SIMPLIFIED PRODUCTION OF ANTIMENINGOCOCCIC SERUM

In an attempt to simplify the manufacture of an efficacious antimeningococcus serum an experimental study has been made of a number of sera produced with a few or with single strains of meningococcus, the therapeutic polyvalent serum produced at The Rockefeller Institute with more than 50 strains being used as a standard of comparison. It was found that horses injected with an antigen limited to five, three, or even one strain yielded sera with a range of agglutinins covering in high dilution practically all the stock strains used in producing the polyvalent serum. These sera appeared to equal the polyvalent serum in range and titer of agglutinins, but on further examination fundamental differences were found. Storage for a year had little effect upon the titer and inclusiveness of the polyvalent serum, whereas the monovalent serum had fallen off greatly, especially in regard to secondary or subsidiary agglutinins, so that only a comparatively small number of stock strains was still agglutinated. The serum made with five strains, a regular, a para, and three intermediate meningococci, approached the polyvalent serum in keeping qualities and still agglutinated at the end of this period 39 of the 41 strains tested. Absorption tests also brought out inherent differences in the nature of the polyvalent and the monovalent sera which had appeared to be practically identical in simple agglutination tests. The homologous strain on triple absorption was able to exhaust the monovalent serum completely, but was unable to remove from the polyvalent serum agglutinins to which 30 of 44 different strains were able to react. Absorption with another single strain of the same type removed from the monovalent serum agglutinins for a majority of the test strains but left the polyvalent serum relatively unaffected. It is comparatively easy to produce a serum effective against about 80 per cent of the spinal strains of meningococci encountered. Deficiencies in our knowledge of the antigenic capacities of the meningococcus have led to the more or less empirical use of a large number of cultures in the preparation of a serum effective against the remaining 20 per cent of the strains. How far the number of the latter in the antigen may be reduced without restricting the efficacy of the serum remains yet to be determined. However, the experimental evidence recorded here apparently does not favor the use of an antigen limited to one or too few strains. For example, three or five selected strains produced a serum which agglutinated practically all the strains against which it was tested. But in view of the many observations which point to the greater therapeutic efficacy of a serum made with a larger number of strains we would not as yet advocate a serum prepared with too limited antigens even though it contains at first a wide range of agglutinins. It has been brought out that a monovalent serum contains, in addition .to specific agglutinins, a wide range of common or secondary agglutinins which tend to disappear during storage. The difference between specific and secondary agglutinins is not apparent in simple agglutination tests, but is revealed by absorption tests. It is probable that in a serum prepared with a few strains the same condition exists, whereas in a serum produced with a large number of strains the agglutinins are mainly specific as contrasted with the fact that most of them are secondary in the serum produced with few strains. The question whether secondary agglutinins are therapeutically equivalent to primary or specific agglutinins requires further study.     

A REPORT ON ANTIMENINGITIS VACCINATION AND OBSERVATIONS ON AGGLUTININS IN THE BLOOD OF CHRONIC MENINGOCOCCUS CARRIERS

1. A meningococcus vaccine suspended in salt solution has been given subcutaneously as a prophylactic to about 3,700 volunteers in three injections of 2,000 million, 4,000 million, and 4,000 or 8,000 million cocci at weekly intervals. 2. These doses rarely caused more than the mildest local and general reactions. Exceptionally a more severe reaction emphasized the presence of an unusual individual susceptibility to the vaccine. In such instances the symptoms were in part those of meningeal irritation and sometimes simulated the onset of meningitis. 3. Specific meningococcus agglutinins have been demonstrated in the blood serum of vaccinated men as compared with normal controls. 4. Moreover, agglutinins have been demonstrated in the blood serum of chronic carriers of the meningococcus. Evidence is thus brought forward that the relative immunity of chronic carriers to epidemic meningitis may be due to the presence of specific antibodies in the blood stream.     

EXPERIMENTAL STUDIES OF THE NASOPHARYNGEAL SECRETIONS FROM INFLUENZA PATIENTS : XI. ANTIBODIES IN THE BLOOD AFTER RECOVERY FROM EPIDEMIC INFLUENZA.

