Œdema and nephritis; a critical, experimental and clinical study of the physiology and pathology of water absorption in the living organism

Front matter

BOOKS BY DR. FISCHER

PUBLISHED BY

JOHN WILEY & SONS, Inc.

PREFACE TO THE THIRD EDITION vii

Doris Wulff. Renewed thanks are due Harry M. Levy, who has continued his generous support of the Joseph Eichberg Laboratory in spite of its seeming vagaries. For inspiration to scientific work and for example in perseverance and courage I have times without number turned to the builder of resurgent medical Cincinnati, Christian R. Holmes.

Martin H. Fischer.

University of Cincinnati, June, 1920.

Preface To The Second Edition

These pages give in combined form the contents of the 1909 Nathan Lewis Hatfield Prize Essay of the College of Physicians of Philadelphia, and of the 1911 Cartwright Prize Essay of the Alumni of the College of Physicians and Surgeons of Columbia University, New York, previously published as separate volumes bearing the titles " (Edema " and " Nephritis." The close association between the two made their appearance in combined form seem advisable. The chief changes which time has rendered necessary consist of additions to the general text embodying the results of later experimental and clinical observations in good part not readily accessible to English readers — the main argument remains as before.

Throughout the text are mentioned those who with me did the day's work. These references to James J. Hogan, Edmund M. Baehr, Gertrude Moore, Marian 0. Hooker, Thomas H. Kelly, Hayward G. Thomas, William H. Strietmann, Anne Sykes and Carl Hiller but ill express my indebtedness to them. Nor would I fail to acknowledge the intelligent and faithful help of my technical assistant, Josef Kupka. In these paragraphs I can only record my keen appreciation of what they did.

To Lauder W. Jones I have often turned for help in matters chemical, to Louis Trenchard More in matters physical. Alfred Brodbeck made possible the observations on athletes. Charles Goosman gave of his time and skill to prepare the photomicrographs. Charles Hecker and Peter Scherrer made many of the other photographs. To all these I would express my sincere thanks.

The now old views restated and elaborated in this volume have not gone unchallenged. Where these challenges have

ix

X

PREFACE TO THE SECOND EDITION sprung from scientific doubt it has not been difficult to reach common ground by discussion. Where the personal has entered into the spirit of the attack I have succeeded, in part at least, in keeping silent. As this is my wish for the future, will the interested reader of disputed points examine the evidence away from the noise of the pleading attorneys?

Much of the older work and most of the newer in this volume was shaped in the Josefh Eichberg Laboratory of Physiology in the University of Cincinnati. The atmosphere prevailing there, which recognizes that the new is born as a minority point of view and hence is unpopular, and that the function of a university is to give it sanctuary, has been made possible by the generosity of Harry M. Levy.

Martin H. Fischer.

University of Cincinnati, 1914.

Part Two Absorption And Secretion In Individual Cells And Tissues

PAGE

I. The Problem 41

II. The Absorption of Water by Colloids 44

1. Remarks on Colloids: Nomenclature 44

2. Observations on the Swelling of Fibrin 61

3. Observations on the Swelling of Gelatin 75

4. Observations on the Swelling of Gluten 129

5. Observations on the Swelling of Aleuronat 133

6. Hydration and Dehydration in Liquid Colloids 145

7. On the Nature of the Increased and Decreased Hydration

Capacity of the Proteins 148

III. The Analogy between the Swelling of Certain Protein Colloids and

the Swelling of Protoplasm 151

1. The Analogy between the Absorption of Water by Certain

Protein Colloids and by Muscle 152

2. The Analogy between the Absorption of Water by Certain

Protein Colloids and by the Eye 1 69

3. The Analogy between the Absorption of Water by Certain

Protein Colloids and by Nervous Tissue 178

IV. The Biological Significance of the Analogy between the Absorption

of Water by Certain Protein Colloids and the Absorption of Water by Different Tissues 193

