Chemical pathology : being a discussion of general pathology from the standpoint of the chemical processes involved

Front matter

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Preface To The Fourth Edition

The rapid growth of interest in the chemical problems of medical and biological science is shown by the great increase in the amount of material which must be included in each succeeding edition. Although this latest edition has been subjected to extensive revision and many minor alterations, yet the general plan has not been changed. The rapidly growing information concerning the nutritional factors that are essential to growth and repair, and without which serious " Deficiency Diseases" may arise, has necessitated the introduction of a new chapter to cover this subject, the importance of which has been accentuated by the war and its sequels. The growing bulk of material on the Reactions of Immunity required a rearrangement of this material, so that a separate chapter on Anaphylaxis and Allergy has been provided, for purposes of convenience. Numerous sections have been entirely rewritten, and few pages have not required revision or addition.

In order to prevent the increasing material that must be included from resulting in too cumbersome a volume, much more of the matter is printed in smaller type. It is hoped that this arrangement will achieve its aim without serious reduction in facility of use. The author recognizes fully that it would be easily possible to report the existing state of knowledge on the topics covered in " Chemical Pathology" in a much briefer space, if only completely established evidence were included. With the object of serving as a guide to investigators, and with the hope of stimulating further investigations, much more than this minimal amount of existing evidence is included. It is also recognized that the brief discussion of the elementary principles of physical chemistry and the fundamentals of the physics and chemistry of living cells, which constitutes the introductory chapter, may be out of place in a work on Pathology, and the elimination of this chapter has been seriously considered. Repeated assurances of the usefulness of such a presentation, however, have resulted in its. retention, at least for the present.

As with all previous editions, my indebtedness must be acknowledged to numerous colleagues who have kindly read over the sections of this book which most closely concern their own fields, and especially to the members of my Department and of the Sprague Institute who have made many useful suggestions. The chapter on Diabetes is, as before, contributed by Dr. R. T. Woodyatt, Director of the Laboratory of Clinical Research of the Otho S. A. Sprague Memorial Institute.

H. G. W.

Chicago, III., Juhj, 1920.

Preface To The First Edition

During the past score of years the subject of biological chemistry has attracted the attention and labors of a constantly increasing number of investigators, many of whom have, for one reason or another, been interested in pathological conditions. Sometimes the physiologist has sought for light on his problems in the evidence afforded by related pathological conditions. Frequently clinicians have studied the metabolic changes and the composition of the products of disease processes. Relatively seldom, unfortunately, has the pathologist attacked his problems by chemical methods. From the above and other sources have come scattered fragments of information concerning the chemical changes that occur in pathological phenomena. Only when bearing upon conditions such as gout and diabetes, which concern alike the physiologist, the clinician, and the pathologist, have the fragments been moulded together into a homogeneous whole. For the most part they still remain isolated, uncorrelated, frequently unconfirmed items of information, scattered through medical, chemical, physiological, and physical literature.

It has been the aim of the writer to collect these scattered fragments as completely as possible, and to use them as a basis for a consideration of General Pathology from the standpoint of the chemical processes which occur in pathological conditions. Owing to the diffusely scattered conditions of the literature on which this work is based, it cannot be claimed that all of the many contributions from which useful information might be obtained have been noticed; but it is hoped that a sufficiently thorough collection of material has been made to afford a fair basis for a consideration of "Chemical Pathology." The time seems ripe for an effort of this nature. Within the past few years great and encouraging advances have been made in biological chemistry, which in many instances seem to throw fight upon pathological processes. In medicine, the use of chemical methods in the study of clinical manifestations has become more general, and has yielded valuable information. Pathologists have come to feel that the opportunities for the acquirement of knowledge by means of morphological studies have become reduced to a minimum, while the fields of pathological physiology and chemistry lie still almost unexplored. The development of research upon the subject of natural and acquired immunity has presented innumerable problems, all of which are essentially chemical. And perhaps most important of all is the general

8 PREFACE TO THE FIRST EDITION

awakening of an appreciation of the importance of physiological chemistry to medical science, which has led to the introduction of laboratory courses on this subject in every medical school worthy of the name.

