arranging the records and analyzing the results, it is probable that various observers engaged in clinical research would prefer to pursue their work on plans of their own. It is not for these that the following outline has been made. It has been felt that a uniform plan of procedure is a vital necessity for clinical research. No doubt uniformity of procedure would increase precision in observation and facilitate the comparison and analysis of the records of observations. It is my personal belief, however, that general directions are all that are necessary to be agreed upon, that

the detailed work can be left to the knowledge, the skill, the judgment of the various observers.

Nothing further need be said here on analysis. The detailed method of procedure can refer only to the course of observation and the arrangement of the phenomena of diseases in vivo and post-mortem.

A. GENERAL DIRECTIONS FOR CLINICAL OBSERVATION.

The observation of cases designed for clinical research should begin with noting the symptoms of the patient and then, on the basis of this information, general and specific inquiry should be made, for the purpose of certainty and enlargement of our information, as to (1) the exact character and intensity of the symptoms; (2) their exact locality or changeability of position; (3) the exact order of their occurrence; (4) their physiologic reactions in point of time, position, atmospheric and dietetic conditions, rest and sleep, work and exercise, mental and bodily hardships, etc.; (5) the precise time or date of the commencement, aggravation, amelioration, cessation and recurrence of the symptoms; (6) the supposed cause or causes, and the interval between the supposed cause or causes and the appearance of the first symptom of the disease:

(a) The symptoms should be written down as nearly as possible in the patient's own words and expressions; and, where he fails, we should note what his friends and attendants have to say, without interruption on our part.

(b) Inquiries for amplification and correction should be made by non-leading, general questions as to (1) the symptoms complained of; and (2) as to the condition of those parts and functions of the body that have not entered into the complaint of the patient. This latter part of the inquiry is best done. by proceeding anatomically from the head downwards to the extremities.

(c) A picture of the patient's disease thus having been developed, further inquiry may then be made by leading questions, seeking to determine the real connection of the symptoms with the anatomical source, the antecedents, and the peculiar physiological reactions complained of.

(d) If there be still doubt as to certain symptoms, inquiry may be made by questions implying a contrary sense, and if the contrary is maintained by the patient, his symptoms may be accepted as subjective evidences of disease.

(e) The order of procedure should be to go from local to remote, and from remote to general symp

toms.

Active observation begins as soon as the patient has finished giving his symptoms and a probable diagnosis is developed. We should search for all functional and organic evidences of disease and note every anomaly of form, number, color, size, position, sound and odor, resistance, heat and sensibility, expression and movement:

(a) The objective examination should begin at the external surface, and proceed thence to the internal cavities, fluids and structures, by both clinical and laboratory methods of immediate and mediate inspection, palpation, percussion, auscultation, mensuration and calculation. The subjective symptoms, being expressions of functional derangements, indicate the necessary region for objective examina

tion, but wherever permissible the objective examination should be as complete as possible and extend over the whole body.

(b) Clinical tests apply to the organism as a whole, and should elicit the vital phenomena of heat, of pulse and heart movements, of blood pressure, of breath and breathing, of strength, of sensibility and reflex action, of speech and intellection, and of adventitious pathological alterations involving various organs, and through them the constitution of the whole organism.

(c) Laboratory tests apply to organs, tissues or fluids detached from the organism and should be employed in every case for eliciting the condition. of the urine and the blood, the condition of every fluid secretion or discharge involved in a disease, the condition of every organ and tissue removed from the body in vivo and post mortem.

(d) In clinically undefined diseases, the laboratory by its chemical, pathological, histological and bacteriological methods may clear up the true nature of the affection. On the other hand, the laboratory tests alone are not always sufficient to establish the presence of disease. Bacteriological findings, for instance, are not sufficient in themselves to establish disease. A person may carry bacteria without being diseased. The bacteriological test may be negative and clinical findings may indicate disease. Postinfective conditions can be determined only clinically. The natural course of the pathological processes is the criterion. The laboratory findings must harmonize with the clinical findings. It must be remembered, however, that a negative laboratory finding may indicate only the fact that the thing sought for has not been found and not that the thing is not there. Ordinarily, the laboratory tests should be invoked to give certainty to subjective symptoms. For clinical research, both the clinical and the laboratory tests are indispensable and should be applied exhaustively.