2. Criticism of the Osmotic Theory of Water Absorption by

Protoplasm 195

3. Criticism of the Lipoid Membrane Theory. . . 201

4. Adequacy of the Colloid-chemical Theory of Absorption and

Secretion 204

5. Absorption and Secretion of Dissolved Substances by Proto-

plasm 206

xi xii

TABLE OF CONTENTS

Part Three (edema Page

I. Introduction 217

II. The Cause of (Edema Resides in the Tissues 220

III. ' On the Nature and Cause of (Edema 232

1. An Abnormal Production or Accumulation of Acids or

Conditions Predisposing Thereto Exist in all States in which We Encounter (Edema 233

2. Any Means by which an Abnormal Production or Accumula-

tion of Acid in a Tissue May be Brought about is a Means

of Producing an (Edema 243

3. Those Conditions which are Capable of Decreasing the Hydra-

tion of (Protein) Colloids Decrease (Edema, while Those Unable to do so do not Affect It 249

4. On (Edema Due to Other than Acid Causes 262

IV. On the Passive Congestion (Edemas of the Kidney and the Liver 268

V. On the Nature and Cause of Pulmonary (Edema 276

VI. Syneresis and the Accumulation of Fluid in the Body Cavities in

VII. Concluding Remarks ,,,,,, 285

Part Four Absorption And Secretion In The Complex Organism

I. The General Problem 293

II. On Absorption 296

1. General Remarks on the Physico-chemical Structure of an

Absorbing System in the Complex Organism , . . . . 296

2. Absorption from the Peritoneal Cavity 299

3. Absorption from the Castro-Intestinal Tract 311

4. Historical and Critical Remarks on the Theory of Absorption.

Peritoneal and Alimentary Absorption of Dissolved Substances 315

III. On Secretion 325

2. General Remarks on the Structure of a Secreting System in

the Complex Organism 326

3. A Model Illustrating Some Phases of Urinary Secretion 327

4. The Output of Water by the Kidney 330

5. On the Colloid-chemical Action of the Diuretic Salts. How the

Saline Diuretics Produce Diuresis 339

6. On the Colloid-chemistry of Sugar Diuresis 349

TABLE OF CONTENTS xiii

7. Discussion of the Mechanism of Water Secretion by the

Kidney. Some General Conditions Influencing Water Output. Diuretics of the Second Order.. - 357

8. Historical and Critical Remarks on Urinary Secretion 362

9. Transition from the Physiological to the Pathological in

Kidney Function 365

10. The Secretion of Dissolved Substances 367

11. A Second Model Illustrating Some Phases of Kidney Secre-

tion i 371

12. A Third Model Illustrating Some Phases of Kidney Secretion . . 380

13. Concluding Remarks on Absorption and Secretion. Lymph

Formation. Vasomotor and Secretory Nerves 397

IV. Maintenance of the Circulating Fluids in the Body 403

1 . Why the Blood Remains in the Blood Vessels 403

2. On the Treatment of Shock 415

3. Critical Remarks on Shock 423

Part Five

THE COLLOID-CHEMICAL THEORY OF WATER ABSORPTION AND SOME PROBLEMS IN BIOLOGY, PHYSIOLOGY AND PATHOLOGY

I. Turgor, Plasmolysis and Plasmoptysis 429

II. On the Absorption of Water by Spermatozoa, Epithelial Cells and

White Blood Corpuscles 430

III. On the Interpretation of Some Experiments on Water Absorption

by Muscle 433

IV. On the Nature of Hemolysis 438

V. On Growth and Some Growth Phenomena 446

VI. On the Contraction of Catgut and the Nature of Muscle Contraction 451

1. Observations on the Contraction of Catgut 452

2. Interpretation of Experimental Findings . 459

3. On the Analogy between the Described Contractions of Catgut

and the Contraction of Striated Muscle 461

4. Historical and Critical Remarks 463

Part Six Nephritis

I. The Thesis 473

II. An Abnormal Production or Accumulation of Acid in the Kidney

Occurs in Every Case of Nephritis 475

III. Any Means which Leads to an Increased Production or Accumulation of Acid in the Kidney is a Means of Producing Nephritis 488 xiv TABLE OF CONTENTS