A book on Chemical Pathology should, therefore, seek to supply information to a varied group of readers. It should furnish collateral reading to the student who for the first time goes over the subject of General Pathology, which his text-books usually consider chiefly from the morphological standpoint. It should exploit to the graduate in medicine the advances that are being made along lines that are of fundamental importance to clinical medicine. It should serve for the investigator in biological chemistry or in pathology as a source of information concerning the ground upon which the two subjects overlap— -the "Grenzgebiete" of Pathology and Physiological Chemistry. And, above all, it should afford a guide to the sources of our knowledge of these subjects, since nothing but direct familiarity with the original reports of the investigators themselves can give the student an impersonal view of the actual status of the questions under consideration. On account of this multiplicity of the objects in view, it has often been necessary to consider certain topics from more than one standpoint; which explains, perhaps, certain apparent irregularities in the style and manner of treatment.

It has been assumed that the reader has at least an elementary knowledge of organic and physiological chemistry. For the benefit of those whose studies in these subjects date back some years, it has seemed advisable to include in an introductory chapter an epitome of the more modern views concerning the chemistry of the protein molecule, the composition of the animal cell, and the principles of physical chemistry, in as far as they apply to biological problems. The general consideration of "Enzymes" in Chapter II is written with a similar object. In discussing these fundamental topics it has seemed advisable to omit detailed references to the numerous original sources, — these may be found quoted in the special text-books cited in the foot-notes; but in presenting the more distinctly pathological topics the attempt has been made to render all the important literature available to the reader and investigator. To economize space, a complete bibliography has not been inserted when this exists already collected in some readily accessible review or original article; hence the references cited in the foot-notes will generally be found to include only the more recent publications. These references have been so selected, however, that they will be found to furnish bibliographical matter sufficient to lead the investigator to all the important literature on the topics covered in this book. As to those subjects (such as gout, diabetes, and gastro-intestinal putrefaction) which, because of their great practical clinical interest, have already been discussed in available monographs at greater length than the scope of this work would permit, it has seemed appropriate merely to summarize the most recent views and

Preface To The First Edition 9

advances, referring the reader to the special treatises for the general and historical discussions.

It is with the greatest pleasure that I acknowledge my indebtedness to many colleagues in the University of Chicago, who have kindly read the sections of my manuscript that touch upon their own special fields, and whose criticism and advice have been of the greatest assistance; their number alone prevents my thanking them by name. Most particularly, however, must I express my debt to my former instructor, Professor Lafayette B. Mendel, of Yale University, whose kindly criticism and suggestions have been of inestimable value. For constant assistance in the preparation of the manuscript, and for the revision of the bibliography, I am indebted to my wife.

H. G. W.

CHAPTER I Page

Introduction 17

Chemistry of the Essential Cell Constituents 18

Fats and Lipoids (Lipins) 22

Carbohydrates 23

Inorganic Substances 24

The Physical Chemistry of the Cell and Its Constituents ....... 24

Crystalloids and Their Properties 24

The Structure of the Cell in Relation to Its Chemistry and Physics ... 39

The Nucleus 40

The Cytoplasm 42

The Cell-wall - 45

Chapter VII

Chemistry of the Immunity Reactions — Antigens, Specificity, Antitoxins, Agglutinins, Precipitins, Opsonins, and Related Subjects 159

