f,s- f-t^ '^- ^.11 .;^ BACTERML PYROGENS PYROGEN/C POLYSACCHARIDES of BACTERIAL ORIGIN An Annotated Bibliography BAXTER LABORATORIES, INC. Morton Grove, fUinoit BACTERIAL PYROGENS (Particularly Pyrogenic Polysaccharides of Bacterial Origin) An Annotated Bibliography §^=° Leonard G. Ginger, Ph. D. "" " Assistant Scientific Director : a William F. Windle, Ph.D., Sc, D, Scientific Director and lone E. Johnson, A. B. Librarian BAXTER LABORATORIES, INC. Morton Grove - Illinois MAY, 1952 67721 '•'M' PREFACE Although there has been a general awareness for many years that the inadvertent occurrence of fever following the parenteral administration of fluids is related to some product of microbial metabolism^ it is only within the past several decades that studies have led to the isolation from microbial sources of pyrogenic materials of a polysaccharide nature possessing remarkable physiologic activity. It is now appreciated that the vague phenomena, which formerly were called "non-specific, foreign protein reactions," have a common etiology. Trace contamination of a protein is usually sufficient to result in the formation of enough of the pyrogenic polysaccharide complex to impart the observed type of activity. As a consequence it is likely that protein is not the primary causative agent. The recent availability of pyrogenic polysaccharides has stimulated basic science investigations, leading to the rea- lization that these extremely active substances are capable of eliciting a miscellany of complex physiological changes, even in sub-febrile doses, which appear to be of therapeutic Importance, This annotated bibliography was compiled to provide a selected list of references, particularly relating to pyrogenic polysaccharides of bacterial origin, to acquaint the worker in this field with the published investigations and to aid in orienting and focusing current researches. Out of necessity, the bibliography also includes many perti- nent references on vaccines. It must be emphasized, however, that a very significant number of references relating to non-specific, foreign protein therapy have been deliberately omitted because of the conviction that it is practically impossible to duplicate many of such materials; hence such information is not of practical significance. Some refer- ences in this latter category have been included in selected instances where deemed desirable. 11 The period covered by this bibliography extends from 1785 through March, 1952. It is grossly arranged in numbered chronological order but is alphabetical within each year» To facilitate usage, an author index and an extensive subject index are provided. A great number of the references in very recent years is concerned with investigations involving the use of a purified pyrogenic substance called PYROMEN. The name of this prepara- tion has been changed to PIROMEN. Particular attention is directed to this alteration in name to avoid the possible con- fusion that might otherwise arise with the appearance of both names in the published literature. It is a particular pleasure to acknowledge the efforts of Miss Ella Salmonsen, Medical Librarian, John Crerar Library, and Miss Jean Reilley, Medical Reference Librarian, American Medical Association, in providing necessary reference mater- ials and much valuable advice. Mrs. Maud Hinson prepared the extensive index, and several members of our own staff, in par- ticular, Mrs. Helen Heartstedt, Mrs. Mae Swanson, and Mrs. Joyce Eckhart, contributed significantly in the compilation and record- ing of the bibliographic material. The Editors May 1, 1952 * Extended in The Addendum to August, 1952 ERRATA ?ARY V ■^ Abstract Line Shoiild read 18 39 Ih 79 132 137 163 203 207 226 230 25^^ 3U0 35^^ kok lj-21 U30 506 509 511 561 617 619 629 631 661 67k 6Q3 112. 728 736 752 3 8 10 6 k 7 Ik 2 12 2 13 2 5 11 3 5 5 10 2 3 6 6 1^ 14 11 12 3 10 32 6 16 h 2 1 11 "Riforma" "Metchnikoff" "vacuolation" " contract ions " "mechanism" "appears" "leukocytes" "lueischen" "markedly "by" "glutathione" "gram-positive organisms" "praecox" "antichancroid" "criterion" "cotton" "testing" "E2O2" "diastases" "Handhook" "sclerosis" "Seitz" "pyocyaneus" "reviews" "nucleoprotein" "Electric" "decrease" "aspecific" "resumes" "release" "synthetic" "volume" "leul«)cyte" "leukocyte" "Chambers" "lymphocytes" t -17 8 5 1. DICKINSON, C. An Inquiry Into the Nature and Causes of Fever (with a f*evlew of the several opinions concerning Its proximate cause as ad- vanced by different authors and particularly as delivered from the practical chair in The University of Edinburgh, etc.) Edinburgh, I785 The Edinburgh theory on the etiology of fever is stated to be that a product of tissue destruction ("putrefaction") pro- duces fever. - 1 8 2 6 - 2. BLACK, J, A comparative View of the More Intimate Nature of Fever London, I826 -1837- 3. CLUTTERBUCK, H„ An Essay on Pyrexia or Symptomatic Fever as illustrative of the Nature of Fever In General ~~ London, 1837 Black and Clutterbuck considered fever an overt manifestation of an awakening of the defensive powers of the cells against toxins in the blood stream. -1855 k. PANSUM, P. L. P. "Zur Lehre von der putriden Oder septischen Infectionen," (On the study of the putrid or septic Infections) Schmidt's Jahrbucher (Leipzig) I855 -18 5 5- A toxic principle found in decomposing protein substances was soluble in water but not in alcohol. Sterilization did not alter its toxicity. In minute quantities it was capable of producing fever, and the lethal dose for the dog was only 0.012 Gm, -1865- 5, BILLROTH, TH. Beobactungstudien uber wundfieber und (accidentelle) Wundkrank- heiten (Observational studies on wound fever and accidental wound infections) Arch, f, klin. Chir. 6:372-495, I865 Related findings were observed earlier. Fever appeared during the course of injections in patients. Chemical products in the medicaments were first considered to be the pyrexial agents. After a rise in temperature was noted when ordinary distilled water was injected, it was concluded that the solvents were probably contaminated . -1866- 6. FRESE, H. Experimente lle Beitrage zur Aetiologie des Fiebers (Experimental contribution on the etiology of fevers) Berlin, 1866 In decomposing tissue a soluble toxic material can be secured which resists boiling and passes through filters. - 1 8 7 2 - MANASSEIN, W, Ueber die wasserigen und alkoholischen Extracte der Muskeln und der Leber von fieberenden und hungernden Thleren (On aqueous - 1 8 7 2 - and alcohol extract of muscle and liver of fasting, feverish animals) Arch. Path. Anat . 