PAGE

IV. Nephritis Due to Other than Acid Causes 502

V. The Albuminuria . . . 504

2. Observations on the ''Solution " of Colloid (Protein) Gels 508

3. On the Relation between Swelling and "Solution" in Protein

Colloids 519

4. Critical Remarks 530

VI. The Morphological Changes in the Kidney 532

2. Classification of the Nephritides. Correlation of the Morpho-

logical Changes in the Kidneys with Some Clinical Manifestations 533

3. The Changes in the Size and in the Color of the Kidney in

Nephritis (Cloudy Swelling) 540

4. The Bleeding into and from the Kidney in Nephritis (Hemor-

rhage by Diapedesis) 555

5. On the Origin and the Different Types of Tube Casts 560

VII. Some Responses to Criticism 567

1. On the Swelling of Gelatin in Polybasic Acids and their Salts. . 567

2. On the Liquefaction or "Solution" of Gelatin in Polybasic

Acids and their Salts 596

3. On the Swelling of Fibrin in Polybasic Acids their Salts 602

VIII. On the Alleged Consequences of Kidney Disease 614

1 . On the Relation of Vascular Disease to Nephritis 615

2. On the (Edema of Nephritis 626

3. On the "Uremia" of Nephritis. 628

4. Reinterpretation of the Relation of Nephritis to the Clinical

Manifestations Associated Therewith 629

5. Remarks on the Etiology of Vascular Disease 634

IX. The Disturbances in Secretion in Nephritis 636

1. General Considerations 636

2. The Secretion of Water by the Nephritic Kidney 638

3. The Secretion of Dissolved Substances by the Nephritic

Kidney 640

X. Some Experimental Foundations for the Treatment of Nephritis.

Fallacy of Salt Restriction in Nephritis and (Edema 648

2. Asphyxial Nephritis 649

3. Nephritis Produced by Injecting Acid 655

4. Nephritis Due to Temporary Closure of the Renal Vessels 659 •

5. Interpretation of Experimental Findings 663

6. Inhibit ive Effects of Alkaline Salts on the Albuminuria of Hard

Work 665

XI. On the Treatment of Nephritis 667

2. Diet in Nephritis 669

3. Water Consumption in Nephritis 674

TABLE OF CONTENTS xv

PAGE

4. The Role of Salts in Nephritis. 676

5. More Aggressive Methods of Alkali and Salt Administration. . . 678

6. The Treatment of Severe Cases of Nephritis . . . 686

7. Clinical Abstracts and Comment 696

8. Dehydration Therapy in Other (Edemas 731

9. On (Edema as an Alleged Consequence of Sodium Chlorid

Retention 731

10. On the Treatment of Anasarca and Ascities. Comment on

the Sodium Chlorid Restriction Therapy 738

XII. Diagnosis and Prognosis in Nephritis 746

1. Judging the Nephritic. Prognosis 746

2. Underlying Principles and Clinical Value of Kidney Efficiency

Tests 757

3. On Acidity Measurements of the Urine 765

4. Limitations of Indicator Methods 775

5. Ammonia Determinations, Acetone Compounds, "Acidosis,"

and Coma 778

XIII. Prophylactic Measures Against Nephritis. Care of the Surgical

and Medical Patient 783

Part Seven Gla Ucoma

I. On the Nature and Cause of Glaucoma 795

II. On the Relief of Glaucoma 797

1. Local Measures 797

2. Systemic Measures 799

III. Some Comments 802

IV. On the Nature of Corneal Opacities 806

V. Closing Remarks 810

Part Eight Appendix

I. The Relation of Mouth Infection to Systemic Disease 815

2. Historical Remarks 817

3. Infections of the Blood Stream and Systemic Disease. 818

4. Modification of Micro-organisms through Environment 821

5. Fundamental Systemic Pathology 823

6. Points of Entrance for Systemic Infection 832

7. Illustrative Case Reports , . . . . 834

8. Remarks on Some Dental Procedures 836 xvi TABLE OF CONTENTS

PAGE