Antigens 160

Non-Protein Antigens 161

Specificity of Immune Reactions 165

Toxins and Antitoxins 172

Chemical Nature of Antitoxins 175

Agglutinins and Agglutination 178

Precipitins 184

Opsonins 188

The Meiostagmin Reaction 189

The Epiphanin Reaction 190

CHAPTER VIII Chemistry of the Immunity Reactions (Continued)— Anaphylaxis or

Allergy, Abderhalden Reaction 191

Anaphylactogens ". 191

Anaphylatoxin 194

Anaphvlactin 201

Hay Fever 203

Abderhalden Reaction 204

CHAPTER IX Chemistry of the Immunity Reactions (Continued)— Bacteriolysis

Hemolysis, Complement Fixation, and Serum Cytotoxins . . . 206

Serum Bacteriolysis 206

Cytotoxins 209

Hemolysis by Khown Chemical and Physical Agencies 211

Hemolysis by Serum 214

Hemolysis by Bacteria 219

Page

Hemolysis by Vegetable Poisons 220

Hemolysis by Venoms 223

Hemolysis in Disease 224

Complement Fixation and Wassermann Reactions 229

Cytolysis in General , 233

CHAPTER X Chemical Means of Defense Against Non-Antigenic Poisons .... 237

Inorganc Poisons 240

Organic Poisons 241

CHAPTER XI Ameboid Motion and Phagocytosis 248

Chemotaxis 248

Chemotaxis of Leucocytes 250

Phagocytosis 255

Theories of Chemotaxis and Phagocytosis 259

Artificial Imitations of Ameboid Movement 260

Relation of the Above Experiments to the Phenomena Exhibited by Leucocytes in Inflammation 263

Suppuration 267

Composition of Pus 269

Sputum 273

CHAPTER XII Proliferation and Regeneration 276

Chemical Basis of Growth and Repair 279

Vitamines or Food Hormones and Deficiency Diseases 280

Beriberi _ 283

Keratomalacia or Xerophthalmia 284

Nutritional Dropsy (War Dropsy or Famine Edema) 285

Scurvy 286

Pellagra 287

CHAPTER XIII Disturbances of Circulation and Diseases of the Blood 290

The Composition of the Blood 290

Hemorrhage 293

Hemophilia 298

Anemia and the Specific Anemias 301

Secondary Anemias 301

Chlorosis 303

Pernicious Anemia 305

Leukemia 309

Hyperemia 312

Active Hyperemia 312

Passive Hyperemia 313

Thrombosis 315

Fibrin Formation 315

The Formation of Thrombi 323

Embolism 325

Infarction 327

CHAPTER XIV Page

Absorption of Lymph 338

The Pathogenesis of Edema 340

Special Causes of Edema 348

Composition of Edematous Fluids 352

Varieties of Edematous Fluids 358

Chemistry of Pneumothorax 365

Chapter XV

Retrogressive Changes (Necrosis, Gangrene, Rigor Mortis, Parenchymatous Degeneration) 367

Causes of Necrosis 371

Varieties of Necrosis 382

Fat Necrosis 387

Gangrene 391

Rigor Mortis " 392

Atrophy 395

Cloudy Swelling 396

CHAPTER XVI Retrogressive Processes (Continued), Fatty, Amyloid, Hyaline, Colloid