(e) The objective examination should extend to the dead body as well as the living body.

B. ANATOMICAL ARRANGEMENT OF CLINICAL OBSERVATIONS.

An anatomical arrangement of clinical observations must present the subjective symptoms and objective conditions to be observed in the living, and the objective conditions to be observed in the dead, of the particular region or organ, but the arrangement must not be taken to mean more than a method to point out the order in which clinical phenomena. may best be looked for and noted accurately and comprehensively. It is to be remembered that usually more than one anatomical region is involved in disease, and that symptoms and signs overlap. In the following development of clinical observations under anatomical headings, it has been deemed best. to divide the course of observations into four parts: (1) the subjective symptoms or alterations of function; (2) the important antecedents of health and disease, of heredity and environment; (3) the methods of examination; (4) objective signs or organic alterations in vivo and post mortem.

1. THE NEUROMUSCULAR SYSTEM.

A. Symptoms of sensation, intellection, emotion, motion, including sleep and speech.

The

Pain in the head, back, limbs, viscera, along the course of nerves and muscles, in bones and jointscomplained of by word of mouth, cries, or by putting finger or hand to the seat of pain. character of the pain: acute or obtuse, deep or superficial, throbbing or bursting, burning, drawing, pressive, shooting, tearing, lancinating, bruised or aching? or mere soreness and heaviness? intense or tolerable? Locality: constant or changing, wandering in various directions, unilateral or bilateral, symmetric or asymmetric? Duration: continuous, mittent or periodic? Reactions: influenced by pressure, function, light, sound, motion, rest, posture, weather, food, time of day or night? Concomittants: nausea, vomiting, cough, fainting, palpitation of the heart, pulsation of carotids? Antecedents: fall, blow, strain, dietetic imprudence, brain work, excitement, sexual and other excesses,

etc.

Paraesthetic sensations: numbness, weakness, coldness, tingling, burning, glowing, sparkling, creeping, crawling, pricking, itching, etc. Visual, auditory, olfactory, gustatory, tactile disturbances, hallucinations, illusions.

Visceral sensations: anesthesia, hypesthesia, hyperesthesia, hyphedonia, hyperhedonia, sphincteric disturbances, circulatory and respiratory disturb

ances.

Dreaminess, delirium, stupor, somnolence, coma, and other impairments of consciousness.

Disturbed, deficient, protracted sleep. Sleepiness, Sleeplessness. Dreams. Somniloquism. Somnambulism.

Irritability and excitability of temper, Eccentricities. Weeping. Impelling ideas. Fear. Anxiety. Apathy. Aversions. Rage. Passions.

Defective, exaggerated or perverted memory, ideation, and judgment. Delusions. Defective or perverted attention. Stupidity and incapacity. Confusion,

Speechlessness and garrulity. Faulty, disconnected, incoherent speech. Confusion of words. Soliloquism.

Vertigo, spasms, weakness, unsteadiness of gait, and inability to move. Unintentional movements.

As the function of the nervous system is to harmonize all the other functions of the body, it is evident that nervous conditions give rise to the most manifold symptoms of general, visceral and sensory characters, but further elucidation is here not deemed necessary.

B. ANAMNESTIC ANTECEDENTS OF HEREDITY.

Previous nervous diseases, syphilis, acute infectious diseases, blood intoxications, alcoholism, plumbism, tobacco poisoning, trauma, colds, frights,'

etc.

C. COURSE OF EXAMINATION.

External observation of the head and neck: (a) the frontal, parietal, occipital regions, the fontanelles-for pulsations, tumors, depressions, extravasations, solutions of continuity, murmurs, etc.; (b) the eyes and face-for the expression of countenance, change of color, local spasms and palsies; (c) the neck-for pulsation, murmurs, thyroid growths, etc.