9. Some Suggestions 840

10. The Foul Breath and the Coated Tongue 845

11. On Extraction 848

12. Concluding Remarks 851

II. Diagnosis, Prognosis and Treatment in Nephritis. (A Clinical

Lecture) 852

1. (Edema in the Absence of Circulation 852

2. The " Nephritis" of Heart Disease 854

3. The Nephritis of General Intoxication 863

4. Spotty Parenchymatous Nephritis Due to Infection of the Kid-

ney (Infectious Nephritis) 876

5. Spotty Parenchymatous Nephritis Due to Vascular Disease

(Chronic Interstitial Nephritis) 880

A. Ambulatory Type : 880

B. The Cardiac Type with Chronic Interstitial Nephritis. 888

C. The Cerebral Type with Chronic Interstitial Nephritis. . . . 890

Part One

In this first part is given in running form a resume of the entire volume. The busy reader may accept as much of the argument as here outlined upon the abbreviated evidence accompanying it as he chooses. By turning to the page references given in the text the detailed observations will be found on which are based the more dogmatically stated conclusions contained in these first paragraphs.

Part Two

So practical a question as the treatment of glaucoma, uremia or anuria is intimately associated with the problem of oedema. This problem of cedema, the question of how a cell, an organism or the body as a whole comes to hold an abnormally large amount of water is in its turn but a subheading of that still greater problem, why living matter holds any water at all and why under normal circumstances it holds so constant an amount. Various hypotheses have been proposed by animal and plant physiologists, by pathologists and clinicians to explain such normal and abnormal water absorption, but all are inadequate to account for more than the smallest fraction of the phenomena observed.

The absorption of water by living matter under physiological and pathological circumstances is determined by the colloids contained in it and their state. The major portion of the chemical substances which make up protoplasm exists there in colloid form. A discussion of the properties of colloids with particular reference to the matter of water absorption is therefore in order. (See pages 41-44.)

About the middle of the last century it was noted that chemical substances differ in the rate at which they diffuse through solvents. The group which diffuse but slowly and which are for the most part amorphous, of high molecular weight, without osmotic pressure, and pseudo-soluble, are known as colloids, while those which diffuse rapidly, are of low molecular weight, have osmotic pressure, and form true solutions, are known as crystalloids. Among the former are found glue, gelatin, albumin and starch; among the latter, cane sugar, common salt and urea. While we are seemingly classifying substances we should really speak of the colloid and crystalloid states, for later observations have shown that it is not its chemical character which identifies the colloid, but rather the physical state of the substance, practically all substances being capable of existing in either of these two forms. (See pages 44-49.)

The colloids themselves do not all show the same properties. On the one hand there are those which enter into close association with their solvent (lyophilic or hydrophilic colloids) ; on the other, those which do not (lyophobic or hydrophobic colloids) . Gelatin, dextrin, starch, glue, vegetable fibers, albumin and gums are examples of the former class; the colloid metals, metallic hydroxids and sulphids are examples of the latter. (See pages 49- 61.)