and Glycogenic Infiltration and Degeneration 400

Physiological Formation of Fat 40 1

Pathological Fat Accumulation 401

Pathogenesis of Fatty Metamorphosis , 409

Processes Related to Fatty Metamorphosis 412

Adipocere 412

Pathological Occurrence of Fatty Acids 418

Pathological Occurrence of Cholesterol 419

Amyloid Degeneration 421

The Origin of Amyloid 425

Hyaline Degeneration 427

Colloid Degeneration 429

Mucoid Degeneration 430

Glycogen in Pathological Processes 432

Physiological Occurrence 433

Pathological Occurrence 434

CHAPTER XX Pathological Conditions Due to, or Associated with, Abnormalities

in Metabolism, Including Autointoxication 530

Toxemias of Pregnancy 540

Eclampsia 541

Chemical Changes of Acute Yellow Atrophy 550

Acid Intoxication and Acetonuria 555

Diabetic Coma 558

Acidosis and Acetonuria in Conditions Other than Diabetes .... 563

Alkalosis 566

Acetonuria Without Marked Acidosis 567

Fatigue ; 569

The Poisons Produced in Superficial Burns 571

Chapter XXI

G astro-Intestinal "Autointoxication" and Related Metabolic Disturbances 574

I. The Constituents of the Digestive Fluids 575

II. Products of Normal Digestion 575

III. Products of Putrefaction and Fermentation 578

A. Protein Putrefaction 578

The Pressor Bases 584

Alkaptonuria 586

Cystine and Cystinuria 590

B. Products of Fermentation of Carbohydrates 592

C. Products of the Decomposition of Fats 592

Results of Gastro-intestinal Intoxication 593

Acute Intestinal Obstruction 596

CHAPTER XXII Diseases of the Thyroid 597

The Functions of the Thyroid 597

Chemistry of Goiter 604

Myxedema and Cretinism 607

Page

Exophthalmic Goiter 609

The Parathyroids 613

The Adrenals and Addison's Disease 615

Addison's Disease 620

The Hypophysis and Acromegaly 621

Thymus and Other Ductless Glands 624

CHAPTER XXIII The Chemistry of Uric Acid 626

Formation of Uric Acid 628

Destruction of Uric Acid 632

The Occurrence of Uric Acid in the Blood, Tissues and Urine 634

Gout 636

Uric-acid Infarcts 640

CHAPTER XXIV Carbohydrate Physiology 644

The Blood Sugar ' 649

The State of the Sugar in the Blood 650

Diose 652

Trioses 653

Tetroses 656

Pentoses 656

Chronic Pentosuria ." 657

Hexoses 657

Galactose 661

Levulose (Fructose) 662

Polysaccharides 663

Glycosurias 664

Phlorhizin Diabetes 666

Pancreas Diabetes and Diabetes Mellitus 671

Index 679

CHEMICAL PATHOLOGY

Introduction

Since Virchow founded modern pathology the unit of all anatomical considerations of disease has been the cell, and in physiology the same unit has been found equally useful. When either physiological or pathological processes are studied from a chemical standpoint, the cell is still found occupying nearly as fundamental a position, for we can seldom go back to molecules and atoms in investigating biological problems. Although we know that within each cell are many different chemical substances, and that numerous different enzymes and other agencies are exerting their influences upon them, yet we find that the reactions are all profoundly affected by the environment in which they occur, and it is the structure of the cell that determines the environment of its chemical constituents. All chemical reactions are modified by physical influences, and an enzyme may have quite a different effect upon a substance when it acts in a test-tube from what it will have when in a living cell, whose structure permits the diffusion of one substance while preventing that of another, and where countless other substances and enzymes may participate in the changes. The cell is the structural unit of the living organism, and as by its physical properties it modifies chemical processes, so it becomes practically the unit in physiological and pathological chemistry. All consideration of the chemistry of disease must thus refer back to the chemistry and physics of the normal cell, and on this account a brief resume of these subjects may serve as a fitting introduction to the strictly pathological matters to follow.1

As applied to the animal tissues, the term "cell" is entirely a misnomer, for it describes accurately only such forms of " cells" as are

1 Of necessity, only so much of the very extensive literature on cell structure and cell chemistry can be considered as will have direct bearing upon the subject matter to follow, referring the reader for more detailed information to such works as Wilson's "The Cell in Development and Inheritance;" Mathews' " Physiological Chemistry;" Hammarsten's "Physiological Chemistry;" Gurwitsch's "Morphologie und Biologie der Zelle;" Hober's " Physikalische Chemie der Zelle und der Gewebe;" Hamburger's "Osmotischer Druck und Ionenlehre;" Loeb's "Dynamics of Living Matter;" Oppenheimer's "Handbuch der Biochemie;" and Bottazzi, "Handbuch der vergl. Physiologie," Vol. I, for general discussion, and to the most important monographs for treatment of special points. 2 17 found in plants, in which the prominent feature is the limiting wall, forming a cell to enclose a fluid content. In most instances the "cell" answers better to the definition, "a mass of protoplasm;" but usage makes language, and no possible confusion can arise from the prevailing universal use of the original term, except, perhaps, that the term is prone to carry with it the thought of the walls of the cell being much more prominent than they really are. This is not so unfortunate a result, perhaps, for, as we shall see later, the limiting surfaces of the cell, even when too thin to be readily demonstrable, may play a much more important part in cell chemistry than their appearance indicates.

