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Vegetables must before eaten be boiled to a mash; salads, legumes, spinach, sorrel, green beans, etc., must be cooked till quite tender.

Fruits should be stewed or baked before being eaten, grapes alone being excepted. In this dietary I allow eggs, on condition that they be soft-boiled or eaten raw. For drinks, beer seems to me preferable to wine in a strictly vegetable regimen.

I shall now finish what I have to say on the subject by briefly alluding to the dietetic treatment of diseases of the intestine. I shall concern myself here only with constipation and diarrhœa, two diseases in which diet has a most happy influence. Let us begin with constipation.

Constipation is often tributary to an appropriate alimentary regimen, and it may in truth be said that to the constipated the diet treatment is worth more than the medicinal.

As a general rule, it will be enough simply to augment the quantity of the fæcal matters if you wish to obtain regular stools, and as the excreta are constituted by the waste products of digestion, and in particular by cellulose which escapes the action of the digestive juices, it is for the most part by giving foods containing cellulose in abundance, such as bran bread, green vegetables, salads, spinach, sorrel, tomatoes, etc., that you can by dietetic means promote alvine evacuations. Recall to mind in this connection the singular remark of Voit, who affirms that by examining the fæcal matters deposited along the roads one may judge of the richness of a country. In places where the peasants eat meat, the fæces are hard; where, on the contrary, the food is of a purely vegetable kind, they are soft, and resemble cow-dung.

To these herbaceous substances, to these green vegetables, you may add certain articles of diet which, in constipation, possess curative properties. Thus, gingerbread eaten in large quantity is very generally laxative; fruits, and especially grapes, have this quality in a high degree. In the grape-cure, diarrhea is one of the effects which is reckoned upon with certainty; melons, oranges, and lemons are used for the same purpose. Baked apples, especially when cooked with molasses, have loosening properties.

of often determining stools by its presence, it also, in more than one instance, was the cause of intestinal occlusion by the accumulation of these seeds in the intestine.

Flaxseed-meal is a good means for overcoming constipation when taken in the way which I prescribe. You macerate a tablespoonful of the ground seeds in a gill of water, steep an hour, and swallow the whole at meal-time. By all these little means you may succeed in maintaining regularity of the stools, though some obstinate cases resist them altogether. I come now to the dietetic treatment of diarrhea.

From a dietetic point of view, we should distinguish abdominal fluxes determined by affections of the small intestine from those due to affections of the large intestine. It is especially with reference to the first that diet renders us important service. It will hardly be disputed that in chronic diarrhœas an appropriate dietary regimen is the sine qua non. This regimen is altogether based on the employment of the four following alimentary substances: milk, raw meat, peptones, and meat-powders.

Milk occupies the first place in the dietetics of abdominal fluxes, and it is by the milk diet rigorously carried out that you will obtain the mastery of these affections. I know, in fact, of but one form of chronic diarrhea that is rebellious to this treatment, as it is in fact to all other treatments. I refer to tuberculous diarrhea. I have said rigorously carried out, for infractions of this exclusive regimen perpetuate the diarrhea instead of curing it, and we often see in our troops who return from the far East the sad consequences of such infractions of the milk diet.

The patient, finding himself a little better, and tired of milk, abandons this regimen, to go back to it again as soon as the disease increases in intensity; the diarrhea is perpetuated, and the patient eventually succumbs. First, then, an exclusive milk diet; then raw meat and meat-powders. I much prefer the meat-powders to the raw meat, but it is necessary to proceed with extreme caution, and proportion the quantities of these azotized aliments to the state of the intestine.

Bazile Ferris preferred the peptones to raw meat and meat-powder, giving them along with the milk diet. You may at times use these peptones with benefit; then you may, little by little, increase the daily fare of your patient, being guided by your knowledge of the digestibility of the articles of food which Just as laxative properties have been ascribed to certain aliments, so, also, others have been regarded as constipating. In this connection I may mention quinces, and substances that contain tannin, such as artichokes. White of egg has also been utilized in these cases. All these means are absolutely secondary, and play a doubtful rôle in the cure of diarrhœa.