56:220-247, 1S72-1873 Glycogen depletion of organs during febrile processes was noted - 1 8 7 3 - S. SENATOR, H. Untersuchungen Uber die fieberhaften Process und seine Behand - lung (Research in the febrile process and its treatment) Berlin, Hirschwald, l873 - 1 8 7 6 - 9. BURDON -SANDERSON, J. On the process of fever Practitioner 16:257-337, 417, I876 The term "pyrogens" was coined to cover all fever-producing agents . 10. SCHULEIN, W. Uber das Verhaltnis der perlpheren zu centralen Temperatur im Fieber (On the relationship of peripheral to internal temperature in fever) Arch. Path. Anat. 66:109-110, I876 A vasoconstrictive mechanism, produced by fever directly or indirectly, raises internal temperatures. ^ - 1 8 7 3 - 11. ILIFPE, W. Remarkable oscillation of temperature without apparent cause Lancet 2:728, I878 A patient without other symptoms in whom an increase or decrease in body temperature appeared regularly was described. The cause was not found. - 1 8 8 7 - 12. VON JAUREGG, Jo WAGNER Ueber die Einwirking fleberhafter Erkrankungen auf Psychosen (Action of fever-increasing Illnesses on psychotic patients) Jahrbuch fur Psychiat . Bd . 7:9^-102, I887-8 It was noted that progressive paralysis in long-established neurosyphilis appeared to improve under the stress of acute, accidental Infections. The fever engendered was considered , to be the curative agent. In attempting to reproduce these bene- ficial results, von Jauregg utilized both crude typhoid vaccine and injections of malarial parasites, in his later studies, (1917). In the years between I887 and I909, he secured favorable results through the use of Koch's old tuberculin. -1889 13. ROUSSY, G. Recherches experimentales . Substances calorigenes et frigori- genes d'origine microbienne; Pyretogenine et Prigorlgenine (Experimental researches. Calorigenic and frigorific substances of microbial origin; Pyretogenine and Prigorlgenine.) Gaz. d'Hopit. (Paris) 62:171, I889 Fever and chills were caused by two separate principles residing in bacteria; these were released by lytic action of enzymes and diastases within the body. Roussy isolated these substances from gram-negative organisms. 5 -18 8 9- 14, ROUSSY, G. Recherches cllnlques et experlmentales sur la pathogenle de la fievre: Theorie gen^rale sur la nature et les r6les physlolo- glques et pathogene des diastases ou ferments solubles (Clinical and experimental research on the pathogeny of fever: General theory on the nature and physiologic and pathogenic roles of diastases or soluble ferments) Gaz. med, de Liege I88-I89, i, 289-293, I889. See also: Gaz Hopit, (Paris) 62:286-289, I889 and Arch, de physiol. norm et path, (Paris) 5:355-370, I89O, Abstract, J. A.M. A. 12:517, I889 The work of Roussy on the enzymatic etiology of fevers was forgotten in the interest awakened by the school headed by Pasteur, -1891 15. BUCHNER, H, Tuberculin reaktion durch Protelne nicht-specifischer bacterlen (A tuberculin reaction through nonspecific bacterial protein) Munch, med. Wchnschr. 38:841-842, I89I 16. RICHTER, P. Experimentelle Untersuchungen uber Antipyrese and Pyrese, nervose and kunstliche Hyperthermie (Experimental research on anti-pyrese and pyrese, nervous and artificial hyperthermia) Arch. f. path, Anat . 73:118-165, I89I - 1 8 9 2 - 17. KANTHACK, A, A, Acute leukocytosis produced by bacterial products Brit, M, J, 1:1301, I892 The author injected sterilized or filtered cultures of Vibrio Metchnikovi , B, pyocyaneus and yeast intravenously into the rabbit, producing immediate pyrexia, initial leukopenia which - 1 8 9 2 - was succeeded by marked leukocytosis. The latter was mainly an increase in eosinophils, and the neutrophils were only slightly increased. The increase in leukocytes often lasted over 72 hours. -18 9 3- 18. CENTANNI, E. Ueber infektious Pieber. Das Fiebergift der Bactereri (On in- fectious fever. Fever toxins of bacteria) Deutsch. med, Wchnschr. 20:148-150; I76-178, 1893 Reforma Med, 256, 1893 A number of pathogens were investigated for the presence of the fever toxin: Diplococcus pneumoniae , B. typhi , B, coli , B. aerogenes and pyocyaneus, the pyrogenic Staphylococci and that of erysipelas, the bacilli of anthrax and tuberculosis, the vibrio ( Metschnikof f , Finkler , and Deneke ) and the organisms of tetanus. Influenza and diphtheria. Activity for fever pro- duction appeared to be present in all these toxins and in ex- tracts from the bacterial cells. Centanni found pyrogenic ability of bacterial toxins was not proportional to toxicity; all appeared to contain the same volume of Pyrotoxina bacterlca, a water-soluble concentrate, non -albuminoid in character. 19. COLEY, W. B. The treatment of malignant tumors by repeated inoculations of e]:'ysipelas: With a report of ten original cases Am. J. Med. Sci. 105:487-489, I893 Pure culture material of S. erysipelatis was injected in ten cases of inoperable or recurrent carcinoma or sarcoma. Even without production of frank erysipelas, response was favorable, parti- cularly in the sarcomas. The curative action is believed to be a systemic rather than a localized one, 20. RUMPF, T. Die Behandlung des Typhus abdominalis mit abgetodtaten Culturen des Bacillus pyocyaneus (Treatment of typhus abdominalis with killed cultures of Bacillus pyocyaneus ) - 1 8 9 3 - Deutsch. med. Wchnschr, 19s 987, 1893 - 1 8 9 4 - 21. CENTANNI, E. Ueber Infektlous Fieber (On infectious fever) Chera. Zentr. (4th Series) 6:597, 189^ Pyrotoxina bacterica , the fever-producing substance from bact- erial cells, was extracted from the organisms following a period of heating (3 hours at 60° C.) and subsequently a more intense treatment at the boiling point. Filtration through a porous clay filter followed; the concentrate was precipitated with absolute alcohol, and the albuminous fraction removed. Repre- cipitation and dialysis precedes drying in vacuo . Administered in superficial vessels under the; skin, a chemo- tactic reaction of the local variety is produced. No suppura- tion appears, but there is a powerful leukocyte attraction. Larger doses bring forth a flattened , edematous swelling and adja- cent blood vessels become hemorrhagic . The chromatin portion of the bacterial cell may be the site of origin of the fever toxin. 