The former of these two groups is of greatest biological importance, for the bulk of protoplasm is made of it. An attempt is therefore made to define the difference between the two groups more closely. Beginning with the now generally accepted belief that a colloid system results whenever one material is divided into a second with the degree of subdivision coarser than molecular and not yet so coarse as to come into the physical realm of the mechanical mixtures, it is pointed out that a hydrophobic or lyophobic colloid results whenever the subdivided material is not a solvent for the dispersion medium; a hydrophilic or lyophilic colloid when the subdivided material is such a solvent. Illustrations are introduced of the different types of systems that may be thus produced. Beginning at the top is a system consisting of a true solution of a in b while at the bottom is another true solution of b in a. Between these extremes exist two zones of mixed systems, one under the topmost consisting of a subdivision of solvated a particles in a solution of a in b, and below this a system of reverse type, namely, one of a subdivision of a solution of a in b in hydrated a as an enveloping or external phase. On the basis of the existence of these different systems are explained the meanings of such terms as solubility, solvation capacity, swelling, sol and gel, gelation capacity, syneresis and hysteresis.

To discover some of the properties of the lyophilic colloids, particularly their relation to the absorption of solvent, the biologically important colloids, fibrin, gelatin, gluten, aleuronat and blood serum are studied. (See pages 61-151.)

Fibrin absorbs more water (swells more) in any acid solution than it does in pure water. Within certain limits the amount of water thus absorbed increases with the concentration of the acid, but when a certain concentration is exceeded the fibrin swells less than in lower concentrations. The same is true of alkalies. The addition of any salt, even a neutral salt, to the solution of any acid or alkali reduces the amount that the fibrin swells and this the more the higher the concentration of the salt. When equivalent concentrations of different salts are compared some are found more active in this regard than others. Thus, the chlorid, bromid and iodid are less capable of dehydrating fibrin than the acetate, while yet more powerful are the sulphate, phosphate and citrate. When the effects of basic radicals are compared potassium, sodium and ammonium are found less active than magnesium, calcium or strontium, while copper and iron are most effective of all. Non-electrolytes are comparatively ineffective in reducing the swelling in the presence of an acid or alkali. They are not, however, entirely without effect. Among the non-electrolytes the sugars deserve special mention because these produce a considerable dehydrating effect. When dextrose, levulose and saccharose are compared the last named is found particularly powerful. The taking up and giving off of water by fibrin represents in large measure a reversible process. In addition to the acids and alkalies there exist a number of other substances which are capable of increasing its hydration capacity. Urea and pyridin and possibly some of the amins are to be mentioned in this class. The hydrations produced by these substances are of a different type from those produced by acids and alkalies, for they are not readily reducible through salts, while they are through various non-electrolytes (sugars), a behavior the opposite of that observed in acid or alkali hydration. (See pages 61-75.)

What has been said of fibrin is not characteristic of it alone, but is true of all proteins, as illustrated by the identical behavior of gelatin, gluten and aleuronat. (See pages 75-145.)

What has been said of the solid colloids holds also for the liquid colloids such as blood serum, fluid gelatin or egg white. The hydration and dehydration in such liquid colloids can be followed by noting the changes in their viscosity, hydration being betrayed by an increase in viscosity, dehydration by a decrease. (See pages 145-151.)

The behavior of the more solid colloids corresponds to the behavior of the more solid constituents of our body, as the tissues ; that of the liquid with the fluids permeating these solid structures, namely, the blood, the lymph, the cerebro-spinal fluid, etc.

It can be shown that every tissue takes up water or gives it off under conditions identical with those which cause protein colloids to do this. Thus, muscle, eyes or nervous tissues swell more in acid or alkali than in water, and this the more, within certain limits, the higher the concentration. Beyond a certain optimal concentration the tissues begin to lose water. The addition of any salt to the acid or alkali produces a dehydrating effect, and this is the greater the higher the concentration of the salt. At the same concentration different salts are unequally effective, and here again their order parallels that observed on simple proteins. The non-elect rolytes as compared with the elect rolytes are less effective. The processes of hydration and dehydration in all these tissues are largely reversible. Urea is observed in all these tissues to lead to an increased hydration. (See pages 151-192.)