But there are two substances which have been especially vaunted in the treatment of constipation,-white mustard-seed and linseedmeal. Didier was the great advocate of white mustard-seed. This laxative agent, which was once very much in vogue, now seems to have gone out of fashion. If it had the advantage | you order.

In the diarrhea of infancy milk is still the remedial agent par excellence (the milk being suited to the age of the infant), and whenever you see in your little patients frequent greenish discharges, be persuaded that this diarrhœa results either from cold or the use of improper food. You well understand that you may augment the constipating properties of the milk by the addition of lime-water, which is very serviceable in such cases.

I shall finish this course of lectures on alimentary therapeutics by a final lecture on diet in fevers.

CRITICAL OBSERVATIONS AND EXPERIMENTAL STUDIES on THE INFLUENCE OF PHARMACOLOGICAL AGENTS ON PERIPHERAL VESSELS.*

I

BY PROF. R. KOBERT.†

PART I.

N the same way that Schmiedeberg and Bunge studied on the excised kidney the formation of hippuric acid, and W. von Schroeders and W. Salomon|| on the excised liver the formation of urea, may we also study the action of pharmacological agents on other organs thus kept artificially in functional activity.

This action may manifest itself in affecting the movements and variations in volume of the respective organ, in increasing or decreasing its secretion if it be a gland, and, finally, in altering the vascular calibre of arteries and veins.

Investigations relating to the movements of excised, or at least as well as possible isolated, organs have been instituted for physiological and pharmacological purposes on the iris of cold- and warm-blooded animals; on the uri

* A brief abstract of the results of this work has appeared in the Tageblatt der Strassburger Naturforscherversammlung (Strassburg, Trübner, 1885), p. 425.

+ Chief of the Pharmacological Laboratory at Dorpat, Russia.

Virchow's Archiv, vol. vi., 1877, p. 233.
Ibid., vol. xv., 1882, p. 387.

|| Ibid., vol. xcvii., 1884, p. 149.

nary bladder and the œsophagus of the frog; on the wing-membrane of the bat; on the external ear of the rabbit; on the heart of reptiles, amphibious animals, and fish; on skeleton-muscles of dogs; and on the intestines, stomach, and uterus of various warmblooded animals. Critically viewed, however, it is clear that the interpretation of phenomena thus observed cannot be otherwise but arbitrary until the technique of keeping an organ alive-in most cases this consists only in conducting a uniform current of adequate blood through the isolated organ-has been sufficiently studied and perfected. And this cannot, of course, be accomplished in a few isolated trials.

In view of the scanty experimental material in existence, I thought it appropriate to institute a more extensive series of experiments on the action of the most well-known pharmacological agents, for the sole purpose of studying the alterations in the velocity of the blood-current. I must remark that sufficiently numerous preceding experiments have demonstrated that my modus operandi of bloodtransfusion insures the vitality of the respective organs for several hours, and procures a uniform sanguineous current.

The first trials with conduction of blood through surviving organs of warm-blooded animals appear to have been made by Alexander Schmidt, under the direction of Ludwig in Leipzig. He conducted, with an approximately equal pressure, the blood of a dog through a dog's kidney placed in a heat-box, in order to study the generation of carbonic acid. These experiments, however, did not produce any results of pharmacological interest. The subsequent labors of P. Heyer,** and particularly of A. Mosso,tt on the other hand, which were likewise executed at the Leipzig Institute, have attained a high degree of perfection and claim our interest. The pharmacological results of these labors refer to nicotine, atropine, carbonic oxide, hydrate of chloral, and cyanide of potassium. Mosso continued, later on, these experiments in Italy, with various modifications; but these publications have never been seen by me.

"The Respiration within the Blood." Second Treatise. Proceedings of the Royal Saxon Society of Sciences of Leipzig; Mathem. Physic. Class, Proceedings of Meeting of November 9, 1867, p. 113.

** Expériences sur la Circulation du Sang dans les Organes isolés. Bruxelles, 1873.

†† "Some New Properties of Vascular Walls." Proceedings of the Royal Saxonian Society of Sciences, ( Leipzig, vol. xxvi., 1874, p. 305.

