Scobey-Is Human Poliomyelitis Caused By An Exogenous Virus?

Is Human Poliomyelitis Caused By An Exogenous Virus?

by Ralph R. Scobey, M.D.

Science (1954) v51, p117:

Note from Jim West: This article was originally published as a 2-part series (April and May, 1954) - at the time of the Salk Vaccine Field Trials, Spring 1954.

• Introduction  
• Relationship Between Toxicology And Virology  
• The Nature Of A Virus  
• Medical approaches to polio are ineffective because of the ingrained concept of the exogenous virus.
• Poison And Toxic Activating Factors  
• Incubation Period Of Human Poliomyelitis Versus Experimental Animal Poliomyelitis  
• Precipitators Of Human Poliomyelitis  
• Comparative Pathology Of Human Versus Experimental Animal Poliomyelitis  
• Antibody Formation And Human Poliomyelitis  
• Koch's Postulates And Human Poliomyelitis  
• Biochemical Factors In Human Poliomyelitis  
• Experimental Animal Poliomyelitis In Human Beings  
• Comment  
• Summary  

Introduction

It is now nearly half a century since Landsteiner2 and Flexner and Lewis3 established the basis for the virus theory of the cause of poliomyelitis. Since that time the virus has been isolated, purified, classified into strains, photographed, cultured, and vaccines prepared with it in the experimental laboratory. However, human poliomyelitis remains still an enigma and many things concerning it cannot be explained by the exogenous virus theory. Landon4 stated, in 1938, that experimental evidence points to a filtrable virus as the causative agent of poliomyelitis, although so far as the human subject is concerned the theory still is not definitely proved. Van Rooyen and Rhodes5, ten years later (1948), make the following significant remark concerning this fact: “Theories of the pathogenesis of human poliomyelitis have resulted largely from experimental work on monkeys rather than on observations on the patient.” A theory is valid only if it explains all facts without exception. Poliovirus causality has definitely not been proven as of 1954.

The writer6,8 has emphasized repeatedly, as have others, that, despite the finding of a virus associated with cases of human poliomyelitis, the fundamental cause of this disease appears to be a poisonous or toxic activator and that the fundamental problem, as far as the human disease is concerned, is one of chemistry. The clues are numerous, well known, and too strong to be ignored; they have not been followed adequately. It is the purpose of this report to simplify, as much as possible, this concept of the cause of human poliomyelitis and to show that there may be an intimate relationship between virus diseases and diseases resulting from toxic causes.  

Relationship Between Toxicology And Virology

The association of viruses with cases of poisoning is a well recognized fact. It is illustrated by the herpes simplex that follows the injection of vaccines, milk, colloidal metals, ingestion of foodstuffs, general anaesthesia, etc.5, 19-21 and the herpes zoster that follows the intake or injection of arsenic, bismuth and sulfonamides, and carbon monoxide, alcohol, or phenobarbital poisoning22-24. Ritchen and Kantor25 (1947) reported herpes zoster as a toxic manifestation from the administration of antimony in the treatment of schistosomiasis. Both herpes simplex and herpes zoster occur at times in association with infectious diseases which appears to indicate that toxins produced in the course of these specific diseases may be responsible. The lesions of both herpes simplex and herpes zoster, regardless of the primary cause, are histologically characterized by intranuclear inclusion bodies, and a virus can be isolated from the lesions. Fixation occurs between the sera of cases of arsenical or bismuth zoster and zoster antigen26. "...a well recognized fact."

Modern explanations are that herpes manifest during periods of stress.

In 1900, there occurred an epidemic of arsenical poisoning in and around Manchester, England, involving several thousand beer drinkers27-29. For fully six months the etiology was not discovered and the patients exhibited in sequence digestive symptoms, nasal and pharyngeal catarrh, bronchitis, acute skin lesions, disturbances of sensibility, motor paralysis, pigmentation and keratoses, Reynolds28, toward the end of this period, observing an unusually large number of cases of herpes zoster during the epidemic and recalling numerous reports of this type of eruption occurring in association with arsenical poisoning, came to the conclusion that this drug must be the source of the epidemic. Investigations revealed that the arsenic originated from Spanish pyrites that war used in the making of sulfuric acid which was employed for the preparation of sugars used in the brewing of beer. Thus, the cause of a mysterious epidemic with many protean features, viz, gastro-intestinal, respiratory, dermatological, and nervous symptoms was eventually unraveled by finding the clue in a: virus disease which was a concomitant feature. There was clearly a cause and effect relationship.

In the earlier literature there appeared many reports of cases of poliomyelitis complicating or following the common infectious diseases, viz, measles, scarlet fever, influenza, smallpox, etc., which were interpreted as resulting from the effects of the toxins of the original disease on the anterior horn cells of the spinal cord. More recent work, which indicates a similar situation, is the poliomyelitis following the injection of toxic antigens, viz, pertussis vaccine and diphtheria toxoid. The writer already has discussed this form of human poliomyelitis in a previous report 8.

A clue to a relationship between virus diseases and diseases resulting from toxic causes appears to exist in the inclusion body. These bodies were considered to occur only in virus diseases and to be composed of numerous virus particles or elementary bodies. However, it is now known that inclusion bodies occur not only in virus diseases but also in a variety of other diseases, including those resulting from poisons and toxins. Although transfer experiments with experimental animals have not always been possible with material containing inclusion bodies, the reason why viral material is present in some cases and not in others has not been explained.  

Blackman30 (1936) found intranuclear inclusion bodies in the kidneys and livers of children dying from the effects of acute lead poisoning and lead encephalitis. He was able to produce them experimentally in the kidneys and livers of white rats by administering lead carbonate in water mixed with the food that was fed to the animals.  

Wolff and Orton31 (1932) found intranuclear inclusion bodies similar to those found in poliomyelitis in a number of conditions, including toxemia of pregnancy, tuberculous meningitis, chronic basilar meningitis, myasthenia gravis, tetanus, acute suppurative leptomeningitis, chronic epidemic encephalitis, meningeal fibroblastoma, pernicious anemia, dissecting aneurism, chronic pulmonary tuberculosis, cerebral epidermoid, suppurative thrombophlebitis of uterus and pelvic veins, aneurism of the right anterior cerebral artery (ruptured), spongioblastoma multiforme, and protoplasmic astrocytoma.  

Hembacker and O’Leary32 (1930) showed that repetitive stimulation by electricity of the axon brings about granulation of the chromatin and its clumping about the nucleolus. The chromatin mass resembled the nuclear inclusions which have been considered pathognomic of several virus infections. Davenport et al22 (1931) found that nuclear inclusions occurred with great regularity in extirpated ganglia in hypertonic solutions. They attributed them to disturbed osmotic conditions in the cells. Lee34 (1933) observed nuclear changes following the intravenous injection of various solutions. These included 50 per cent sodium chloride, distilled water and salyrgan. Intranuclear inclusion bodies were observed which simulated those described by Covell35 (1930) in the nerve cells of acute anterior poliomyelitis.  