The morphological division of the cell into cell wall, cytoplasm, nucleus, and nucleolus can hardly be followed out chemically, for if we surmount to some extent the difficulties in the way of studying the different portions separately, we find that the differences between them are rather quantitative than qualitative. And, furthermore, however different the cells of one organ or tissue may appear from those of another organ or tissue under the microscope, when analyzed by the chemical methods at present at our disposal we find the differences very slight indeed. Certain substances are found in every living cell, and in quantities usually not greatly dissimilar; hence they are assumed to be the most important constituents of protoplasm, and are sometimes called the primary constituents of the cell. Many other secondary constituents may also be present, some of which are so nearly universal that we are not sure but that they really are primary cell components; such are fat and glycogen. Others are characteristics of certain cells, such as melanin and keratin, or specific products of cell metabolism, such as mucin and the specific enzymes. The great histological and chemical differences existing between different tissues depend often on these secondary products, as in fat tissue and squamous epithelium; or upon the intercellular substance, as with connective tissue, cartilage, bone, etc., which may be looked upon as products of cell activity.

Protoplasm, as the term is generally used, includes the various primary constituents with the fluids permeating or dissolving them, but does not include the more conspicuous secondary constituents, such as fat droplets, pigment granules, etc., nor the cell membrane when such exists. Evidently it is a very indefinite term, to be avoided as much as possible, particularly because of the confusion as to whether it includes the nucleus or not, different authors differing in this respect in their usage of the word.

CHEMISTRY OF THE ESSENTIAL CELL CONSTITUENTS

To enumerate the primary or essential constituents of the cell absolutely is not possible, for the rapid advances in chemistry may alter all classifications without warning, but practically they may be

CHEMISTRY OF PROTEINS 19

grouped under the headings of proteins, lipins, carbohydrates, salts, and water, and no attempt will be made to give here more than the most essential features concerning each.

In the last few years we have obtained something approaching a scientific understanding of the chemical nature of this great group of the most highly complex bodies known to chemistry. Our information has been obtained almost exclusively through studies of the products obtained by splitting up the protein molecule, for as yet relatively little has been accomplished through synthesis. Proteins can be decomposed by the action upon them of acids or alkalies in various concentrations, by superheated steam, by digestive ferments, and by bacteria. The products obtained in these different ways are not all the same, for some substances may be formed by oxidation, reduction, decomposition, combination, or condensation of the various products of simple cleavage, and it is necessary to distinguish between the primary cleavage products (those which exist as radicals within the molecule) and the secondary products (those not existing preformed in the molecule but formed by transformation of the primary products). This can usually be done, and it is found that so far as the primary products are concerned, it makes little difference which method of cleavage (or hydrolysis, since in the splitting, water is combined with the organic substances) is used.

At first the proteins split up into compounds still possessing many of the features of the typical protein molecule, such as albumoses and peptones, and these bodies are then further resolved into simpler substances, which are not aggregates of several smaller molecules as are the proteins, and which can be obtained in pure crystalline form. No matter which method is used we find the process going through these stages, and, as before mentioned, the primary crystalline products obtained are practically the same quantitatively as well as qualitatively. Some methods, e. g., bacterial decomposition, however, lead in the end to more profound or different decomposition of the cleavage products into secondary substances. The similarity of the results obtained in these different ways indicates that there are definite lines of cleavage in the protein molecule along which separation takes place, independent of the nature of the agency at work, and that the substances obtained represent the "building stones" of the entire molecule.

These substances all have in common one important point: each one is an acid, which has a NH2 group substituted for a hydrogen atom on the carbon nearest the acid radical (the a-position). It makes no difference what the rest of the radicals are, whether they are simple chains (leucine), or members of the cyclic or aromatic series (tyrosine), or sulphur-containing bodies (cystine), without exception this relation of a NH2 group to an acid radical is constant, as in this formula:

NH2

/ R— CH— COOH.