Although Bacterium pneumosintes is a stable organism which agglutinates only in low dilutions of the serum of actively immunized rabbits, the serological reactions of this microorganism have always been found to be consistent and specific. The results of the agglutination and precipitation reactions described in this paper indicate that the serum of normal persons does not contain demonstrable agglutinins or precipitins for Bacterium pneumosintes. By contrast, agglutinins have been demonstrated in the serum of seventeen persons among nineteen who were examined from 10 days to 5 months after recovery from epidemic influenza. The serum of ten persons who had influenza, followed in three instances by pneumonia, 2½ to 3½ years before, proved negative. In one instance the appearance of specific agglutinins against Bacterium pneumosintes was found to be coincident with an attack of uncomplicated influenza. In twelve of fifteen instances in which agglutinins were found, precipitins against Bacterium pneumosintes were demonstrated also. It is noteworthy that these antibodies may persist in the blood at least 5 months after recovery from the disease.     

EXPERIMENTAL STUDIES OF THE NASOPHARYNGEAL SECRETIONS FROM INFLUENZA PATIENTS : VII. SEROLOGICAL REACTIONS.

Cultivation of Bacterium pneumosintes in the collodion sac dialysate of a tissue medium produces an antigen suitable for serological tests. Injection of dialysate cultures of Bacterium pneumosintes into rabbits results in the production of antibodies demonstrable by agglutination, precipitation, complement fixation, and phagocytic reactions. Four strains of Bacterium pneumosintes, three from the first epidemic influenzal wave (1918–19) and one from the second (1920), show identical antigenic characters. The blood serum of rabbits experimentally injected with the glycerolated active material of rabbit passages contains specific agglutinins for Bacterium pneumosintes, whereas normal rabbit serum does not.     

AN EXPERIMENTAL STUDY OF THE ADDITIVE AND ANTAGONISTIC ACTIONS OF SODIUM OXALATE,AND SALTS OF MAGNESIUM AND CALCIUM IN THE RABBIT

The foregoing experiments establish firmly the following facts. Subcutaneous or intramuscular injections of sodium oxalate in subtoxic doses, when administered to an animal which received a subminimal dose of magnesium sulphate, produce profound anesthesia and paralysis of long duration, although the usual effects of sodium oxalate alone are of a stimulating character. This fact is, in general, in harmony with the results reported by Starkenstein who, however, seems to have used the combination of the two salts in one solution; namely, that of magnesium oxalate. The combined injections of subminimal doses of sodium oxalate and magnesium sulphate produce a strong reduction, or even, at times, a complete abolition of the conductivity of the motor nerve endings. An intravenous injection of calcium salts brings on a recovery from the profound and prolonged effects of the combined action of sodium oxalate and magnesium sulphate, which is as prompt as is observed in experiments in which effective doses of magnesium alone were given. This fact is the more noteworthy, since depressions of long duration produced by prolonged continuous injections of magnesium solutions alone do not respond very promptly and effectively to calcium injections. As will be recalled, the starting point for our investigation was the hypothesis that substances which are capable of precipitating calcium—a biological antagonist of magnesium—ought to be capable of increasing the depressive effect of magnesium. Our experiments proved that this assumption was correct. This would seem, therefore, to justify the interpretation that the augmenting action of sodium oxalate has its cause in the ability of the latter to precipitate calcium and thus increase within the body the amount of unantagonized magnesium. However, we wish to state expressly that this view is, for the present, still no more than a hypothesis and does not exclude other possible interpretations of our facts. As we pointed out it speaks against this hypothesis that oxalates do not produce phenomena of depression; the toxic symptoms produced by oxalates exhibit distinctly signs of increased and not of decreased irritability.     