Cox and Olitsky36 (1934), in studies on the prevention of experimental equine encephalitis in guinea pigs by means of virus adsorbed on aluminum hydroxide, observed intranuclear inclusion bodies characteristic of encephalitis virus infections in the phagocytic mononuclear and giant cells of the induced subcutaneous nodules. When the chemical alone, free from the virus, was introduced under the skin of guinea pigs, similar inclusions were seen in the resulting foreign body reaction. Olitsky and Harford37 (1937) were able to produce intranuclear inclusion bodies, indistinguishable from those observed in virus infections, by the injection of aluminum compounds, ferric hydroxide and carbon. Brain tissue derived from apparently healthy guinea pigs produced similar inclusion bodies when it was injected. Birch and Lucas38. (1948) produced intranuclear inclusion bodies consistently with aluminum oxide injections. Van Rooyen and Rhodes5 (1948) point out: “Histological changes similar to those seen in infective encephalitis may be produced by carbon monoxide poisoning, brain injury, arteriosclerosis, uremia, pregnancy toxemia, and toxic agents like alcohol and lead.”

The Nature Of A Virus  

The word “virus” was originally used only in the singular and meant a poison. Later, with the establishment of a difference between poisons and infectious agents, the word “virus was used only in connection with the latter entities. The word was eventually applied only to those infectious agents capable of passing through filters that retarded ordinary bacteria. The relationship of poisons and viruses was not considered, but, in view of more recent developments, there appears to be a vast field yet to be explored between these two extremes. Originally "virus" meant that the patient was poisoned.

"...a vast field yet to be explored..."

Following the discovery of a virus in association with cases of human poliomyelitis, it was generally accepted, at least as a working hypothesis, that this virus is a small exogenous organism. This hypothesis led to attempts to establish a portal of entry, mechanism of dissemination within the body, and communicability in order to confirm this concept. However, these facts have not been conclusively established after nearly half a century of research. It is now known that the most intimate contacts - such as healthy and sick individuals in one bed, the attendance of physicians and nurses upon the sick, the use of unclean linen, clothes, or beds, unsanitary conditions, insects and animals, post-mortem examinations of poliomyelitis victims, and other factors - have in no wise contributed to the spread of the disease. Yet, the original concept, i.e., that the poliomyelitis virus is an exogenous organism is so deep-rooted in the minds of many physicians, as well as the public, that ineffective and obsolete measures to control human poliomyelitis continue to be employed. "...the most intimate contacts... have in no wise contributed to the spread of [polio]."

Medical approaches to polio are ineffective because of the ingrained concept of the exogenous virus.

The conspicuous achievements of Dr. Wendell M. Stanley39, a chemist, show clearly how unlimited research can bring about remarkable scientific advances, whereas the general acceptance of and adherence to a theory can cause retardation. Stanley reported in 1935, that the tobacco mosaic virus, which had been considered to be a small organism, is a crystalline protein of high molecular weight. Rivers40 (1941), a bacteriologist, described Stanley’s work as follows: “While a few investigators had stated that a chemical agent instead of a microorganism is responsible for tobacco mosaic, Stanley was the first to bring a respectable amount of proof that infectious diseases are not of necessity caused only by microorganisms. Stanley’s findings, which have been confirmed, are extremely important because they have induced a number of investigators in the field of infectious diseases to forsake old ruts and seek new roads to adventure. As much as bacteriologists hate to admit it, Stanley’s proof that tobacco mosaic virus is a chemical agent instead of a microorganism is certainly very impressive. Moreover, every one admits that the agent of tobacco mosaic is transmissible indefinitely in series from plant to plant, a fact beyond dispute, indicating abundant multiplication or reproduction of the virus. Inasmuch as reproduction is usually considered an attribute of life, great confusion and consternation has been caused. In fact, the results of Stanley’s work had the effect of demolishing bombshells on the fortress which Koch and his followers so carefully built to protect the idea that all infectious maladies are caused by living organisms or their toxins. In addition, his findings exasperate biologists who hold that multiplication or reproduction is an attribute only of life.” Scobey is struggling with some of the knowledge gaps that Carrel also experienced to a greater degree, in 1927. The finding that viruses are chemicals, which can be crystallized, that they are genetic entities, was becoming firmly established at the time this article was written.

It was thought, long before Stanley’s discovery was reported, that viruses are the product of tissue cells which have suffered the action of some deleterious influence, this new product in turn being capable of engendering the same change in other cells. Stanley41 emphasized in 1939, that the all important and fundamental problem of virus activity is one of chemical structure, and that it is a straightforward problem of structural chemistry. Enter, virology as molecular biology.

Rivers42 (1932) had stated seven years earlier, before Stanley’s amazing discovery: “The confused state of our knowledge of the viruses at the present time makes it exceedingly difficult to define the nature of these active agents. The easiest way out of the dilemma, however, would be the acceptance of the presumptive evidence that viruses are minute microorganisms. Yet, the easiest way and the one that best fits the experience of the day might not be the right one.” Subsequent developments showed that this presumptive evidence was untenable.  

Stanley’s work showed that the tobacco mosaic virus could not only be crystallized but the virus activity is a specific property of the nucleoprotein of which it is composed. Many strains of the mosaic virus have been isolated and these consist of closely related nucleoproteins. All viruses thus far purified have been found to contain or to consist of nucleoprotein and this fact has led some workers to consider it possible that viruses may be derived from genes or nuclear material. Since Stanley’s discovery, many workers believe that the particles of certain viruses are protein macromolecules that may multiply in their hosts by a process of autocatalysis.  

The concept that is now generally accepted to explain herpes manifestations is that sometime during the life of an individual the herpes viruses enter the human body and remain latent until some factor or factors activate them. The evidence to support this view, however, is still necessarily indirect and it is largely derived from seriological studies. On the other hand, there is much to support the concept presented by Doerr43, a Swiss bacteriologist, in 1938. The exogenous latent (or dormant) virus.

He considered the herpes virus to be endogenous in origin produced within the cells by certain physiological stimuli. Once the agent has been produced it will act on the cells of susceptible animals of different species as a true virus exciting in them, when appropriately injected, the production of an antiserum specifically antagonizing the virus of herpes infection. According to this view, the virus is primarily a derivative of the physiologically modified cells. Jenner44 (1804) speaks about the herpetic fluid as one of the morbid poisons which the body is capable of generating and when generated it may be perpetuated by contact. In a letter dated October 25, 1804, he says: “Children who feed on trash at this season of the year are apt to get distended bellies and on them it often appears about the lips.” The endogenous virus.