22. TEISSIER, J. Des Pyrexies apyretiques ■ (Atypical fevers) Semo med, (Paris) 14:197-199, l894 Teissier noted the prevalence of febrile conditions without other symptoms of specific disease. 30 years later, he applied the knowledge gained through his experience (with Rivallier and ^ Reilley) to the treatment of disease making use of the 'propidon of Delbet, a preparation secured by the digestion of Ps_. aeru - ginosa , streptococci and staphylococci . - 1 8 9 5 - 23. COLEY, W. B. 8 - 1 8 9 5 - Erysipelas toxins and erysipelas serum in the treatment of inoperable malignant tumors. Further observations Med, Rec. 57:609-6l2, 1895 24, CZERNY, V. Uber Heilversuche bei malignant Geschwulsten mit Erysipeltoxinen (On research of healing of malignant growths with erysipeltoxin) Munch, med, Wchnschr, l85:42j 833-835; l895 The use of bacterial toxins in the treatment of malignancies was introduced in conjunction with Emmerich and Scholl. 25, EMMERICH, R« and SCHOLL, H. Klinische Erfahrungen uber die Heilung des Krebses durch Kreb- sserum (Erysipelserum) (Clinical experiences on the healing of cancer with cancerserum (Erysipelserum) Aerztl, Centr. A, (Wien) 7:209; 228; 2^2; 358-360.; 378-381; 706-712, 1895 26, SWAIN, Jo The treatment of malignant tumors by the toxin of the Strepto - coccus eryslpelatis a nd B. prodigiosus Brit, M. J, 2;l4l5, 1895 -1896- 27 COLEY, W. Bo Further observations upon the treatment of malignant tumors with the toxins of erysipelas and Bacillus prodigiosus , with a report of 160 cases Bullo Johns Hopkins Hosp, 65:157, I896 (Abstract) In all cases reported, the tumor was either inoperable or had recurred after surgery; in nearly all, microscopic examination confirmed the diagnosis of malignancy. These patients, observed - 1 8 9 6 - for a period over four years, presented all varieties of car- cinoma or sarcoma. Sarcoma was present In 93> carclncma and epithelioma in 62 patients, "Of the cases of sarcoma nearly one-half showed more or less improvement; the variety that showed the greatest improvement was the spindle-celled , that which showed the least, the melanotic »" - 1 8 9 8 - ■ 28, BATTLE, Wo He A case of sarcoma treated with Coley's Fluid Brit, Med„ J, 2:155^* I898 The complete disappearance of a large tumor of the clavicle, with axillary metastases, followed treatment with Coley's fluid, 29= COLEY, W, Bo The treatment of inoperable sarcoma vjlth the mixed toxins of erysipelas and Bacillus prodigiosus and final results in l4o cases J.A.M.A. 31^389; 456, 1898 The differences between tumor ipesponse to mixed bacterial toxins are pointed out. Results thus far would indicate that the most successful therapeutic results are secured in treatment of spindle-celled sarcoma. In which favorable response has been secured in 50^ or more of the cases. Far more resistant are round -celled sarcomata. No Improvement in melanotic sarcoma has become permanent. The action of the mixed toxins appears to be one of coagulation-necrosis with fatty degeneration, unlike inflammation or local escharotic effects. That the action is specific is shown by the regression which occurs when in- jections are made subcutaneously and in sites removed from the tumor. The dangers attendent on this type of therapy are those of shock, with circulatory collapse, and pyemia of septic origin. The use of the toxins after surgical removal of the tumor is advocated. Mild doses are advocated for this purpose. 10 18 9 8 30. FOWLER, G. Re The use of animal toxins In the treatment of inoperable malig- nant tumors Amo Jo Med, Scl. Il6:l6l-l62, I898 The author presents a review of the use of bacterial toxins in the treatment of neoplasms. Among the reports discussed were those of regressions after accidental infection with ery- sipelas and after use of the septic products of the causative streptococcus. The value of mixed toxins of erysipelas and B. prodigiosus in the treatment of malignancies was assessed. The rationale for the action of Streptococcus eryslpelatis and its toxin is presented. Possibility of new applications of this type of treatment lies in the suggested use of the serum of animals infected with Str, eryslpelatis , of the venom of the cobra capello, and in induced suppuration in malignant growths, - 1 9 3 - 31, MACPAYDEN, A. Upon the immunizing effects of the intracellular contents of the typhoid bacillus as obtained by the disintegration of the or- ganism at the temperature of liquid air Proc, Roy, Soc , (London) 71:351.' 1903 A method for the fractionation of bacterial cellular components is briefly described, - 1 9 6 - 32, COLEY, W. Bo Late results of the treatment of inoperable sarcoma by the mixed toxins of erysipelas and Bacillus prodigiosus Am, J, Med, Sci. 137; 376-78, 1906 The author reviews his work on the treatment of inoperable neo- plastic growths through use of living cultures of Str, erysipelat and its further development in the combined or mixed toxins of 11 -19 6- B. prodlglosus and Str. eryslpelatls . The results obtained In 3y personal cases so treated are summarized. - 1 9 7 - 33. BEEBE, S. P. and TRACY, M. The treatment of experimental tumors with bacterial toxins J. A.M. A. 49:1493-1495, 1907 Inoculations, Intratumorally or at a distance of a number of bacterial toxins produced some regression in lymphosarcoma in the dog. Vaccines of B. prodigiosus alone or in combination with Str . pyogenes vaccine, produced some softening and sloughing of tumor tissue and, in one animal, complete regression. A suspension of a vaccine made from B. coli communis was likewise beneficial. Soluble prodigiosus toxins, and a vaccine from Staphylococcus pyogenes aureus , were valueless for this purpose. 34. COLEY, W. B. Inoperable sarcoma. A further report of cases successfully treated with the mixed toxins of erysipelas and Bacillus prodigiosus Med. Rec. 72:129-131, 1907 The mixed toxins of B^ prodigiosus and Str . eryslpelatls were administered to twelve patients with inoperable sarcoma of the long bones. No recurrence of these tumors could be traced for eight of these patients, observed for periods ranging from three to eight years. Pour other patients were living but had been under care for shorter intervals. Qi^ "^CAl ■ i??ARY J^' ..