INSUSCEPTIBILITY OF PUPS TO CHLOROFORM POISONING DURING THE FIRST THREE WEEKS OF LIFE

Employing the liver necrosis as an index, we find that pups are immune to the poisonous action of chloroform anesthesia. This immunity or resistance to late chloroform poisoning is complete in the first week, very striking during the second and third weeks, and usually disappears during the fourth week of life. Nests of blood-forming cells (blood islands) are numerous in the sinuses of the liver during the first week and normally become progressively less numerous each week until the liver is almost free from these cells at the end of the fourth week of life. It is considered possible that these leucocytes in the blood islands protect the liver against the specific action of a known poison (chloroform). The mechanism of this hypothetical protective action is not understood, but it may consist of a process of neutralization. Perhaps this protective action against poisons is an important part of the functions of white blood cells and may bear an important relationship to the process of inflammation

PREGNANCY AND CHLOROFORM ANESTHESIA : A STUDY OF THE MATERNAL, PLACENTAL, AND FETAL TISSUES.

Pregnant dogs are susceptible to chloroform administered shortly before delivery or during labor, and show the same degree of liver injury as normal dogs, or even a somewhat greater one. Chloroform anesthesia may cause more or less hyaline necrosis in the border zone between the maternal and fetal parts of the placenta that may lead to hemorrhage, placental separation, and premature delivery. Chloroform anesthesia causes no injury to the liver of the fetus nor to any other fetal organ, in spite of the fact that it can be demonstrated to be present in these tissues. These experiments raise objections to the use of chloroform in pregnant women where an anesthetic must be continued for half an hour or longer. Chloroform anesthesia may be admissible for the few minutes at the end of the delivery, but when operative measures are necessary, before or after delivery, it is a dangerous anesthetic and surely capable of producing injury to the liver in the manner recognized in the case of normal persons. Objections may be raised to the application of conclusions derived from experiments on dogs to human cases; but the similarity of the effects of chloroform in man and dog surely affords a sound basis of comparison. Two fundamental facts would seem to be now established: (1) Normal human adults may be fatally poisoned (late chloroform poisoning) by chloroform anesthesia of one half to one hour's duration. (2) Normal and pregnant dogs are equally susceptible to late chloroform poisoning, and may be fatally poisoned by an anesthesia of two hours' duration. Hence one may conclude that probably normal and pregnant human beings are equally susceptible to chloroform poisoning, that chloroform anesthesia during any part of the pregnant period is capable of causing liver necrosis, and, consequently, that chloroform is a dangerous anesthetic

THE PRESENCE OF A WEAK HEMOLYSIN IN THE HOOK WORM AND ITS RELATION TO THE ANEMIA OF UNCINARIASIS

1. The hook worm of man—both the Old and New World types—contains a weak hemolytic agent active in vitro. It is soluble in salt solution, is easily destroyed by heat and acts slowly. 2. The hemolysin is present in all parts of the worm and probably is associated with the intestinal tract. 3. The hook worm of the dog contains a similar hemolysin. 4. These hemolysins are not specific, but will act on human blood as well as on that of the dog and rat. They are only demonstrable in concentrated extracts. 5. Concentrated extracts of the human whip worm may be hemolytic to some bloods. 6. The round worm of man contains no hemolytic principle in any part of its body. 7. It seems very unlikely that this weak hemolysin found in the hook worm can have any relation to the anemia of uncinariasis. 8. Study of the "blood cysts" in the human intestine shows that the hook worm may live in a small amount of the host's blood for days without causing any marked hemolysis

STUDIES ON THE BLOOD PROTEINS : II. THE ALBUMIN-GLOBULIN RATIO IN EXPERIMENTAL INTOXICATIONS AND INFECTIONS.

The intoxication which develops as the result of a simple obstruction or a closed intestinal loop is accompanied by definite changes in the coagulable proteins of the blood serum. These changes consist essentially in an alteration in the normal albumin-globulin ratio; the globulin fraction is greatly increased and at times the normal relation of the two fractions may show a complete inversion. The increase in the globulin content of the blood serum is most marked in the animals which show some of the complications met with in loop animals,—rupture of the loop and peritonitis. In the latter conditions especially, the globulin increase is rapid and large. We believe this reaction to be of diagnostic value in acute infections attended by the sudden liberation and absorption of a toxic exudate. Infections and intoxications produced by inflammatory irritants are also accompanied by a rise in the blood globulins. This observation suggests that tissue disintegration with absorption of toxic products is responsible for the changes noted, and that bacterial invasion is important only in as far as it gives rise to toxic substances. Animals which have developed a tolerance to proteose intoxication following the periodic injection of small doses of proteose do not show a globulin increase. These experiments do not support the view that the rise in globulins observed in these experimental conditions is an expression of a resistance or tolerance developed by the animal. From the experimental evidence it seems more probable that the alteration in the partition of the blood protein fractions is one of the results of the metabolic disturbance which has been shown to occur in these conditions