Reports of experimental work have appeared, leading to claims that normal cells have been induced to manufacture certain viruses. Carrel45 (1926) was able to produce tumors resembling Rous’ sarcoma and transmissible by cell-free filtrates with indol, arsenic, or tar in chicken embryo. Carrel’s observations have been confirmed by other workers. Fischer46 (1926), by treating cultures of normal cells with arsenic obtained on one occasion a filtrable virus capable of causing tumors. Copisarow47 (1939) says: “The predominance of infection over spontaneity cannot remain indefinitely a stereotyped assumption and tends to swing pendulum-like (at least in the domain of viruses) back to synthetic inception, with an intermediate position as an ultimate restpoint.” "Spontaneous" disease vs. cause ("infection").There is much evidence to indicate that the poliomyelitis virus is synthesized or activated within the human body instead of entering it as commonly assumed. Each poliomyelitis victim evidently develops, as a result of an exogenous factor, an autogenous infectious agent which is not transmissible under natural conditions to other human beings. However, when this infectious agent is concentrated it can be inoculated into experimental animals to produce experimental animal poliomyelitis. Thus, there is a chain of chemical reactions from the time that a human is exposed to a poison or toxin until a virus is synthesized or activated. The experimental disease, on the other hand, using the product (virus) resulting from the poison activator, is purely a virus infection. The failure to demonstrate in the prevention and treatment of natural human poliomyelitis the efficacy of blood serum, the vaccines of Kolmer and Brodie, zinc sulfate nasal sprays, the sulfa drug, darvisul (phenosulfazole), and gamma globulin, although their value was proven conclusively in experimental animal poliomyelitis, appears to indicate clearly an entirely different mechanism in the natural human disease in contrast to the artificial disease in experimental animals. These facts are represented in Chart 1.omitted

Poison And Toxic Activating Factors

There are potential poisonous and toxic activating factors present in food and water during epidemics of poliomyelitis that can account for much that has been thus far unexplainable by the exogenous virus theory. Fruits, vegetables, milk and water have been mentioned many times in relation to the cause of human poliomyelitis by medical writers, and they are suspected frequently by the laity. Specific instances of an etiological relationship between fruits, vegetables, milk and water and human poliomyelitis have been reported infrequently, however, because of the fact that epidemiological studies are limited almost exclusively to possible person to person contacts and carriers of an exogenous virus. Sabin48 (1951), although insisting on the exogenous virus etiology of human poliomyelitis, implicates food and drink as important factors in the cause of the disease. However, little attention has been given to the kind or the source of the food or drink used by poliomyelitis patients prior to or during epidemics of this disease, even in the search for an exogenous virus. In this section, in terms of the dominant theory of poliovirus causality, Scobey presents the case for poliovirus activation by toxins.

'...little attention has been given to the kind or the source of the food or drink used by poliomyelitis patients prior to or during epidemics..." This is important, as Scobey begins to list epidemics where food was found was suspected to be a possible cause.

Dr. H. C. Emerson49 (1909 [date of article]), Massachusetts State Inspector of Health, District 14, investigating an epidemic of poliomyelitis in that state [date of epidemic is 1908], made careful inquiries regarding the food that had been eaten by the patients. He found in six cases that fruit and berries had been a large item of the diet. In the case of two infants, bananas and berries had been given in the diet in addition to breast milk. In three cases of poliomyelitis, the illness was attributed to the eating of large amounts of blackberries and blueberries. In one case the illness was credited to eating heartily of English mulberries. In 39 instances it was stated that food supplies were bought from fruit and vegetable peddlers in their localities. Draper50 (1935) recorded a series of cases of poliomyelitis which he considered to have originated from the fruit purchased from a Greek fruit dealer. Barber51 (1939) reported four cases of poliomyelitis that developed simultaneously on the same day from the eating of strawberries in a single house of an English boarding school. Barber points out that the simultaneous onset of these cases resembled food poisoning. Goldstein et al52 (1946) reported an epidemic of polioencephalitis at a naval training school among cadets. The epidemic was explosive in character and involved over 100 persons. Epidemiological evidence suggested that some food served in the mess hall was the cause of the disease. A HARpub analysis of Herbert C. Emerson's 1908 report and maps of the period reveal that the disease epicenter was a small industrial town with 3 cotton mills, situated close together on a river, upstream from all of the polio cases. Circa 1908, large scale production began of carbon tetrachloride which was commonly used to extract oil from cotton seeds and it was used as an agricultural fumigant. Emerson states that not a single case of polio was found in children who were exclusively breast-fed. In the 1950s, Sabin discovered that milk confers protection against polio. See dairy milk analysis.

Gebhardt and McKay58 (1946) investigated an epidemic of poliomyelitis in Utah in 1946. The only food in common in all cases in the survey were fresh fruits and vegetables. The writers point out that the peach, pear, apple and tomato production peaks closely parallel peaks of epidemics of poliomyelitis and that when several cases of this disease occur in a family at about the same time, it can be explained by a common food source. The authors state that their data appears to fit into the jigsaw puzzle of epidemic poliomyletitis. Produce, as a source of toxins.

Lepine et al54 (1952) point out that during the occupation of France by the Germans, adults, and even young children, ate large amounts of salads, as no other food was easily available, and the incidence of poliomyelitis was about twice as great as usual. Raw milk and even butter may be the cause of some cases of poliomyelitis, they state. Investigations in France, they point out, favor the digestive origin of poliomyelitis and the cases in the region of Paris are best explained by the ingestion of foods, such as green vegetation. HARpub: Fresh, unwashed, unprocessed, pesticides?

Wickman55 (1913) first suggested milk in connection with an outbreak of poliomyelitis. In the parish of Ukla a case appeared on October 6, 1905. The father of the patient had a dairy farm. Another son and four other children of the neighborhood were stricken with the disease on October 20. Altogether six families were attacked, and ten cases occurred; all were supplied with milk by the father of the initial case. HARpub: Dairy products can be primary carriers of pesticides because of their lipid content. Virologist, Stefan Lanka states that dairy products are beneficial except to the degree that they are denatured.

Dingman5 (1916) reported a small outbreak of poliomyelitis in an institution which resulted from the use of milk from a common source. The cases occurred in three different and widely separated Jewish boarding homes at Spring Valley, N.Y. The house mothers of these homes were quite positive, even before the diagnosis of poliomyelitis was made, that the milk was the cause. The eight cases of the disease were the only ones which had developed in or about Spring Valley up to that time and for some weeks after. Many milk examples follow.

Knapp et al. (1926) reported an outbreak in December of ten cases of poliomyelitis in Cortland, N.Y. which was traced to the milk supplied by one dealer. The epidemic started abruptly and ceased with the discontinuance of the milk.  

Aycock58 (1927) reported a poliomyelitis epidemic of unusual severity caused by milk in Broadstairs, England, in October 1926. The outbreak started and subsided suddenly, 62 cases being reported between October 14 and 29, 31 of these appeared on October 14 and the five days following. Multiple cases occurred in private boarding schools having little communication with the town or with each other. Four visitors, who had left Broadstairs just prior to the epidemic, developed the disease at the height of the epidemic in Broadstairs in widely separated places practically simultaneously with each other and with the majority of the cases in Broadstairs. Investigation disclosed that practically all the cases of poliomyelitis in this epidemic were supplied with milk from the same dealer and from a single farm.  