Through this arrangement every one of the constituents of the protein molecule is provided with a group with a strong basic character and a group with a strong acid character, and hence it is possible for them to unite with one another in indefinite numbers, and, because of the great variety of individuals, in practically an infinite number of combinations. It is believed that it is in just this way that the protein molecule is built up. By artificially uniting various cleavage products Emil Fischer succeeded in producing large molecules made up of several amino-acid radicals (called by him "polypeptids")3 which show some of the characteristics of the peptones, and this is the nearest that investigators have yet come to synthesizing a protein molecule. The union is accomplished by the splitting off of water, corresponding to the addition of water that occurs when the protein

2 For the complete literature of this subject see "The Chemical Constitution of the Proteins," Plimmer, London, 1917; "The General Character of the Proteins," Schryver, London, 1912; "The Vegetable Proteins," Osborne, London, 1910 (all in the series of "Monographs on Biochemistry"). Also "The Physical Chemistry of the Proteins," T. B. Robertson, New York, 1918.

3 Reviewed by Fischer, in Ber. deut. Chem. Gesell., 1906 (39), 530.

molecule undergoes cleavage. It may be illustrated by showing the formation of the simplest polypeptid, glycylglycine,

NH20 NH2 O

CH2— C— I OH + H 1 HN — CH2 — COOH = CH2 — C — HN — CH2— COOH + H2O.

(glycine) (glycine) (glycylglycine)

For these reasons it is believed that the protein molecule consists of great numbers of amino-acid groups, combined with one another through their basic and acid radicals, and that the various proteins are different from one another because they contain different numbers or varieties or orders of combination of amino-acids. For example, the globin of hemoglobin yields no glycine on hydrolysis, while gelatin yields 16.5 per cent. On the other hand, gelatin is free from tyrosine. Some of the protamins (proteins obtained chiefly from spermatozoa) yield as high as 58 to 84 per cent, of arginine, while the simpler amino-acids with but one N (monoamino-acids) are scanty, and most varieties are lacking.

It will be noticed that when two amino-acids unite, as seen in the formation of glycylglycine, an acid radical and a basic radical are still left free. In this may be seen the explanation of the peculiar amphoteric nature of proteins. As long as these two groups are free the proteins can combine with either acids or bases, as they are well known to do, and hence they react as either acids or bases under different conditions.

It must not be imagined that the structure of the complete molecule is simply a long straight chain of amino-acids joined only in the same way as are the components of glycylglycine. The existence of the diamino-acids, of the benzene rings, of hydroxy! groups, (as in serine or tyrosine), of ring compounds, (as pyrrolidine carboxylic acid), of substances with two acid groups, (as glutaminic and aspartic acid), adds complications to the formation until it is impossible to estimate just how all the various building stones may be arranged. We must bear in mind the size of the protein molecule, which Hofmeister has estimated (for serum albumin) as having a molecular weight of 10,166, and for hemoglobin the molecular weight has been estimated at 16,669. Within such a "giant molecule" there is room for variety almost beyond computation.

The Proteins of the Cell. — By physiological chemists proteins are classified into simple 'proteins, of which egg and serum albumin are types; and compound proteins, which are characterized by having some special non-protein group which can be split off, leaving behind a characteristic protein residue, e. g., nucleo-proteins, glyco-proteins. As primary cell constituents the following varieties of proteins may be mentioned; albumin, globulin, nucleo-protein, nucleo-albumin or phospho-protein, and insoluble proteins. At one time it was thought that cytoplasm consisted chiefly of albumin, like white of egg, but we now know that this forms but a small part of the cell proteins, often occurring only as traces. It is held by some that true albumin occurs only as a building or intermediate cleavage product of the more complicated forms of cellular proteins, and is itself of relatively slight importance in cell life, not participating in chemical changes except as a food-stuff.

Albumins are characterized chiefly by their greater solubility in water, and in being less easily precipitated than most proteins. They seem to be a fundamental type of proteins. The three forms of albumin that have been described in animal tissues or products are egg-albumin, lactalbumin of milk, and serum albumin ; probably cell albumin is most closely related to the last, and what has been described as cell albumin is perhaps in many cases but serum albumin that has been imperfectly removed.