THE PATHOGENESIS OF ICTERUS

These experiments indicate that, in obstructive jaundice, the bile which escapes from the liver is absorbed by the hepatic capillaries and carried by the blood to the kidneys. The presence of a thoracic duct fistula influences in no way the development of icterus after total obstruction of the common bile duct. Bile pigments, sufficient to give a Salkowski test, may or may not appear in the lymph of the thoracic duct in such experiments, their appearance possibly depending upon the rapidity of bile secretion and the amount of lymph flow. Chronic icterus developing in an animal with a thoracic duct fistula gives an interesting distribution of bile pigments in the body fluids. The lymph and pericardial fluid contain the same amount, which is much less than the content of bile pigment in the blood serum and urine. It seems clear that in both acute and chronic obstructive jaundice the lymphatic apparatus takes no essential or active part in the absorption of bile pigments from the liver. At best, the lymphatic system is a secondary factor in the mechanism of jaundice

FIBRINOGEN OF THE BLOOD AS INFLUENCED BY THE LIVER NECROSIS OF CHLOROFORM POISONING

1. Chloroform anesthesia for two hours or more will cause more or less central liver necrosis in dogs, depending on the length of the anesthesia and the susceptibility of the animal. 2. If the fibrinogen of the blood of such an animal be estimated at intervals, it is found that this proteid shows a drop corresponding to the amount of liver necrosis. 3. By administering chloroform, the fibrinogen may be almost eliminated from the circulating blood, and the poisoned animal may bleed for hours from small skin pricks or cuts. 4. The liver can recover from a grave injury due to chloroform and return practically to a normal condition in about ten days. 5. The fibrinogen reappears in the blood as the liver effects its repair. It seems that the quantity of fibrinogen present is a good indicator of the liver efficiency and a fairly accurate index of the amount of liver injury. 6. Shortly after the recovery of the liver from an injury due to chloroform, one may find an excess of fibrinogen in the blood. 7. In severe cases of chloroform poisoning, the calcium of the blood was normal or slightly increased, and the thrombin was normal. 8. These experiments give no evidence that the formation of thrombin or prothrombin is dependent upon liver activity. 9. The hemorrhages of chloroform poisoning are due not to lack of blood clotting but to inefficient coagulation. The clot has not the body and toughness supplied by the fibrinogen, and is, therefore, unable to check even capillary hemorrhage. 10. Fibrinogen is either formed in the liver or is wholly dependent upon liver activity for its production

I. RENAL FUNCTION INFLUENCED BY INTESTINAL OBSTRUCTION

Associated with the intoxication of intestinal obstruction there exists a definite impairment of the excretory function of the kidneys. The degree of functional depression corresponds roughly with the intensity of the clinical intoxication. The decrease in the urea ratio and in the capacity of the kidneys to excrete sodium chloride is more marked than is the percentage decrease of phenolsulfonephthalein elimination. The great increase in the non-protein nitrogen of the blood usually observed in acute intestinal obstruction, which has hitherto been explained as being due entirely to an increased rate of protein catabolism, is due in part to retention of the products released from the injured cell protein. It is probable that the impaired renal function is due to direct action of the toxic substances upon the renal epithelium. The actual demonstration of this renal injury is perhaps the strongest evidence so far obtained to prove the presence of an actual toxic substance in the blood during intestinal obstruction. This obscure disability of the kidneys during the height of the intoxication of acute ileus should always be considered in the clinical management of this condition. It may also serve as a guide to indicate the degree of intoxication