H. Davide59 (1928) reported a small outbreak of poliomyelitis in North Sweden caused by milk.  

Rosenow60 (1932) described an outbreak of poliomyelitis traceable to milk and cream in a midwestern college. Most of the students roomed in the six dormitories on the campus; a few lived in town near the campus. All ate their meals in large dining rooms in three of the dormitories. The epidemic occurred abruptly in the late autumn. There were eight frank and several abortive cases which developed within a period of six days. The epidemic disappeared as suddenly as it appeared after the discontinuation of the milk and cream. The milk and cream supplied by the college dairy was served at only one of the dining rooms for women from which two cases of poliomyelitis developed and at the dining room for men from which six cases developed. Numerous students eating in these particular dining rooms had symptoms that comrnonly occur during the early stages of poliomyelitis, chiefly gastro-intestinal and nervous system manifestations.  

Rosenow et al.61 (1933) described an epidemic of poliomyelitis at White Bear Lake, Minnesota, which was caused by milk. The incidence of multiple cases in family groups was unusually high. The epidemic occurred late in the autumn in several explosive outbreaks during and immediately after spells of warm weather.  

Kling62 (1928) supported the theory that poliomyelitis could be spread by means of water supplies. He observed that the disease first broke out near the water supply in the hills, cases occurring successively as the stream descended. Gard63 (1938) stressed the importance of increased rainfall and mentioned a laborer who was alleged to have contracted poliomyelitis a few days after drinldng water from a ditch. Paul and Trask64 (1941) found, during an epidemic of poliomyelitis, that the distribution of cases followed a water course. Casey65 (1945) incriminated the water supplies for sporadic cases occurring in a small parish in Alabama, in one village out of numerous areas involved. They point out that a connection between water and epidemic poliomyelitis cannot be disregarded. McFarland et al.66 (1946) described an epidemic of poliomyelitis, explosive in character, which began in Mauritius, in February, and terminated in April. Three cyclones hit the island, one before and two during the epidemic period, and rainfall was less than average. Flour and vegetables were the staple diet because of the war. There was an increasing prevalence of intestinal complaints when the poliomyelitis epidemic began. In fact, there was an explosive rise in them in the second half of February. In one village, Triolot, an explosive epidemic of poliomyelitis appeared to have been caused by the eating of ices.  

In order to understand the relationship of fruits, vegetables, milk and water to poliomyelitis. we must realize that under certain conditions they may contain poisons or toxins which can constitute activating factors. During droughts, for example, the incidence of poliomyelitis is usually very much increased. It is this lack of water from rainfall, which is necessary for the proper growth and maturity of vegetation, that causes the development of toxic products in fruits and vegetables. They are to be found in greater concentration in unripened than in ripened fruits and vegetables  

[This Page Missing] 

Incubation Period Of Human Poliomyelitis Versus Experimental Animal Poliomyelitis  

Agreement regarding the incubation period of cases of human poliomyelitis has been based almost entirely on the results of animal experiments with the virus of the disease. It is a well known fact that cases of human poliomyelitis in a home, institution or community occur almost simultaneously and are often described as explosive in character. This fact is typical of the effects of poisoning. On the other hand, where experiments on animals in the laboratory are carried out with the virus, a definite incubation period can be established according to the manner in which the virus is administered, its concentration, and the species of animal that is employed. It has always been difficult to reconcile the fact that human poliomyelitis has a short incubation period of one to three days. according to Wickman55 and others, where the virus would necessarily have to traverse the natural barriers in order to set up infection in the central nervous system and an incubation period of as long as nine or more days in the experimental disease, where the virus is inoculated directly into the central nervous system. Incubation period in humans is 1 to 3 days, yet more than 9 days in lab animals.

Multiple cases in families present the nearest approach to the grouping of epidemiologically connected cases. There is no conclusive proof that the disease spreads under such circumstances like a contagious or infectious disease. The cases in these families occur simultaneously as in cases of poisoning. Avcock and Eaton71 (1925) collected the records of 576 multple cases in 253 families. They found that the proportion of secondary cases is highest on the day of the appearance of the first case, and the proportion tends to diminish steadily as time elapses.  

Precipitators Of Human Poliomyelitis  

Certain factors appear to be necessary in many cases for precipitating the manifestations of human poliomyelitis. These include fatigue, chilling, trauma, heat and humidity. operative procedures, or pregnancy. Similar factors are well known precipitators of the manifestations of lead toxicity. Neurological manifestations of lead poisoning, and presumably other poisons, occur more frequently in hot weather than during any other season of the year. Suzuki and Kanako72 (1924), Fukushima and Matsumato73 (1928). Blackman74 (1937), Rappaport and Rubin75 (1941), and Guannattasio et al.76 (1951) have all pointed out this fact. It is well known that the neurological manifestations of alcohol poisoning (delirium tremens) can be precipitated by overexertion, exposure, operations, trauma, shock, fright and acute inflammatory disease.  

Comparative Pathology Of Human Versus Experimental Animal Poliomyelitis  

The differences between human poliomyelitis and the experimental animal disease is definitely shown by the divergence of the pathological lesions in the two diseases. It must be admitted that the pathological lesions in the nervous system of experimental animal poliomyelitis are similar to, if not identical with, those in cases of human poliomyelitis. However, the visceral lesions that occur in cases of human poliornyelitis cannot be reproduced in the experimental animal with the virus regardless of the manner of administration or its concentration. Thus, there are to be found in human poliornyelitis many evidences of pathology besides the presence of a virus and viral reaction. In the stomach there is a very high incidence of submucosal petechial hemorrhage associated with intense congestion of the mucosa. Myocarditis, accompanied by mycardial degeneration, has been found in a high percentage of cases. In the parenchymatous organs, especially the liver and kidneys, there is usually demonstrated degeneration of the sort usually described as cloudy swelling. Landon and Smith77 (1934 ) pointed out that the granular degeneration of the parenchyrnatous cells, as well as fatty degeneration represent toxic changes. They state also that the kidneys in cases of human poliomyelitis show changes that may be attributed to a general systemic toxemia. In practically all cases of human poliomyelitis there is intense congestion of the blood vessels throughout the body. Laboratory polio is not human polio.