■,v^i ' -1908- 35. LANGE, F. Experimentelle Untersuchungen uber das verhalten der LeukS^yten nach Injektionen von Bakterienextrakten (Experimental investiga- tions on the behavior of leukocytes after bacterial extract Injections) 12 - 1 9 8 - Deutsch. Arch. f. klin. Med. 9^:552-55^, 1908 The initial drop in leukocytes may Indicate transient storage in sites of the most Intense activity of bacterial toxins. Local and total increases in certain of the cell types are discussed . -19 9- 36, COLEY, W. B. The treatment of inoperable sarcoma by bacterial toxins (The mixed toxins of the Streptococcus erysipelatis and the Bacillus prodigiosus Proc. Roy. Soc, Med. (Surg. Lectures) Ft, III. 3:1-4, I909 In summarizing the results obtained in all cases of inoperable sarcoma treated with Coley's mixed toxins, the theories on the modus operandi of these toxins, prophylactic indications, mode and length of administration are presented. The toxic side effects are enumerated. - 1 9 1 - 37. LOEB, L. The treatment of inoperable sarcoma by erysipelas and prodi- giosus toxins J. A.M. A. 5^:262-264, I9IO The author states that approximately 4 to 9 per cent of cases of inoperable sarcoma treated with the toxins of Str . erysipe - latis and B. prodigiosus are cured, but the modus operandi remains obscure. 13 - 1 9 1 1 - 38. BENDIX, B., and BERGMANN, J. Uber das sogennante Kochsalzf ieber (On the so-called Salt Fever') Monatschr. f. Kinderhellk. 11:337-88, 1911 After injections of physiologic saline solution^ unexpected temperature Increases were noted. Careful preparation of the solution and care in injection appeared to prevent the reaction which was considered to be the result of bacterial contamina- tion. 39. HORT, E. C. and PENPOLD, W. J. The dangers of saline injections Brit. M. J. 2:1589, 1911 In a study of the undesirable effects which frequently follow injection of saline solution in both humans and animals, the authors listed: the production of fever, rigors, subnormal temperature, diarrhea, intestinal hemorrhage, Cheyne-Stokes breathing, and, with hypertonic solutions or rapid injection, convulsions and sudden death. Pulmonary edema may follow the injection of large amounts of solution. Vaculation of hepatic cells and changes in heart muscle and renal tissue have been noted on histologic examination. Bacterial products in ^^?ater^ and not the saline^ are responsible for these changes. After filtration and heating of water, 19^ of the animals used in this study showed slight febrile reactions; only a few organisms were found on culture, and the protein content was very small. When freshly distilled water was used for solutions, few reactions occurred, but when water was used after standing in sterile vessels, fever was produced in direct proportion to the amount injected. A solution containing 73,000 organisms per cc , was used 10 days after distillation; it produced a far less intense elevation of temperature than a sample two months old which contained but 40 organisms. When the con- taminated solution was centrifuged, the pyrogenic substance v^as found to be concentrated just below the surface of the supernatant fluid. This pyrogen was heat-stable and passed readily through a Berkefeld filter. 40. KILIANI, M. Pharmakologische Wertbestimmung der technischen Piebermittel (Pharmacologic evaluation of technical fever materials) Arch, inter, d. pharmacodyn. et d. therap, 20:333-352, 1911 1^ -19 11- 41. LOWENSTEIN, J. Zur Behandlung die progressiven Paralysis mit nucleinsauren Injektionen (On the treatment of progressive paralysis with nucleic acid injections) Klin. Wchnschr. (Berlin) 48:7l4-7l6, I9II The later work of Meyer and Fischer corroborated that of Lowenstein who found nucleic acid to be superior to tuberculin ('old' tuberculin of Koch) for arrest of progressive paralysis. The mechanism by which results were achieved was unexplained and remissions were not permanent , 42, MULLER^ P s Ueber den Bakteriengehalt des in Apotheken erhaltllchen distil- lieiften Wassers (On the bacterial content of distilled waters stored in pharmacies) Munch, med, Wchnschr, 58:2739^ 1911 43. NOBEL, E, Zur Kenntnls des temperaturensteigernden Giftes des Bakterium Coll communis (To the knowledge of information on temperature- increasing toxins of Bo coll communis ) Arch, Exper, Path, u, Pharmakol, 68:371-382, I9II An active factor which produced fever was removed from the cells of B, coli communis after hydrolysis, extraction and dialysis c Its characteristics resembled those of cleavage products of protein. 44. THOMSON, D. A remarkable daily variation in leukocytes in several diseases (Malarial fever, Hodgkln's disease, cancer) Brit, Mo J, 1:1586, I9II During the sporulation of malarial parasites, toxins are lib- erated In the blood stream, the mononucleated leukocytes de- crease in number, and the total leukocyte count is lower as the temperature rises. When fever declines^ the mononuclear cells increase. Even after quinine therapy, marked leukocytosis occurs at the same hour as that of the last sporulation of Plasmodia, 15 -19 11- The reduction of the population of malarial parasites is accompanied by a change from severe leukopenia to a marked in- crease in white cells. Five to ten million dead parasites mixed with corpuscles will stimulate leukocytosis for one hour; this is a good diagnostic sign for malaria. In Hodgkin's disease a daily variation in leukocytes from 6,000 to 754-000 per cm,, may be noted. The mononuclear cells account for 50 to 80 per cent of the increase. A similar change is seen in cancer of the stomach, but fever is absent. The similarity between the leukocyte picture in malaria and that seen in malignancies leads one toward acceptance of the virus theory of etiology for the latter. 