HEMOGLOBIN PRODUCTION FACTORS IN THE HUMAN LIVER : III. ANEMIAS—PRIMARY, APLASTIC AND SECONDARY—LEUKEMIAS

Biological assay of the human liver in various types of anemia shows conspicuous differences in the concentration of hemoglobin producing factors. Pernicious anemia shows very high values and the liver in untreated cases may show maximal storage of the hemoglobin producing factors. Liver therapy reduces this store as the missing factor is supplied and new hemoglobin and red cells can be turned out by the marrow. Aplastic anemia likewise shows high concentration of hemoglobin producing factors as there is no outlet for this material through the red marrow. Secondary anemia due to loss of blood will show low normal values but even long standing severe anemia will not seriously deplete this store of hemoglobin producing factors in the liver. Secondary anemia due to blood destruction within the body shows higher values and some excess store of hemoglobin producing factors and iron. Leukemia gives a biological assay like secondary anemia due to blood loss and always presents definite anemia. Iron analyses show conspicuous differences and iron concentration within the liver parenchyma does not in any way parallel the concentration of hemoglobin producing factors. The highest values for iron concentration are found in aplastic anemia (70 mg. per cent)— high values in pernicious anemia (51 mg. per cent)—normal values in leukemia (13 mg. per cent)—and low values in anemia due to loss of blood (5.3 mg. per cent). These findings should aid in a more complete understanding of the pathogenesis and internal metabolism of various anemias

HEMOGLOBIN PRODUCTION FACTORS IN THE HUMAN LIVER : ANEMIAS, HYPOPROTEINEMIA, CIRRHOSIS, PIGMENT ABNORMALITIES, AND PREGANCY

Human liver tissue has been assayed to determine the amount of hemoglobin production factors in normal and abnormal states. Standardized dogs made anemic by blood removal have been used in this biological assay. Normal animal liver as control is rated as 100 per cent. Normal human liver tissue as compared with the normal animal control contains more of these hemoglobin production factors—a biological assay ratio of 120 to 160 per cent. Infections, acute and chronic, do not appear to modify these values, the concentration of hemoglobin-producing factors falling within the normal range. Pernicious anemia and aplastic anemia both show large liver stores of hemoglobin-producing factors—a biological assay ratio of 200 to 240 per cent. Therapy in pernicious anemia reduces these liver stores as new red cells are formed. Secondary anemia presents a low normal or subnormal liver store of hemoglobin-producing factors—an assay of 60 to 130 per cent. Hemochromatosis, erythroblastic anemia, and hemolytic icterus in spite of large iron deposits in the liver usually show a biological assay which is normal or close to normal. Polycythemia shows low reserve stores of hemoglobin-producing factors. Leukemias present a wide range of values discussed above. Hypoproteinemia almost always is associated with low reserve stores of hemoglobin-producing factors in the liver—biological assays of 60 to 80 per cent. Hypoproteinemia means a depletion of body protein reserve stores including the labile protein liver reserves—a strong indication that the prehemoglobin material (or globin) is related to these liver stores. Pregnancy, eclampsia, and lactation all may present subnormal liver stores of hemoglobin-producing factors. Exhaustion of protein stores lowers the barrier to infection and renders the liver very susceptible to many toxic substances. It should not be difficult to correct hypoproteinemia under these conditions and thus relieve the patient of a real hazard

BILE FISTULAS AND RELATED ABNORMALITIES : BLEEDING, OSTEOPOROSIS, CHOLELITHIASIS AND DUODENAL ULCERS

A clearer understanding of the various abnormalities which may develop in relation to the experimental or clinical bile fistula will be of value to the laboratory worker as well as to the physician and surgeon. A better comprehension of these diseased conditions will make for a saner analysis of the great mass of experimental data relating to the various types of bile fistula. Too frequently in the literature the bile fistula material is used to debate a physiological state whereas in reality the animal is in a pathological condition. It is possible but not easy to keep a bile fistula dog in a normal state for months or years if proper attention is given to the diet and physical state. The most significant abnormalities are—intestinal disturbances, spontaneous bleeding, osteoporosis, cholelithiasis and duodenal ulcer. Three types of bile fistula were used in our experiments and each one has its advantages and disadvantages. Intestinal intoxication is best controlled by diet, by whole bile or bile salts or combinations of dog and ox bile. Spontaneous bleeding seems to be due to the loss of something by way of the bile and this can be prevented by bile feeding. The blood deficiency appears to be a lack of prothrombin. Osteoporosis appears inevitably after many months if bile is excluded from the intestine. This state is related to the lack of absorption of vitamin D. It is of some interest that liver feeding will prevent it. Duodenal ulcers and cholelithiasis are common in bile fistula dogs and absolute control or prevention is not easy. It may be restated that bile secretion into the intestine is necessary for normal health and even for actual continuation of life beyond a few months' period. Some of these experimental data should be of value to physicians and surgeons in the care and study of human fistula cases and should emphasize the necessity of prompt dietary control