The widespread lymphoid hyperplasia found consistently in gross and microscopic autopsy examinations in cases of human poliomyelitis never has been explained on the basis of a virus infection. There is involvement of Fever’s patches and the solitary follicles of the gastro-intestinal tract, mesenteric and retroperitoneal lymph nodes, peribronchial lymph nodes, thymus, malpighian corpuscles of the spleen, tonsils, adenoid tissue of the nose and throat, and the lymph nodes of the neck, axilla, groin, and other parts. Burrows78 (1931) in a series of about fifty autopsies, noted that the maximum amount of lymphoid hyperplasia was in Peyer’s patches and the solitary lymph follicles of the gastro-intestinal tract and the mesenteric lymph nodes. He felt that the nerve tissue changes were secondary to those existing in the lymph channels of this tissue. It is a well known fact that lymphoid hyperplasia can occur as a result of poisons and toxins. Doubtless the lymphoid hyperplasia in human poliolmyelitis is an expression on the part of the body to poisons and toxins in which protection is afforded by hyperplasia of its reserve forces, the lymphatic apparatus.  

The intense reaction in the gastro-intestinal tract not only exp)lains the reaction to a poison but likewise the clinical manifestations of gastro-intestinal irritation that so frequently occur in cases of human polionwelitis. Although many workers have postulated that the gastro-intestinal tract is the portal of entry of the poliornyelitis virus into the human body, this never has been lroven conclusively. Numerous investigators have failed to infect monkeys when the virus has been administered orally even in high concentration and in no case have the gastro-intestinal tract lesions Ot human poliomyelitis been duplicated in experimental animals. The virus that is recovered from the feces of human poliomyelitis is probably synthesized or activated within the gastro-intestinal tract and is excreted therefrom without gaining entrance to the hody. This conclusion appears to be justified by the failure to infect animals orally, and by the work of Gards of Sweden. Gards extensive studies suggested that intestinal protein is an avirulent or non-neurotropic varient of the poliornyelitis virus, a normal inhabitant of the intestines. This intestinal protein (virus), according to Gard, is non-pathogenic, but under the influence of exogenous factors is pathogenic when injected into experimental animals. Fuirther proof that the virus in the intestinal tract does not enter the human body to cause human poliomyelitis is indicated by repeated failures to isolate a virus from the blood stream, although human poliomyelitis is generally considered to be a generalized systemic infection. The isolation of a virus from the blood stream would not necessarily indicate that it gained access to the body from the external environment.  

Antibody Formation And Human Poliomyelitis  

There has been much controversy regarding the interpretation of the presence of poliomyelitis virus neutralizing antibodies in human sera. It is now assumed that these antibodies develop following non-paralytic and probably non-symptomatic infection with the virus (hiring childhood as well as in frank cases of paralytic poliomyehitis. Some workers have tried to prove the contagiousness of human poliomyelitis by demonstrating elevated antibodies in contacts. Other workers have been unable to find the antibodies increased in contacts80. Poliomyelitis can develop in the presence of neutralizing antibodies and many patients convalescent from the disease show no antibody. The serums of guinea-pigs and rabbits do not contain neutralizing antibody for monkey passage virus, though it is well known that these animals possess an absolute immunity to the virus. Further, antibodies are found in a high percentage of natives of lands in which poliomyelitis is unknown and paradoxically in a much smaller percentage of the population where the disease occurs in epidemic form. The extent of natural resistance to human poliomyehitis is utterly disproportionate to the quantities of virus which is postulated to he present in the general population by analogy with the results of experimental animal poliomyelitis. Antibodies bear no relationship to presence of polio.

It is noteworthy that the appearance of neutralizing antibodies in the blood after the injection of the poliomyelitis virus is very uncertain evidence of parallel immunity to the natural disease81. This fact was shown clearly by Kramer82, in 1936. He vaccinated a group of children with vaccine and two months later found that 50 per cent had developed neutralizing antibodies. However, in a parallel uninoculated group of children, 41 per cent had also developed antibodies. Kramer’s results were in essential agreement with those of Aycock and Hudson83, who found an increase of 28.6 per cent of immunes among the vaccinated children in their series as compared with an increase of 22.8 per cent of inimunes in the unvaccinated control group. Neither of these writers considered the small difference of any practical value in favor of the vaccinated group. No significant difference in antibody formation between vaccinated and control groups.

Koch's Postulates And Human Poliomyelitis  

Koch’s first and one of his most important postulates emphasizes that a parasite must be found in every case of the disease in order to state that that particular parasite is the cause of the disease. In 1952, there were nearly 58,000 cases diagnosed as poliomyelitis in the United States, 75 per cent of which were paralytic. Attempts to isolate the virus from the excretions were carried out in little more than one per cent. In the remaining 99 per cent, a virus was merely assumed to have been present. That the paralysis in this large group might have had many causes is obvious. It is not to be overlooked that a significant number of spinal cords removed from children dying in the acute stage of poliomyelitis are incapable of producing paralysis after intracerebral inoculation in the monkey. Poliovirus not found in a significant number of paralytic polio cases, using intracerebral inoculation test..

Korns84 (1953), N. Y. State Public Health Officer, states that the isolation of the poliomyelitis virus for diagnostic purposes is almost never done and is of little practical value, while at the same time being a very difficult procedure. He points out further that isolation of the poliomyelitis virus from the patient by no means establishes the diagnosis since the virus is widely prevalent in the population during epidemic periods without producing disease. Bell85, epidemiologist, National Institutes of Health, states that the isolation of a virus from poliomyelitis patients is not a routine or reportable procedure; it is carried out only in conjunction with research studies. Serological tests of acute and convalescent blood specimens, he says, are often of no value for determining the cause of the current infection in poliomyelitis because in this disease the antibodies are usually in good titer at the time of onset of symptoms. Isolation of poliovirus has no diagnostic value.

Poliovirus antibody tests have no diagnostic value.

Biochemical Factors In Human Poliomyelitis  

There appear to be certain physiological and chemical factors which seem to be necessary for the development of human poliomyelitis and for the synthesis or activation of the virus. Hormonal imbalance has been suggested as an important factor by a number of writers in predisposing an individual to poliomyelitis. Stern86 (1911) found that a considerable number of cases of this disease showed some symptom’s of Basedow’s disease. i.e., goiter, tachycardia, tremor, nervousness, etc. Wynkoop87 (1916) suggested that human poliomyelitis is a disease caused by negation of glandular efficiency. Draper88 (1932) noted signs in his patients that tended to point toward endocrine deficiencies. The mothers of these poliomyelitis patients not infrequently had moderate or marked exophthalmos or thyroid enlargement. Inglessi89 (1932) found hypocholesterolemia in thirty children with poliomyelitis during the acute stage and for some time in the paralytic stage. Jungeblut90 (1932) suggested that the mass protection enjoyed by the adult human population rests primarily on the normal function of the endocrine balance characteristic of mature age. Later91 (1935) he stated that the protective action against poliomyelitis probably lies in the normal physiological function of the organism and that the main cause for susceptibility is a hormonaldysfunction. Prophylaxis he suggests must consist mainly in correcting the individual susceptibility on a general physiologic-hygienic basis. Aycock92 (1940) stated that the susceptibility to poliomyelitis is determined by an inherent endocrinopathy which is largely subclinical. Aycock93 (1940) found a higher average excretion of estrogenic substance in a group of poliomyelitis patients from one to twenty years after an attack of this disease and noted that there was nothino to indicate that this was a sequel of poliomyelitis. This fact suggested to him that endocrinopathy as a basis of susceptibility does not lie in a simple deficiency in the elaboration of estrogenic substance, but rather in some discrepancy in its economy. Aycock pointed out the frequency with which the paralytic disease tends to parallel certain seasonal and climatic fluctuations in physiologic processes. “Such a correlation suggests,” he says, “that susceptibility to paralytic poliomyelitis does not lie in any fixed anatomical character, but is dependent on some physiological process." HARpub: Children rather than adults usually acquire polio. Children up to age 7 have a growing, exposed, unsheathed CNS.