45. WECHSELMANN, W. Neuere ETfahrungen uber Intravenbse Salvarsaninjektionen ohne Reaktions Erscheinungen (More recent experiences with intraven- ous salvarsan injections without appearance of reactions) Munch, med, Wchnschr, 58:1510, I9II Febrile reactions after salvarsan injection were frequently reported in the literature during the first five years after use of the Ehrlich synthetic began, German physicians sought to place blame upon the solvent (Wasserfehler) while French writers considered the inherent toxicity of arsephenamin re- sponsible, Wechselmann found that temperature elevations per- sisted in some instances after special treatment and prompt use of the distilled water solvent. The toxic principle therein resisted both autoclaving and filtration. - 1 9 1 2 - 46, GREENWOOD, H, H. Note on a case of melanotic sarcoma treated by Coley's Fluids Lancet 25.881, I912 Coley reported that the mixed toxins of Str. erysipelatis and B, prodigiosus were of very limited benefit in melanotic sarcoma, A report is presented of the recurrence, in a rapidly spreading form, of melanotic sarcoma previously removed by surgical means. As a last resort, the mixed toxins were administered. The patient had a complete regression and regrowth had not occurred in one and one-haif years. 16 - 1 9 1 2 - 47o HORT, E, and PENPOLD, Wo J. Microorganisms and their relation to fever J. Hyg„ 12:361-390, 1912 Basic arguments are presented for each of the two opposing theories on the origin of bacterial pyrogens. One school of thought, dating from the days of Roussy, would place origin within the tissues and fluids of the host, others consider alien sources (bacterial contamination) responsible for genesis, This discussion considers the possibilities that pyrogens are liberated from bacteria during disintegration within the body or when grown in vitro and that they may be the results of enzymatic breakdown of metabollzable materials, in body tissues or in synthetic media = 43 „ HORT, Ee and PENFOLD, W, J, A critical study of experimental fever Proc. Roy« Soc . Med = (London) Series B, 85:174-186, I912 The tet^ms 'water fever', 'salt fever', 'sugar fever', 'ferment fever ^ and 'tissue fever' have been applied to pyrexial phenomena in the past. Such terms are misleading c A single entity may be responsible for the appearance of all fever » Its appearance in contaminated water would account for the universality of pyrexiae The present procedures for isolating such materials are insufficiently standardized for reliability in results, 49 o HORT, E. C, and PENPOLD, W. J. The relation of salvarsan fever to other forms of injection fever Proco Roy, Soc. Med, (Pt. III. Pathology) 5:131-139, 1912 On the basis of the theory presented by Wechselraan, who found gross contamination of medicinal solutions by bacterial pro- ducts to be responsible for so-called 'salvarsan fever '^ the authors studied the pyrogenetic properties of undegraded bacterial protein as well as the efficacy of filtration for the production of nonpyrogenlc solutions. They noted, on fil- tration, a fever-producing substance passed through ordinary bacterial filters from salvarsan solution and other fluids. "Salvarsan fever is (not) necessarily due to the injection of organisms grown on water or saline", they reported, but were unable to determine whether or not pyrogens were products of bacterial protein decomposition. Safeguards against pyrogenic contamination of distilled water were described. 17 - 1 9 1 2 - 50. LUDKE, H. Ueber Partlalglfte Im baktlerlen Protoplasma (On Partial toxin in bacterial protoplasm) Deutsch, Arch, f. klin. Med. 105:411-432, 1912 51. MORESCHI, C. and GOLGI, A. Dei rapporto anafilassi e febre (Pyrogenic action of typhoid anaphylatoxin) Policlln. (Med. Secto) 19:431-441, 1912 Subcutaneous Injection of typhoid anaphylatoxin in rabbits produced elevations of body temperature initially but only mild hypersensitive reactions without pyrexia when the injection was repeated. 52. SAMELSON, S, Uber das sogenannte Kochsalzf ieber (On so-called 'Salt Fever') Monatschr, f, Kinderhellk. 11:125-133, I912 53 o SEBASTIANI, V. I varii tipl febrile riprodotti con un' pirotossino batterica (Varied types of fever reproduced by a bacterial pyrogen) Arch, dl Biol. (Pirenze) 66:137-154, I912 A single toxic principle is released by many bacterial specimens When released in the blood stream of animals or humans it pro- duces a shock phase, followed by fever, with changes in the blood picture. To the pyrogenic agent isolated from B, prodi- £i£sus, the name "pyrotoxin" was applied. ~ 54. VON JAUREGG, J. WAGNER- IJeber Behandlung der progresslven Paralyse mit Bacterientoxinen (On treatment of progressive paralysis with bacterial toxins) Wiener klin. Wchnschr, 25:61-63, 1912 After long experience with the use of malarial therapy and the Ola tuberculin of Koch in the treatment of neurosyphilis. Von Jauregg, with Josef Halban, injected therapeutically killed 18 - 1 9 1 2 - cultures of staphylococci and streptococci. The temperatures of patients with tabes and luetic Involvement of the central nervous system were not elevated to the degree seen after old tuberculin, but it was noteworthy that relapse was less frequently seen after treatment. - 1 9 1 3 - 55. CITRON, J. and LESCHKE, E, Ueber den Elnfluss der Ausschaltung des Zwlschenhlrns auf das infectl'dse und nichtinfectlBse Fleber (On the influence of the transection of the midbrain on infectious and non-infectious fever) Zeltschro f<, Exper, Path, u, Therap, 14:379-390, 1913 Febrile response could not be elicited in the rabbit after section of the medial hypothalamus at the anterior border of the midbrain o Biological pyrogenic agents ( Trypanosoma nagana and staphylococci ), colloids and chemicals were equally ineffec- tive, 56. FERNANDO -TORRES, P. R, Vacunoterapla o antlgenoterapla antlflca Seman. med. 22:1557, 1913 Typhoid vaccines may be used as nonspecific therapy in condi- tions other than typhoid itself. Torres suggested that the action of such bacterial materials might be dual, the antigenlc- immunlzlng factor affecting one mechanism for defense, while a second principle produces a more obscured cellular activity. 