In 1877, J. Bernstein* advanced the following axiom, which held true also of the pharmacological science: Irritation of the sciatic nerve of a dog's thigh traversed by the blood of a (curarized) dog does not produce vascular contraction any more than during life, but provokes vascular dilatation. As Sadlert and Gaskell, employing the same plan of bloodconduction, did not observe any alterations in the width of the current, Bernstein is inclined to attribute the vascular dilatation observed by him to the vessels of the skin. Later, in

conduction the blood becomes essentially altered and ultimately unfit for use.

These are the most important data which have been recorded in regard to experiments on surviving organs of warm-blooded animals and the influence of pharmacological agents on such organs. The few serviceable experiments instituted with blood-conduction on cold-blooded animals, especially on frogs and turtles, will be referred to below. They are, however, of secondary importance, and are only of value when viewed as experiments

1879, Filehne § made some interesting experi-parallel to those instituted on warm-blooded

animals. The following are the two principal objections which must be urged against these experiments : 1. In no instance was there but a single organ traversed by the blood, but invariably the entire body, excepting the heart; hence it was impossible to tell which organ had caused the increase and decrease of the traversing current observed by the

ments with the conduction of blood through a rabbit's ear. These experiments showed the action of nitrite of amyl to be of central origin. In 1880, Salvioli || demonstrated that by conducting blood through excised sections of the intestines certain phenomena of life could be accurately studied. He mentioned as such the absorption of peptone, the intestinal peristaltic movements, the increase of the ascend- | experimenter. 2. The medium of conduc

ing blood-current in poisoning with atropine and tincture of opium, and the decrease of the current in nicotine-poisoning. In the same manner, Albertoni investigated later the action of cotoin on the intestines, and found that this agent increases the quantity of blood traversing the bowels. By bloodconduction through the posterior extremities of the dog, N. Rubenow** showed in 1880 that an infusion of adonis vernalis contracts temporarily the blood-vessels independently of the central nervous system.

In 1883, Abelés, experimenting with bloodconduction on excised kidneys, arrived at the conclusion that urea increases the bloodcurrent in this organ. Of high value for the

tion used was in nearly every instance a solution of chloride of sodium, which was, besides, often mixed with blood foreign to the animal. Subjected to such a treatment the vascular walls, which in this connection play of course the most essential rôle, rapidly underwent pathological changes or even lost their vital energy. Although the defects of these procedures have been openly exposed by Glax and Klemensiewicz‡‡ in 1882, such researches are nevertheless constantly cited as embodying a scientific testimony. The mentioned experimenters showed that frogs treated in the manner indicated became invariably edematous, even when by opening the auricles the flowing off of the traversing

knowledge of results obtained by blood-con- | liquid had been greatly favored and the pressduction are also the experiments of M. von Freyft and M. Gruber, in which the technique has reached the highest degree of perfection. In these painstaking works (which appeared after the conclusion of my pertinent researches) it was also shown that during the

* Pflüger's Archiv, vol. xv., 1877, p. 575; vide also Lépine, Compt. Rend. de la Soc. de Biol., 1876, 4 Mars. † Proc. of the Royal Sax. Soc. of Sciences; Mathem. Physic. Class, 1869, p. 189.

† Ibid., 1876, p. 45.

Du Bois-Reymond's Archiv, 1879, p. 385. || Ibid., 1880, Supplem., p. 95.

Ibid., vol. xvii., 1883, p. 291.

**"The Physiological and Therapeutic Action of Adonis Vernalis upon the Circulation." Inaug. Dissert. Petersburg, 1880; vide also Schmidt's Jahrb., vol. cxcvii. p. 196, and Deutsches Archiv für Klin. Med., vol. xxxiii., 1883, p. 262.

†† Du Bois-Reymond's Archiv, 1885, pp. 519 and 533.

ure employed was an exceedingly low one. The velocity of the off-flowing liquid decreases, of course, simultaneously with the formation of the edema, provided the pressure of the incoming liquid remains uniform. To avert these drawbacks two procedures in particular have been proposed. The first is that of Sidney Ringer §§ and H. G. Beyer, ||| and consists in substituting for the solution of chloride of sodium a mixture of 100 c.c. of a seventy-five per cent. solution of chloride of sodium + 5 c.c. of a solution of chloride of

# "Contributions to the Knowledge of Inflammation." First Communication. Wiener Academ. Sitzungsb., vol. lxxxiv., section iii., 1882, p. 216.