The well known fact that virus activity, as well as the reaction to poisons and toxins, produces chromatolysis in an affected nerve cell indicates the necessity for knowledge of the localization of materials and chemical reactions within the cell. Chromatolysis suggests a shift in the balance of a steady state by differential inhibition or acceleration of complex enzyme-regulated reactions94. “In addition to the specific production of chromatolytic changes by toxins and neurotropic viruses, interference with enzyme mechanisms by homonal imbalances or dietary deficiencies might conceivably in extreme cases produce the phenomenon of chromatolysis.”94 Aycock and Foley95 (1945) stress the fact that motor neurone disease may be brought about by an enhancing or inhibiting action on one or more of the enzyme systems.  

A study of the biochemical changes that arise during the course of human poliomyelitis has not been followed adequately, but a few important clues have been reported. One of these consists of the presence of coproporphyrin III in the urine of poliomyelitis patients96; another is the appearance in the blood of increased amounts of guanidine.98 It is not to be overlooked that both of these chemicals are present in the body in increased amounts in cases of poisoning by a number of toxic agents.  

Kaplan et al.100 (1938-39) described an increase of proteases in the cerebrospinal fluid of cases of human poliomyelitis. Kovacs101 found (1953) in this disease that there are no changes of acid soluble inorganic phosphorus resulting from the interaction of enzymes and phosphorus-containing organic material in the cerebrospinal fluid. In acute bacterial meningitis, on the other hand, a great increase of phosphorus was usually evident. Kovacs102 (1953) studied the nucleases in the cerebraspinal fluid in cases of human poliornyelitis and found consistently high values. His findings suggested some direct connection between chromatolvsis and ribonuclease activity.  

The fact that ascorbic acid103-105, thiamin106-113. methylene blue114, as well as iodine115 have been successfully employed by some workers in the treatment of human poliomyelitis. suggests that certain biochemical disturbances within the body during the course of the disease can be corrected with chemotherapy. In the treatment of a case of hulbar poliomyelitis, Eskwith116 (1951) postulated that dimercaprol (PAL) might be effective because in heavy metal poisoning it combines with the metals and protects certain enzymes - those containing a sulfhydryl group - from combination with the poison and because viruses seem to cause necrosis by destroying or inhibiting certain intracellular enzyme systems. He reasoned that if glutathione and other sulfhydryl containing enzymes and tissue protein can be injured by heavy metals, it seems quite possible that they can combine with and be injured by other substances besides metals. Similarly, it is quite possible, he thought, that since dimercaprol contains two sulfhydryl groups, it may protect the enzymes from these non-metallic toxic agents. Eskwith’s patient was a 4 1/2 year old girl who had required a tracheotomy and oxygen therapy and whose clinical course was steadily downhill until the dimercaprol injections were given. At the end of 24 hours after therapy was begun, the patient was clinically improved and consciousness rapidly followed. Eskwith learned subsequently that some work had been done with dimercaprol in relation to neurotropic virus infections in experimental animals and that there was no evidence of its efficacy. This fact appears to confirm the belief that human poliomyelitis and the artifically produced experimental animal disease are two entirely different entities. 

Experimental Animal Poliomyelitis In Human Beings  

Once the poliomyelitis virus is recovered from human and extrahuman sources many (diversified experiments can be carried out in the laboratory with experimental animals. The unfortunate thing, however, is that these laboratory experiments on animals are interpreted as being applicable to the human disease from whence the virus was obtained and that unjustified conclusions are drawn.  

Realizing that an animal will develop experimental poliomyelitis from a virus introduced into its body in an abnormal manner, one can expect that a human being also can develop poliomyelitis of the experimental animal type under the same conditions. Thus, there is to be found in the medical literature reports of the development of poliomyelitis in technicians117-120 working in laboratories with concentrated forms of the poliomyelitis virus. In these cases the portal of entry of the virus is doubtless an abrasion, scratch, laceration or needle prick. A case of poliomyelitis in a technician118, which followed the contamination by a virus of a scratch, failed to show at autopsy the pathological lesions characteristic of human poliomyelitis arising in a natural manner. It is significant that in this case the gastro-intestinal tract revealed no lesions and no virus was present in the intestinal contents. Over the past 40 years these are the only reported cases of poliomyelitis developing in laboratory workers. Essentially, there have been no polio cases in laboratory workers in 40 years.

If humans are injected with a concentrated form of active virus, it is natural to expect that they would develop the same type of poliomyelitis that occurs in experimental animals following the injection of the virus. Actually, this did occur in 1935, when some children who received a poliomyelitis vaccine prepared with the virus obtained from experimental animals developed poliomyelitis; half of them died.121 Significant facts of great importance in these cases were that the incubation period of 6 to 14 days following the injections corresponds with the incubation period of experimental animal poliomyelitis; the fact that the level of the spinal cord first affected corresponded with the extremity in which the injection was made. i.e., the same limb or the contralateral limb parallels recent observations. It is now known, for example, that poliomyelitis con occur following the injection of toxic antigens during the summer months, i.e., pertussis vaccine and diphtheria toxoid and that the paralysis occurs in the same limb or the contralateral limb where the antigen is injected. Injections create a highly abnormal situation. Injections of many things, such as cellular material or peach skin can cause disease.

Comment  

The evidence never has been strong nor very convincing that an exogenous virus enters the human body to cause poliomyelitis. Consequently. year after year, new concepts are presented and old ones discarded that are intended to show where the virus originates outside the body and to establish its portal of entry into the body. Clearly evident are the facts that there is more to indicate that the virus of poliomyelitis is of endogenous origin. "Clearly evident... the virus of poliomyelitis is of endogenous origin."

Whether or not one is of the opinion that a poison or virus, or both, are responsible for human poliomyelitis, it is obvious that the fruit, vegetables, milk, and water used by the poliomyelitis patient prior to his or her illness should be carefully considered. If by careful inquiry a fruit, vegetable, milk, or water source is found, prevention of other cases of this disease can be brought about by warning the public. Regarding the unsaid word: Pollution.