The acceptance of the view that the colloids of the tissues and their state are primarily responsible for the amount of water held by them constitutes a tacit criticism of every theory of water absorption thus far advanced. These theories may be called for short, the osmotic theory conjointly with which we may consider that modification of it known as the lipoid membrane theory, and the pressure theory. The pressure theory is criticised later. (See pages 193-195.)

The osmotic theory assumes that cells are surrounded by semipermeable membranes through which water but no dissolved substances can pass. The movement of water is occasioned by differences in the concentration of dissolved substances within and without the cell, the water being carried in the direction of the higher concentration whether existing within or without the cell. In thus accounting for the migration of water into and out of cells it becomes impossible to get dissolved substances through. Such a conception of the living cell is an impossible one because the cell must be and is able to absorb all manner of foodstuffs and get rid of the products of its metabolism. To meet this situation the original osmotic theory has been modified by saying that the membrane is permeable to some or all substances at some or all times. But when this postulate is granted concentration differences between the inside and the outside of the cell can no longer come to pass, for the dissolved substances will simply move from regions of higher to regions of lower concentration. The forces active for the movement of water therefore disappear. Adherents of the osmotic theory can move either water or dissolved substances, but they cannot move both, and yet in living cells this must be possible. (See pages 195-201.) 1 The lipoid membrane theory suffers from much the same defects as the original osmotic one. In assuming the outer layer of cells to be fatlike in character, it may become possible to explain more easily the entrance of fat-soluble substances, but since fat is no solvent for water, for salts and for many of the normal products of cell metabolism, this conception is also biologically impossible, for all these can and must be able to pass into and out of cells. (See pages 201-203.)

The mosaic theory, which holds part of the cell membrane to be 11 protoplasmic " in character, another part lipoid, suffers from the combined defects of the osmotic and lipoid theory. (See page 203.) »

In the colloid-chemical theory there is no need for membranes about the cells. The absorption of water is governed by the laws which govern the hydration and dehydration of lyophilic colloids. The differences between the concentration of dissolved substances found inside and outside of the cell are accounted for through differences in relative solubility, differences in adsorption and differences in chemical constitution. The cell conceived of as a colloid matrix can not only absorb and secrete water, but it can also absorb and secrete any dissolved substance at the same time, and the two processes may run in the same direction or in opposite directions as physiological and biological observation demands. (See pages 204-206.)

The conception that cells are surrounded by osmotic or lipoid membranes has been used to explain not only the absorption of water, but also the biological characteristics of the absorption of dissolved substances. In essence this problem asks why different parts of the same cell or different cells bathed by the same blood and lymph do not all hold the same amount of dissolved substance. The membrane theory attempts to explain such concentration differences by saying that the membranes are partially permeable or impermeable to these dissolved substances. In discarding the osmotic conception of water absorption we discarded also this mechanism for the maintenance of concentration differences. What have we to put in its place? (See pages 206-207.)

We are familiar in physical chemistry with a number of illustrations of inequalities in the distribution of dissolved substances between different phases even though no membranes exist between them. Thus, when a substance is more soluble in one solvent than in another, it will collect in greater concentration in that in which it is the more soluble; or the adsorption properties of the colloids may be different as in different cells; or the presence of certain chemical compounds in one phase permits it to combine chemically and so hold a greater amount of a given dissolved substance than another phase in which such are not present or present in less amount. Finally, all three may be active at one and the same time. (See pages 208-213.)

On this basis our conception of the cell becomes that of a mass of protein intimately mixed with more or less fat and fatlike material, the whole immersed in a liquid from which the protein-fat mixture soaks up a certain amount of water and of various substances dissolved in the water, the whole being governed by the laws of equilibrium. (See page 213.)