57. VAUGHAN, V. C, JR. (with J. W. Vaughan) Protein split products in relation to immunity and disease Philadelphia, Lea and Pebiger, 1913 Proteins could be split into two parts, either by enzymatic action within the organism, or by chemical procedures. A soluble poisonous particle remained in the menstruum. This product played an Important role in the genesis of disease; on the in- jection of very minute amounts immune body production was 19 19 13- stlmulated. Vaughan linked infantile diarrhea (cholera Infantum) v;lth the presence of ' thyrotoxlcon ' ^ a biological split protein which he found In Ice cream and milk. -191^- 58. CENTANNI, E. Uber den chemlsche Wlrkung des Bakterlenglfte (Chemical action of bacterial toxins) Zentro Blochem, BlophySo l6:4l5, 1914 A basic product of secondary albumin cleavage and not an amino acid or simple polypeptide carried the pyrogenic charac- teristics found in bacterial proteins. The substance ivas dialyzable, 59 JOACHIM^ A. 1 1 i" ' Uber zehn Falle von geheilter Paralyses progressive nach Behand- lung mit Tuberculin (Ten cases of progressive paralysis cured after treatment with tuberculin) Wiener kiln. Wchnschr. 27:l409-l4ll, 1914 Detailed case histories for ten patients who presented evi- dences of psychosis and asocial overt behavior are presented. Remission of the progressive paralysis was accompanied by sub- jective improvement which enabled them to resume normal acti- vities. The manner by which tuberculin alters central nervous tissue in paresis is not clarified. Hyperpyrexia was not empha- sized in this study. -1915- 60, HARMER, T, W. A study of the efficiency of mixed toxins (Coley) in inoperable sarcoma. A critical analysis of 134 microscopically proven cases Boston M. & S. J. 172:331;373; 411; 440, 1915 An analysis of 134 case reports is presented. Criteria met by 20 - 1 9 1 5 - all cases Included: Proof by microscopical examination; pri- mary or recurrent inoperable sarcoma; treatment period three weeks or longer; no other therapy given during mixed toxin treatment. Cases were divided into six groups on the basis of response to therapy. Twelve patients received no benefits from therapy; 5 experienced some softening of the neoplasm but no regression; 20 sarcomas disappeared and regrew after some months; growths disappeared, but metastases were seen later in 10 patients. Some diminution of the size of the sarcoma was seen in 14 patients. The 73 patients for whom apparent cures were obtained justify the use of the toxins in these inoperable cases. The greatest percentage of cure or amelioration was noted in the small round cell type of sarcoma. In a few patients, striking relief from pain was achieved . 61 o LUDKE, H. Die Behandlung des abdominal-typhus mit intravenosen Injektionen von Albumose (Treatment of abdominal typhus through intravenous injections of albumose) Munch, med. Wchnschr. 62:321-323, 1915 Deutero-albumose produced a febrile response when injected intra- venously in treatment of typhoid . Pyrexia might be caused by action of this primary cleavage product of albumin or outside contamination of the solution by pyrogen-yieldlng organisms. 1916- 62, BIELING, R. K, Untersuchungen uber die veranderte Agglutininbildung mit Ruhrbacillen vorbehandleter kaninchen (Research in the changing agglutination picture in animals previously treated with colon bacilli) Ztschr. Immunitatsforschung, u, Exp, Therap, 28:246, I9I6 The agglutinins increased when previous immunization with colon, dysentery or diphtheria bacillus preparations preceded in- fections, such as typhoid. 21 - 1 9 1 6 - 63. GAY, F„ P,, and CHICKERING, H. T. Studies In Typhoid Immunization, VI, Treatment of typhoid fever by intravenous Injections of polyvalent sensitized typhoid vaccine sediment Arch, Int, Med „ 17:303-328, I916 64. HEKTOEN, L. Vaccine treatment J.A.MoA. 66:1591-159i^, 1916 In subacute and chronic localized infections, specific vaccines have, when properly used, valuable stimulatory properties on leukocyte activity and on specific antibody mechanisms. In typhoid fever and, perhaps, in other Infections, intravenous Injection of specific vaccines and other substances may Induce crisis by activity either superimposed upon or varying from the stimulation of antibody production. This the author sees as "a new and Interesting development in the study and treatment of infectious diseases," 65, JONA, J, L, A contribution to the experimental study of fever J. Hyg, 15: 169-194, 1916 A non-protein thermogenic factor was Isolated from B. coll communis and E, typhosa. It was colloidal in form, thermo- stable in dry heat at 110^ C, and resistant to boiling. Or- ganic solvents were ineffective. In combination with calcium it formed inert salts. In minute quantities (4 gammas) it produced fever in the rabbit, 660 MILLER, J. L, and LUSK, P. B, The treatment of arthritis by the intravenous injection of foreign protein J.AoM.A, 66:1756, 1916, See also: J,A.M,A, 67:2010, I916 Typhoid vaccine was given intravenously for the relief of arthritis. Relief of pain followed. The treatment was 22 - 1 9 1 6 - considered primarily one of 'shock'. Unfavorable reactions occurred. In addition to the expected rise in temperature, marked chills, severe malaise and headache were encountered. 67. VAUGHAN, V. e*, JR. Poisonous Proteins, Protein Fever Herter Lecture. J. Lab. Clin. Med. 2:15, I916 The author quotes extensively from other authors in the support of his theory that fever is the result of internal de- struction of proteins. Bacterial infection in its active phase is caused by liberation of 'protein poison' from bacterial cells. This 'protein poison' is the keystone of all protein molecules and is toxic only when set free. Once released, it possesses the power to destroy the structure of other prorelns through the removal of one chemical group. -1917- 68. DAVIS, B. P. and PETERSEN, W. P. A comparative study of lymph and serum ferments during protein shock reactions J. Exper. Medo 26:699-706, I917 A preparation obtained from cultures of B. coll produced shock, increased the flow of lymph and antif erments, and raised pro- tease titers. The concentration of lymph fluid is not parallelled by serum changes. The peptidase titer is not increased in proportion tea protease. Diastase was found to be unchanged. A rise in lipase was noted, 69. DOCHEZ, A. R. and AVERY, 0. T. The elaboration of specific soluble substance by pneumococcus during growth J. Exper, Med, 26:447, 1917 During the growth of young cultures of pneumococci and parti- cularly during the period of maximal multiplication, a specific substance is elaborated by the bacteria and is found in cell- free filtrates. Disintegration of the cell is not required for its liberation. It is stable to high temperatures and 23 - 1 9 1 7 - resists boilings Tryptlc digestion, alcohol, acetone or ether