CHEMISTRY OF PROTEINS 21

Globulins also occur in all cells, but in small amounts in most animal cells except the muscles, whose chief proteins belong to this or a closely related group. The globulins are quite similar to the albumins, so that there is really no sharp line between the two groups. Their insolubility in water separates them from albumins, and their solubility in dilute neutral salt solutions from the more complex proteins. An important feature of the globulins is the low temperature at which they coagulate — some so low that Halliburton4 believes it possible that they may be coagulated within the cells during high fevers.

Hammarsten has long maintained that simple proteins form a relatively insignificant part of the cytoplasm, in opposition to the once-prevalent view that the nucleo-proteins were limited to the nucleus, and that the cytoplasm was chiefly albumin and globulin. The general trend of opinion as influenced by the results of researches has been favorable to his contentions, and we shall probably not be far wrong in accepting his statement that — "The chief mass of the protein substances of the cells does not consist of proteins in the ordinary sense, but consists of more complex phosphorized bodies, and that the globulins and albumins are to be considered as nutritive materials for the cells or as destructive products in the chemical transformation of the protoplasm."5

Nucleo-proteins are considered to be the most important constituents of the cell, both in quantity and in relation to cell activity. In structure the nucleoproteins are very complex, as indicated by the different products yielded on hydrolytic cleavage of the molecule. Furthermore, there are many varieties, depending both upon the nature and proportions of the component parts. They may be described as consisting of two primary constituents — (1) nucleic acid and (2) a protein body, in chemical combination with each other like a salt. The term -nucleic acid covers a large group of substances, which are characterized, on the one hand, by their frequent occurrence bound with proteins, and, on the other hand, by their yielding phosphoric acid and purine bases, pyrimidines and pentoses or hexoses on cleavage. Diagrammatically the manner of cleavage of the nucleoproteins may be indicated as follows:

Nucleo-protein

. /\ nuclein6 protein nucleic acid protein phosphoric acid purine bases, pyrimidines and carbohydrates.

In the cell the nucleo-proteins probably exist partly as solid structures, e. g., the chromatin framework of the nucleus, and partly dissolved in the plasma. An interesting phenomenon is the alteration in the chromatin nucleo-proteins during cell division, when they seem to lose part of the combined protein and approach more nearly pure nucleic acid— just as inorganic salts occur with the acids and bases saturating each other more or less incompletely, e. g., mono-, di-, and tribasic phosphates. In this we have a chemical explanation of the intensity of the staining of dividing nuclei by basic dyes.7

Phosphoproteins resemble nucleo-proteins to the extent that they also yield phosphoric acid, and are somewhat similar in solubility and digestibility. They are essentially different, however, in that they do not yield nucleic acid or purine bases on cleavage. Probably members of this group are also constant components of cells.

Glycoproteins (or gluco-proteins) and phospho-glycoproteins are also believed to occur frequently or constantly in protoplasm. They are compounds of proteins with a sugar or sugar-like group, which probably usually contains nitrogen, thus differing from the ordinary hexoses and pentoses.

4 Halliburton and Mott, Archives of Neurology, 1903 (2), 727; also see Halliburton's "Chemistry of Muscle and Nerve."

3 See Kossel, Mtinch. med. Woch., 1911 (58), 65.

6 Probably nuclein should be considered as merely one variety of nucleoprotein, with less protein than the other varieties.

7 The chemistry of the nucleo-proteins is discussed in the chapter on Uric Acid Metabolism and Gout, Chap, xxiii.

Insoluble proteins, or bodies resembling tbe coagulated proteins in their lack of solubility in various fluids, are left behind after the other proteins have been extracted from the cells. Their significance is not known: whether to a large extent artificially produced or whether a normal structural element of the cell.

Fats and Lipoids (Lipins)8

Lipoids is a term in common use but of indefinite significance; most usually it comprehends the intracellular substances which are soluble in ordinary fat solvents, but which are not simple fats or fatty acids, lecithin and cholesterol being the most important of the lipoids.