Since a poison or virus will cause damage by disturbing normal chemical relationships within the body, particularly enzyme systems, it is imperative. theretore, to determine what chemical changes take place in human poliomyelitis and how they may be restored to normal. It is at this point that much research can be done. A preventive and therapeutic agent could doubtless be developed to maintain or restore normal chemical relationships within the human body to prevent and cure poliomyelitis. It must be seriously considered that if it were possible with a vaccine to prevent the synthesis or activation of the poliomyelitis virus within the human body, it does not follow that a poisonous or toxic activator would be deprived of its ability to cause neurotoxic damage to the lower motor neurone with resulting paralysis. A preventive agent would be an antidote, not a vaccine.

Summary  
1. The exogenous virus theory of cause of human poliomyelitis fails to explain all facts without exception and cannot be considered to be entirely valid.
2. It is emphasized in this report that the fundamental cause of human poliomyelitis appears to be a poison or toxin and that the virus is synthesized or activated within the human body as a result of the poisoning.
3. There appears to be an intimate relationship between virus diseases and diseases resulting from toxic causes. This fact, illustrated by examples, has been stressed.
4. It is pointed out that the poisonous activating factor in cases of human poliomyelitis can originate from fruits, vegetables, milk, and water during epidemics of this disease.
5. The locality influences, seasonal incidence, simultaneous development of multiple cases in homes, institutions and communities, as well as the visceral lesions and other facts, all indicate the association of a poison or toxin with human poliomyelitis.
6. Normal chemical relationships within the body are disturbed in cases of human poliomyelitis; a preventive and therapeutic agent could doubtless be developed to maintain or restore these relationships and thus prevent and cure the disease.  