precipitation do not change its properties. In animals and in humans, experimentally or accidentally infected with the pneumococcus^ a similar or identical substance appears early in the disease process. In blood and urine the specific pre- cipitin reaction may have diagnostic importance, 70, DUPLAN Les colloides et le colloidotherapie (Colloids and colloid therapy) Rev, Int. med, chir, 28s 46-49, 1917 Administration of colloidal toxic bacterial substances during septicemia activates leukocytosis^ both genesis and migration. The osm.otlc tension of the white cells is reduced after phago- cytosis of these colloidal toxins; disintegration of the leuko- cyte is thus hastened. In the circulation the liberated nucleic acids initiate general systemic changes, 71c HOLLER, G, Beobactungen uber die Wirkungsweise parenterale einverleibter Proteink^rper zu therapeutischen Zwecken (Observations on the mode of action of parenterally administered protein for purpose of therapy in infectious diseases) Med. Klin, 13;1038-104l, I917 The death rate in typhoid was reduced to 0,5^ and the average duration of fever to 10 days when a 10^ solution of deutero- albumose was injected in very minute doses once or twice daily. Therapy should be continued until defervescence is well-established , 72, KIBLER, C, S, and McBRIDE, L, P, Intravenous injection of typhoid vaccine J, Infect, Dis, 21sl3-20, I9I7 Intravenous injections of typhoid vaccine were administered to six patients with typhoid fever and to one normal individual. Temperature changes, leukocyte counts, agglutinin and opsonin titers, blood pressure variations and coagulation time were recorded. In both ill and normal patients, chills followed immediately, accompanied by hyperpnea and, in some instance^. 24 - 1 9 1 7 - cyanosis. The second phase brought a rapid temperature rise which reached its peak in 3 to 5 hours. Defervescence extended over some 18 hours. Leukopenia was found during the first phase. The rise in polymorphonuclear cells followed temperature increases. Blood pressure was decreased during the entire period (10 to 15 mrao Hgo) and returned to pre-injection levels within a few days. Coagulation time was unchanged. Three patients were improved under therapy, and typhoid was ap- parently aborted in a second case. There was no improvement in two cases and one fatality followed. 73. KRAUS, R,, PENNA, J. and BONORINO, C, J, Ueber Heterobakterientherapie (On heterologous bacteria therapy) Wiener klin, Wchnschr. 30:869-870, I917 The therapeutic effects derived from a preparation made from the colon bacillus resembled those secured through the use of typhoid vaccine. The same nonspecific and generalized reaction follows foreign protein therapy. A single substance present in all three materials must be the active agent. 74. MEYER, J. and CARLSON, A. J. Hunger and appetite in fever Am. J. Physiol. 44:222-226, 1917 In an attempt to determine the effects of fever on hunger con- tractions and the mechanism through which such effects are mediated, hunger contractiions in the stomach of gastric fistula dogs were observed during a 24 hour period of starvation. After observation of the normal fasting functions of the stomach, the effects of intravenous or subcutaneous injection of the following pyrogenic materials were measured: sodium nucleate, killed B, prodigiosus cultures, peptone, typhoid vaccine and caffeine citrate. ^The changes in hunger contrac- tions produced by external heat were also recorded. Sodium nucleate, B, paratyphoid , tetanus and diphtheria were Incubated with pylorTc strips. Sectioning of splanchnic and vagus nerves and its effect on pyrogenic changes revealed the fact that lower vagus tone appeared to inhibit hunger contraction, but no association with the plexuses in the splanchnic area coilJld be traced. Starvation of neonatal puppies did not induce fever. In, vitro bacterial toxins did not alter activity of stomach muscle. Temperatures of 103° P. prevented hunger contractions. 25 - 1 9 1 7 - 75. SCULLY, F. J. The reaction after intravenous injection of foreign protein J.A.M.Ao 69:20-23, 1917 Patients with articular arthritis experienced pronounced reac- tions after intravenous typhoid vaccine Injections. A chill, accompanied by marked leukopenia, was first noted; rising tem-perature followed with maximal levels appearing within 3 or 4 hours. Leukocytosis, with the absolute increase largely a matter of neutrophil multiplication, marked the max- imal point. The blood pressure mounted during the chill and declined thereafter. Hypotension persisted for 3 to 4 hours, and the return to normal levels was a gradual one. Relief from joint pain was reported by 40^ of the patients after a single Injection; over one-half were benefited by 2 or more Injections. - 1 9 1 8 - 76. AULD, A. G. Pyrogenic therapy. With remarks on colloidal metals Brit. Mo J. ia95, 1918 Various colloidal metals may exert a pyrogenic effect when parenterally Introduced, In the course of his Investigations the author found a marked reaction could be stimulated by the use of a colloidal platinum preparation over one year old. On injection of this material a sharp rigor followed, then pyrexia, headache, and perspiration. The blood pressure reached high levels during the chill period and fell in the febrile interval; the leukocytes began to rise as the fever increased , A suspension of colloidal silver was markedly effective In producing the reaction. The investigator deduced from the identical effects elicited by these metals that the m^tal Itself was not the pyrogenic agent, "If the pyrogen. . .was not colloidal platinum, it matters little therapeutically, as all pyrogenic agents in appropriate doses produce the same effects.,,, Under present conditions typhoid vaccine is prob- ably the best pyrogen to use..." 26 - 1 9 1 S - 77. HASHIMOTO, M. Pleberstudlen uber die spezifische ueberernpf Indlichkeit des Warmzentrums an sensiblslerten Tleren (Fever studies on the excessive sensitivity of heat centers in sensitized animals) Arch. Exper, Pathol. (Leipzig) 78:370-373, 1918 A primary injection of heterologous protein sensitizes certain cells of the temperature-regulating centers » When the specific antigen is again introduced, an immunologic, reaction occurs and fever appears, 78, HASHIMOTO, M, Pleberstudlen, II. Uber die Einfluss unmittelbarer Erwarmung und AbkQhlung des Warmzentrums auf die Temperaturwirkungen von verschiedenen pyrogenen und antipyretlschen Substanzen (Pever studies. II. The influence of direct heating and cooling of the heat centers upon the temperature-activity of various pyrogenic and antipyretic substances) Arch. Exper. Pathol. (Leipzig) 78:39^-395, 1918 Pyrexia induced by typhoid vaccine and by anaphylactic shock can be modified by direct heat or cold applied to the heat regulatory centers. The action of some antipyretics is altered by these measures. 