PROPERTIES OF THE CAUSATIVE AGENT OF A CHICKEN TUMOR : II. THE INACTIVATION OF THE TUMOR-PRODUCING AGENT BY MONOCHROMATIC ULTRA-VIOLET LIGHT

Even though part of the energy of the incident light is probably absorbed by chemical entities which play no part in the specific reaction of inactivation, nevertheless the wave lengths most active in destroying biological cells or agents will presumably be found to be among those absorbed in the highest proportion. This would indicate that the curves here presented are approximately reciprocal to the coefficients of absorption of particular substances, the destruction of which caused the inactivation of the agents or the death of the cells. The similarity between the curves for bacteria, virus, and phage, both in shape and in total involved energies, suggests the presence of a common factor, or of closely related chemical entities, sensitive to ultra-violet light, whereas the data for the tumor agent suggest that its inactivation is due to the destruction of a substance having an essentially different spectral absorption, and therefore of a different chemical character. While the amount of ultra-violet energy required to affect the tumor agent is great, it is still less than that involved in the inactivation of some of the enzymes (7). A study is under way to compare the deduced spectral analysis with the actual coefficients of absorption of the highly purified tumor agent.     

EXPERIMENTAL OBSERVATIONS ON IRRADIATED,NORMAL, AND PARTIALLY PARATHYROIDECTOMIZED RABBITS : III. THE EFFECTS OF INANITION.

The experiments described in the three papers of this series were undertaken to determine if possible the significance of the parathyroid hypertrophy that has repeatedly been found in rabbits after exposure to ultra-violet light. The fact that the hypertrophy was not accompanied by a corresponding increase in blood calcium led us to infer that the upper level of blood calcium concentration is governed by factors independent of parathyroid control, and that the gland hypertrophy under the influence of ultra-violet light might represent a potential functional capacity, or increased factor of safety, to protect the calcium level under conditions of stress or emergency. Partial parathyroidectomy in irradiated rabbits, compared with the same operation in normal controls, resulted in a similar immediate drop in blood calcium; but a more rapid restoration of the calcium level in the irradiated rabbits indicated a more prompt and active response to the emergency on the part of the remaining glands. In the second group of experiments no significant differences were found in the reactions of irradiated, normal, or partially parathyroidectomized rabbits to injections of calcium chloride or of disodium hydrogen phosphate. All three groups of rabbits rapidly eliminated the excess calcium from the blood. Their reactions to large doses of sodium phosphate, given subcutaneously, appeared to be related to phosphate elimination or retention in the individual animals. Those in each group which had phosphate retention in the blood died in acute tetany. So also in the fasting experiments, reported in this paper, no distinctions could be drawn between normal, irradiated, and partially parathyroidectomized rabbits on the basis of their calcium and phosphorus metabolism. Blood calcium was reduced in a similar manner in all three groups of rabbits, and wide individual variations in serum phosphorus levels preclude significant deductions. But the irradiated rabbits suffered disproportionate losses of weight during the fasting period and four of five of them died during the course of the experiment. The deaths of these rabbits are attributed to this more rapid consumption of their own tissues and possibly also to suprarenal injury caused both by fasting and by exposure to ultra-violet light.     

The effects of adjunctive topiramate on cognitive function in patients with epilepsy

PURPOSE: We investigated possible cognitive effects of topiramate (TPM) in polypharmacy on patients with intractable epilepsy. METHODS: Study 1 evaluated 22 consecutively admitted patients whose antiepileptic drugs (AEDs) on admission to the Montreal Neurological Hospital included TPM. Performance on neuropsychological tests administered on and subsequently off TPM was analyzed. Four patients also were tested before taking TPM, allowing comparisons off, then on, and then off the drug again. Measures included intellectual function, verbal and nonverbal memory, language, word and design fluency, somatosensory sensitivity, and motor skills. In Study 2, 16 patients at the Minnesota Epilepsy Group were tested first off, then on TPM with nine cognitive tasks that measured concentration, verbal fluency, language, and psychomotor speed. RESULTS: In Study 1, significant (p < or = 0.01) improvements were observed off TPM on 13 measures including verbal and nonverbal fluency and certain verbal and perceptual tasks. Notably, verbal learning and memory were unaffected; a limited effect was observed on nonverbal memory. Patients tested 3 times scored better in both tests off TPM compared with on this drug. In Study 2, declines on TPM were observed on all measures, significantly (p < or = 0.05) for tests of fluency, sustained concentration, and visual motor processing speed. CONCLUSIONS: TPM was associated with declines in fluency, attention/concentration, processing speed, language skills, and perception; working memory but not retention was affected. As the two studies used an opposite order of testing on versus off TPM, our results clearly show a performance decrement while patients are taking TPM, without respect to which condition is tested first.