References Extensive.
1. Landsteiner, K.: Semaine Med., 28:620, 1908
2. Landsteiner, K.: Wien. Wchnschr., 21:1830, 1908
3. Flexner, S. and Lewis, P. A.: J.A.M.A. 53:1913, Dec. 4, 1909.
4. Landon, J. F.: New York State J. Med 38:1-6, Jan. 1, 1938.
5. Van Rooyen, C. E. and Rhodes, A. J Virus Diseases of Man, 1948.
6. Scobey, R. R.: Arch. Pediat., 63:322-354, July 1946.
7. Scohey, R. R.: Arch. Pediat., 63 :567-580, Nov 1946.
8. Scobey, R. R.: Arch. Pediat., 64:132-l43 March 1947.
9. Scobey, R. R.: Arch. Pediat., 64:350-363 July 1947.
10. Sccbey, K. R.: Arch. Pediat.. 65:131-166 March 1948.
11. Scobey, R. R.: Arch. Pediat., 65:476-492 Sept 1948.
12. Scobev, R. R.: Arch. Pediat., 66:110-130. March 1949; 66:137-172, April 1946.
13. Scobey, R. R.: Arch. Pediat., 66:402-410, Sept. 1949.
14. Scobey, R. R.: Med. Eec., 163:45-63, March 1950.
15. Scohey, R. R.: Arch. Pediat., 67:400.430, Sept. 1950; 67:462-482, Oct. 1950.
16. Scobey, R. R.: Arch. Pediat., 68:220-232, May 1951.
17. Scobey, R. R.: Arch. Pediat., 69:172-193, April 1952.
18. Scobey, R. R.: Arch. Pediat, 70:185.202. June 1953.
19. Fischer, M.: Ztschr. f. Hyg. lnfektkr, 107:102, 1927.
20. Van Rooyen, C. K.; Rhodes, A. J. and Ewing, A. E.: Brit. M. J., 2:298-301, Aug. 30, 1941.
21. Humphrey, J. H. and McClellattd, M.: Brit. M. J., 1:315-318, March 4, 1944.
22. Attmeyer, J.: Arch. Dermat. Syph., Wien. 179 :279, 1939.
23. Levitt, L. and Luppi, J.: Rev. Med. del Rosario, 31:638, July 1941.
24. Caspero, J.: Nervenartz, 15:246, June 1942.
25. Ritchen, J. and Kantor, F.: Clin. Proceedings. 6:125-129, June 1947.
26. Netter. A. and Urbaine, A.: C. R. Soc. Biol., Paris. 90:997. 1934.
27. Row, N.; Barant, F. H. and Warrington, W.B..: Brit. M. J., 1:10 Jan. 5, 1901.
28. Reynolds, C. S. et al: Brit. M. J., 2:1044-1049. Oct. 12, 1901.
29. Editorial: Boston M. & S.J.. 150:49-50. Jan. 14, 1904.
30. Blackman, S. S. Jr.: Bull. Johns Hopkins Hosp., 58:384-404, 1936.
31. Wolff, A. and Orton, S. T.: Bull. Neurol. Inst., N.Y.. 2:194-209, July, 1932.
32. Hembacker, P. and O’Leary. J. L.: Anat. Rec. 46:219, April 1930.
33. Davenport, H. A.; Ransom, S. W. and Terwilliger, E. H.: Anal. Rec., 48:251-254. Feb. 1931.
34. Lee, J.: Proc. Soc. Exper. Biol. & Med., 31:383-385. 1933.
35. Covell, W. P.: Am. J. Path., 8:151-156, March 1932.
36. Cox, H. R. and Olitsky, P. K.: Science, 79:459, May 18. 1934.
37. Oiitsky, P. K. and Harford, C. C.: Am. J. Path.. 13:729-747, Sept. 1937.
38. Birch, F. M. and Lucas, A. H.: Am. J. Path., 18:1051-1058, Sept. 1937.
39. Stanley, W. M.: Science, 81:644-645, June 28, 1935.
40. Rivers, T. H.: Science, 93:143-145. Feb. 14, 1941.
41. Stanley, W. H.: Medicine, 18:431.442, 1939.
42. Rivers, T. M.: Physiol. Rev., 12:423.452 1932
43. Doert, K.: Herpes Febrilis in Doerr. B. and Hollander. C.: Handbuch d. Virusforschung. Wien., Vol. 1, pp. 41-45, 1935.
44. Jenner, E.: Baron’s Life of Jenner, 1538.
45. Carrel. A.: Compt. rend. sec. Biol.. 93:1278. 1925.
46. Fischer, A.: Compt. rend. Soc. Biol., 94:127, 1926.
47. Copisarow, M.: Edinburgh M, J., 46:46-48, Jan. 1938.
48. Sabin, A. B.: J. Pediat., 39:519-531. Nov. 1951.
49. Emerson. H. C. Boston M. & S.J., 151:115-119, July 22, 1909.
50. Draper, G.: Infantile Paralysis. 1935.
51. Barber, G. O.: Brit. M. J., 2:1137. Dec. 7. 1938.
52. Goldstein, Lt. Col. B. H.: Hammon, W. McD. and Vietes, H. R.: J.A.M.A, 131 :569-573. June 15, 1946.
53. Gebhardt, L. P. and McKay, M. H.: J. Pediat., 28:1-13, Jan. 1946.
54. Lepine, P.; Buyer, J. and Sapin-Joboustre, H.: Presse med., 60:1057, July 19. 1952.
55. Wickman, I.:J. Nerv. & Ment. Dis.. Monograph Series. 16:101, 1913.
56. Dingman, J. C.: New York State J. Med., 16:589-590. Dec. 1916.
57. Knaup. A. C.: Godfrey, E. S. Jr. Aycock, W.L.: J.A.M.A., 57:635-639, Aug. 28, 1926.
58. Aycock. W. L.: Ant. J. Hyg., 7:791-803, Nov. 1927.
59. Davide, H.: Office Intern. d’Hyg. Pub, bull. Mans., 20:74, 1928.
60. Rosenow, E. C.: J. Infect. Dis 10:377.425 May-June 1932.
61. Rosenow. E. C.; Rosendaal, H. M. and Thorsrtess, E. T.: J. Pediat., 2:568-593, May 1933.
62. Kling, C.: Bull. Office Internal. dhyg. Pub., 20:1779, 1928.
63. Gard, S.: Bull. Office Internal. d’hyg. Pub .30:933, 1935.
64. Paul, J. R. and Trask, J. B.: J.A.M.A.. 116:493, Feb. 8. 1941.
65. Casey, A. E.: Am. J. Dis. Child., 69:152-156, March 1945.
66. McFarland, A. M.; Dick, G. W. A. and Seddon, H. J.: Quart. J. Med.. 15: 183, 1946.
67. U. S. Dept. of Agriculture: Reports of the Chief, Bureau of Entomology and Plant Quarantine, 1951 and 1952.
68. Lille, K. D. and Smith, M. I.: Pub. Health Rep., 59:979-1020, July 28 - Aug. 4, 1944.
69. Lille, II. D. et al: Arch, Path., 43:127-142. Feb. 1947.
70. Toumey, J .A.and August, M. H.: Am. J. Dis. Child., 46:262-279, Aug. 1933.
71. Aycock, W. L. and Eaton, P.: Am. J. Hyg., 5:724-732, Nov. 1925.
72. Suzuki, T. and Kauako, J.: Orient. Med., 2:55, 1924.
73. Fokushjnra, M. and Matsunsato, H.: Orient. J. Dis. Child., 3:27, 1928.
74. Blackman, S. S.: Bull. Johns Hopkins Hosp., 61:1.43, 1937.
75. Rappaport. M. and Rubin, M. I.: Am. J. Dis. Child., 61:245-255. Feb. 1941.
76. Guannattasio, R. C.; Bedo, A. V. and Pirozzi, M. J.: Am. J. Dis. Child., 84:316-321, Sept. 1952.
77. Landott, J. F. and Smith, L. W.: Poliomyelitis. 1934.
78. Burrows. M. T.: Arch. Int. Med.. 48:33.50, July 1931.
79. Card, S.: Acta med. Scand. Supp.. 143 :1-1 73, 1943.
80. Burnet, F. M. and Jackson, A. V.: Australian J. Exper. Biol. & Med. Sc., 17:261, 1939.
81. Schultz, E. W. and Gebhardt, L. P.: Calif. and West. Med.. 43:111-112, Aug. 1935.
82. Kramer, S. D.: J. Immunol., 31:167-182, Sept. 1936.
83. Aycock, W. L. and Hudson, C. J.: New England J. Med., 214:715-718, April 9, 1936.
84. Korns. R. F.: Personal Communication, 1953.
85. Bell. J - Personal Communication, 1953.
86. Stern, K.: Jahrb. 1. Psychiat. u. Neurol., 32:139, 1911.
87. Wynkoop, D. W.: Med. Rec., 90:936-937, Nov. 25. 1916.
88. Draper, C.: Ant. J. M. Sc., 184:111-118. July 1932.
89. Inglessi, E.: Clint. Pediat., 14:1003, Dec. 1932.
90. Jungeblut. C. W.: .J.A.M.A., 99:2091-2097, Dec. 17, 1932.
91. Jungeblut. C. W. Schsvciz Med. Wchnschr., 65:560, June 15, 1935.
92. Ayeock, W. L.: Proc Third lnternat. Cong. for Microbiology, p. 331, 1940.
93. Avcock, W. L. Endocrinology, 27:49-57, July 1940.
94. Bodian, B. and Mellors, R. C.: J. Exper. Med.. 81:469-487, May 1, 1945.
95. Avcock W. L. and Foley, G. E.: Ann. J. M. Sc., 210:397-419, Sept. 1945.
96. Watson C. J.; Schultze, W.; Hawkins, J. and Baker, A. B.: Proc. Soc. Biol. & Med 64:73-78, 9 Jan. 1947.
97. \Vatson C. J. and Larson, E. A.: Physiol. Rev., 27:478.510, July 1947.
98. Cascio D.: Brasil med., 61:387-390, Nov. 1.15, 1947.
99. Cascio D.: New York State J. Med.. 49:1685.1686, July 15, 1949.
100. Kaplan I.; Cohn D. J.; Lcvinson, A. and Stern, B.: J. Lab. & Ciin. Med., 24:1150 1938 ISa9
101. Kovacs E.: Canada J.M. Sc., 31:358.366, Aug. 1953.
102 Kovacs E.: Canada J.M. Sc., 31:437-446, Dec. 1953.
103. Marshall R.: Med Rec.. 144:32, July 1. 1936.
104. Marshall R.: Med Rec.. 157:281-284, May 1944.
105. Klenner. F. R.: South Med. &- Surg., 111:209-214, July 1949.
106. Stern, E. L.: Am. J. Surg., 39:495-511, March 1938.
107. McCormick. W. L.: Canad. M. J., 33:60-265 March 1938.
108. Nemecek, A.: Med. Kiln., 34:669, May 20, 1938.
109. Hamburger, F.: Wien Kiln. Wchnschr., 51:825. Aug. 5, 1938.
110. McCormick, W. L.: Med. Rec., 150:303-307, Nov. 1, 1939.
111. Helms, K.: M. J. Australia, 1:717, June 14, 1941.
112. Stone, S.: J. Pediat., 22:142, Feb. 1943.
113. Stone, S.: Arch. Phys. Therap., 24:350, June 1943.
114. Massi, L. and Rostorini: Riv. di Olin. Pediat., 44:196-198, March 1948.
115. Scobey, R. R.: Arch. Pediat., 68:309-321, July 1951.
116. Eskwith, I. R.: Am. J. Dis. Child.. 81: 684-686, May 1951.
117. Sabin, A. B. and Ward, R.: Science, 94:113, Aug. 1, 1941.
118. Venner, H. A. and Paul, J. R.: Am. J. M. Sc., 213:9-18, Jan. 1947.
119. Gear, J. H. S. and Roger. L. M.: Quoted by Van Rooyen, C. E. and Rhodes. A. J. in Virus Diseases in Man, 1948.
120. BelIer, K.: Zentralbl. f. Bak., 153:269-273, 1949.
121. Leake, J. P.: J.A.M.A., 105:2152, Dec 28. 1925