Journal of Physiology, vol. iii., 1883, p. 39. |||| "The Influence of Cocaine, Atropine, and Caffeine on the Heart and Blood-Vessels," Amer. Fourn. of the Med. Sciences, No. 179, 1885, p. 53.

calcium (1 to 390) + 2.5 C.C. of five per cent. solution of bicarbonate of sodium + 0.75 c.c. of a one per cent. solution of chlorate of potassium. This substitution is in many instances to be regarded as a decided improvement. (The results obtained with this solution differ, however, from those obtained with blood, as I shall show in the second part of my paper.)

The second plan proposed for the stated purpose was the employment of an artificial heart.

This substitution has two advantages, — first, the circulation was made to closely resemble the natural state, and then the otherwise inevitable thrombosis and subsequent formation of fibrin, resulting from settling (sinking) blood-corpuscles, was largely prevented. This insertion of an artificial heart has been proposed by L. T. Stevens and F. S. Lee.* Independently of these authors, I also made use of an intermittent pressure in various experiments upon frogs, in which I employed Ewald'st respiration apparatus.

On microscopic inspection of sections of the mesentery, or the web of frog, transfused in the manner indicated, pulsation could be made out even in the smallest vessels, and was seen to closely resemble the natural act, and to prevent the sinking of blood-corpuscles to a certain extent. Such pressure-intermissions imitative of cardiac action are, as M. Gruber has lately shown, also of extraordinary value for the transfusion of organs of warm-blooded animals. This observer found that in transfusions without an artificial heart the pressure is to be gradually increased, if the current is intended to be kept up, -a precaution wholly unnecessary when an artificial heart is inserted.

As to the technique of my experiments on warm-blooded animals, I invariably used blood and organs of the same species of animals which was experimented upon. The principal animals of experimentation were dogs, rabbits, sheep, calves, hogs, and horses, and the principal organs the kidney, the

* The action of intermittent pressure and of defibrinated blood upon the blood-vessels of the frog and the terrapin. "Studies from the Biological Laboratory of the Johns Hopkins University," vol. iii., 1884, No. 2, p. 101. (I am greatly indebted to the Johns Hopkins University for the sending of this paper.)

† Ewald and myself first proposed the use of valves for physiological experiments (Pflüger's Arch., vol. xxxi., 1883, p. 167). This contrivance is undoubtedly a very convenient one, as the valves open spontaneously on the slightest excess of pressure, and still close absolutely tight.

‡ Loc. cit., p. 538.

spleen, the liver, the lower extremities, the entire posterior part, the intestines, and the uterus. Dogs and rabbits (in Dorpat also calves) were always killed immediately before the experiment; the other animals were killed in the slaughter-house, and the respective organs, together with the blood, were brought into the Pharmacological Institute, and used at once. By special provision, the animal temperature of these organs was kept up as well as possible. Diluted § or strange blood was never used, as I soon found that the latter showed a toxic action. This statement I feel called upon to emphasize in opposition to Salvioli, who employed strange blood mixed with a seventy per cent. solution of chloride of sodium. The organ was enclosed in a heat-box, having a glass cover, the temperature being retained constant at 38° C. The blood had previously been warmed by a similar process. A febrile rise of temperature39.5° C. and more-is to be carefully guarded against as a certain source of disturbance, due probably to the contraction of the walls of the larger arteries, as observed by Roy and Grünhagen. The arterialization was effected by shaking the blood, and thus mixing it with air.