Part Three

The problem of oedema is also a problem in colloid-chemistry — that of the ways and means by which the normal hydration capacity of the body colloids is heightened. The school of pathologists quite generally upholds the teaching that oedema is produced by changes in the pressure of the circulating fluids of the body (increased blood and lymph pressure) together with an increase in the permeability of the vessel walls. This pressure theory is completely unsatisfactory, for not only may we have extreme degrees of oedema without changes in blood or lymph pressure, but measures which increase blood pressure and should therefore increase oedema are known to produce just the opposite effect. In place of the pressure idea, changes in the tissues and cells have therefore been made to play a role in the development of oedema, but the attempt to define clearly the real nature of these was not made until quite recently when it was taught that increases in the osmotic pressure of the cell contents might lead to an increased absorption of water and thus to oedema. (See pages 217-220.)

The cause of cedema resides in the tissues, which become cedematous not because water is forced into them, but because they suffer changes which make them suck up water. This is proved by the fact that the severest grades of cedema may be produced in the entire absence of any circulation, and consequently in the entire absence of any blood pressure. (See pages 220-232.)

A state of cedema is induced whenever, in the presence of an adequate supply of water, the capacity of the tissue colloids for holding it is increased above that which we are pleased to call normal. Any agency capable, under the conditions . existing in the body, of thus increasing the hydration capacity of the tissue colloids constitutes a cause of cedema. The accumulation of acids within the tissues, brought about either through their abnormal production or through the inadequate removal of such as some consider normally produced in the tissues, is chiefly responsible for this increase in the hydration capacity of the colloids, though the possibility of explaining at least some of it through the production or accumulation of substances (of the type of urea, pyridin, certain amins, etc.) which hydrate colloids as do acids, or through the conversion of colloids having but little capacity for water into such as have a greater capacity must also be borne in mind. (See pages 232-233.)

As it has already been proved that the amount of water absorbed by a tissue is dependent upon its content of lyophilic colloids it must next be shown that conditions capable of increasing their normal hydration capacity are produced in all states of oedema. Of those that might be discussed, an abnormal production and accumulation of acids is considered the most potent, wherefore it receives detailed consideration. (See page 233.)

The proof that such occurs in all states of oedema consists of the following:. An abnormal production or accumulation of acids or conditions predisposing thereto exist in all states in which we encounter cedema. Circulatory disturbances, whether generalized or local, conditions which decrease the oxygen-carrying powers of the blood, as the anemias, various states of inanition, the fevers, the chemical changes following death, as well as poisons of various kinds which are followed by oedema, all represent methods by which the chemistry of the tissues is so altered as to lead to an abnormal production or accumulation of acid in them. (See pages 233-243.)

Conversely, any means by which an abnormal production and accumulation of acid may be brought about in a tissue is followed by an oedema. Thus, the acid production occurring in tissues after death or in poisoning by arsenic, morphin, uranium, chloroform, ether, cocain, etc., is always followed by a retention of water in the body and an oedema. (See pages 243-249.)

Finally, those conditions which are capable of decreasing the hydration of protein colloids decrease oedema, while those which are ineffective in this regard do not do so. Thus, the cedemas developed by amputated frogs' legs laid in water are reduced by all salts, and this the more the higher their concentration. At the same concentration different salts are unequally effective in this regard, and this in the order in which they dehydrate simple proteins swelling in the presence of acid. To meet the criticism that such reduction of oedema is possible in " dead " frogs' legs but not in " living " animals, a parallel series of experiments is introduced on " living " frogs made cedematous by injections of uranium. Sodium chlorid is no exception to the rule; it reduces eedema as does any other salt. (See pages 249-262.)

The possible role of other agencies besides an increased acid content in the development of oedema is discussed, and the importance of such known hydrating substances of protein as the alkalies, urea, pyridin and the amins is emphasized. (See pages 262-268.)

A number of the specific problems presented by oedema as it affects special organs is next considered. Thus, another explanation must be found for the generally accepted belief that the oedema observed in a passively congested kidney, produced, for example, by ligation of the renal vein, is due to an increased capillary pressure and a forcing of fluid into the kidney tissues. Ligation of the renal artery with its consequent decrease in blood pressure is followed by exactly the same kind of change. (See pages 268-271.)