The concomitant lowering of temperature of the blood was immaterial, as the proper temperature could be reached again before the blood re-entered the organ. The blood reservoir was a double one, a smaller one for poisoned blood and a larger one (containing a litre) for normal blood. Both communicated above with an air-filled gasometer, the pressure of which was kept at a constant level by means of a Mariotte bottle. This pressure corresponded always to the pressure indicated by the animal during life. By means of a valve I was enabled to supplant the normal blood-current by a poisoned one, and vice versa, without interruption of the circulation or alteration of the pressure. Care was taken not to mix the blood flowing from the vein, during the poisoning or immediately after, with the normal current. These experiments were regarded as available only when the alteration in the velocity of the current produced by an introduced poison disappeared again under the use of normal blood. In order to render the latter at all feasible the poisoning lasted only ten minutes or less. In the various similar cases recorded in literature

I have detailed below some few successful experiments made with diluted blood on rabbits. The larger majority of these experiments failed, however.

we usually find an omission of the statement that the velocity of the current became normal again after the termination of the poisoning. This neglect detracts largely from the value of such experiments, especially when vascular contraction comes to be considered, as it is well known that at the death of an organ the velocity of the blood current decreases for various reasons. In my experiments the velocity of the current remained almost constant during the first two hours; i.e., became constant again even after repeated poisoning. It was necessary, however, to slowly raise the pressure five to ten millimetres during the stated time. In experiments which lasted four or more hours, the pressure had to be gradually raised fifteen to twenty millimetres in order to reach again the original velocity of the current.

Another point to be considered is the gradual thickening of blood when flowing from a vein into an open vessel, and when shaken up with air. This alteration I endeavored to eliminate by successive additions of small quantities of weakly alkaline solutions of chloride of sodium (physiological solutions).

system die first. In my experiments, however, I succeeded, when transfusing posterior parts and keeping alive the lower portion of the spinal cord, in two and even sometimes in four hours, to elicit muscular tetanus in the lower extremities by means of strong interrupted currents. Likewise successful, in the second hour, was Bernstein's experiment,i.e., increase of the flowing-off quantity under irritation of the sciatic nerve with or without curare. The survival of the kidneys* used for most experiments was proven by the existence of renal pulsation, often very distinct in the second hour, but wholly absent in the third. In other organs this pulsation is less distinct or wholly wanting. In order to convince myself of the vitality of such organs, I used as reagent hydrate of chloral in such great dilution as to barely increase the circulation of fresh organs. If this reaction did not appear after a transfusion of two to three minutes, the organ was regarded as dead and was laid aside.

After the termination of the experiment I often used to examine a portion of the organ microscopically. If the poisoning had not been too intense, the microscopic structure appeared, even after two hours, well preserved, save some small hemorrhagic and ædematous defects.

As to the differential behavior of the single organs towards one and the same poison, we can summarily assert that, excepting the kidney and the liver, all organs react alike qualitatively and almost alike quantitatively. This fact advocates the assumption that the

As to the proportion between the poison employed and the blood, I used such quantities of the former as would be proportionate to the poisoning of the entire body. Substances being insufficient in this concentration were usually likewise also in doses two to five times as large, and have been designated in the charts as having no influence on the velocity of the current. I believe that the reader will have confidence in my experiment when he sees that a large number of sub-toxic effects obtained in these cases refer stances were examined in which no alteration ❘ solely to the vascular walls and not to another of the velocity of the current manifested itself. The occasionally instituted experiments with blood-transfusions, as found in literature, are, I repeat, of little value, for the reason that one doubts whether the experimenter has so far mastered the difficult pertinent technique as to procure a uniformity of the current, even when no toxic agents had been employed.

Another very important point in these researches is to avoid introducing into the blood extracts, greasy substances, strongly acid or strongly alkaline agents, as these alter the velocity of the current by themselves without any additional intoxication. For this reason, then, most of the experiments made with ergotine, extract of digitalis, tinctures, and infusions are without value.

It is well known that in these transfusion experiments the central organs of the nervous

origin, such as the specific tissues of the single organs. The exceptional position of the liver can in this manner be also satisfactorily explained, viz., by the extremely scanty development of muscular tissue in the portal vein. I therefore obtained appreciable results with transfusion, beginning in the hepatic artery, while the transfusion starting from the portal vein led, in most instances, to no results. In the case of the kidney, some few active diuretic agents only make an exception from the above stated rule by acting on this organ more intensely than on others. Of this deviation I shall in some later publication treat in a more detailed manner.

Proceeding now to the significance of the variations in the velocity of the off-flowing current, we find that these may be brought about in the following manner:

* The kidneys cannot well be electrified.

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