79. MEYER, J., COHEN, S, J.^and CARLSON, A. J. Gastric secretion during fever Arch. Int. Med. 21:35^-365, 1918 The underlying mechanslm affecting gastric secretion during fever was studied further through observations of Pavlov pouch dogs in which fever was Induced by intravenous injections of sodium nucleate, inactivated cultures of B. prodlgiosus or external heat. Determinations were made of both free and total HCl, pepsin, chlorides and total secretion volume. External heat (to increase body temperature 2 to 4° P.) or pyrogenic substances decreased total and free acid in gastric secretion, as well as the total volume. A relative increase in pepsin and slight chloride reduction were recorded. During fever, gastrin was ineffective. It was believed that toxins elaborated during fever directly depress the secreting mechanism in the stomach. In particular, the secreting powers of the cells are reduced to a point where nerve impulses can no longer stim- ulate activity. 27 -19 18- 80o WELLS, C. W. Leukopenia and leukocytosis in splenectomized rabbits J. Infect. Dis. 22:502-506, I91S The spleen may exert an influence over the total number of leukocytes during the period of Increase which follows the administration of killed bacteria. In initial leukopenia, the fate of the -leukocytes in the blood from bone marrow and liver parenchyma was studied. Normal levels were maintained in one instance. The mechanism involved was not determined. - 1 9 1 9 - 81, BALCAR, J. 0., SANSUM, W. D. and WOODYATT, R, T. Fever and the water reserve of the body Arch. Int. Med. 24:116-128, I919 The appearance of so-called 'thirst' or 'inanition' fevers (which include the dietary fevers of infants and 'sugar' and 'salt' fever in children and adults) is considered a result of (a) binding of water by electrolytes or organic molecules (b) inadequate amounts of water available for evaporation (c) increased peripheral temperatures. In fever the normal body reserves of water are bound by colloids to an abnormal degree. The marked diuresis and perspiration v^hlch follow the dissolu- tion of fever by crisis are evidences of water liberation. Intake of additional fluid would, rationally, reduce fever. Glucose in solution may, when given intravenously at a rapid rate, encourage water loss through glycosuria diuresis and produce typical 'thirst' fever. Loss of water, which has a high specific heat, may depress the process of evaporation. Hypertonic glucose in a single large Injection did not result in pyrexia except where the water reserve was previously depleted , 82. COWIE, D. M, and CALHOUN, H, Nonspecific therapy in arthritis and infections. A study of the changes in the blood consequent to the intravenous injection of typhoid protein. A consideration of the analogy between the typhoid paroxysm and the malarial paroxysm. 28 -19 19- Arch. Int. Med, 23:69-131, 1919 Ten case reports of patients suffering from arthritic disease or infections are presented. Intravenous typhoid vaccine was injected after prior determinations of both total and differ- ential leukocyte counts. The usual picture of leukopenia followed injections. Leukocytosis appeared during the pyrexial response. Atypical lymphocytes, nucleated red cells and myelo- cytes were found in increasing numbers as the white count in- creased. There was no eosinophilia . Patients who had definite myelocytic response exhibited the best clinical improvement. During fever, swelling and heat increased in Joints, Malarial therapy brings responses similar to those observed after the administration of typhoid vaccine; the common etiolo- gical factor in the reaction is believed to be a protein. The reaction is not an anaphylactic one since eosinophilia is ab- sent. In the leukopenic phase the neutrophils leave the blood stream and enter the tissues; the leukocytic phase is character- ized by overproduction of cells by 'their respective mesenchymal fundaments, ' 83. GOW, A, E. A note on certain phenomena associated with the protein shock reaction and intravenous vaccine therapy Quart, J, Med, 13:82, 1919 After a brief review of the literature describing the use of bacterial proteins, the writer presents 8 case histories illus- trating the application of this type of therapy to varied disease entities, Coliforra bacteria, streptococci, and organisms asso- ciated with respiratory disease were used in the preparation of vaccines. Symptomatic and clinical remissions were obtained in 5 patients. Only with the colon type vaccine was marked leuko- cytosis noted. 84. MtJLLER, E. P. Die Bedeutung des Kasiens in der Milchtherapie (Significance of casein in milk therapy) Munch med. Wchnschr. 66:1233, 1919 The protein in milk does not produce fever after intravenous injection. Milk, from which casein had been removed, still produced fever when injected. An endotoxin of bacterial origin is responsible for such pyrogenic activity. 29 - 1 9 1 9 - 85 o MURPHY, J„ B. and STURM, E, Studies on Lymphoid Activity, III. J, Exper. Med, 292lj 1919 Animals subjected to dry heat, ranging between 45 and 65° C, for 5 to 15 minutes have sharply decreased total leukocyte counts; thereafter a sharp rise In multlnuclear cells takes place. The lymphocytes rise sharply and the Increase may reach 300 per cent. The lymphoid tissue stimulation persists 2 to 3 weeks, 86, MURPHY, J, B, and STURM, E, The lymphocytes In natural and Induced resistance to transplanted cancer J. Exper, Medo 29^25, I919 Stimulation of lymphoid elements through exposure to dry heat Increases Immunity to transplantable tumors. Immunity was Judged by the percentage of inoculation failures in groups of mice, 87, MURPHY, J, B. and STURM, E, Effect of stimulation of the lymphocytes on the rate of growth of spontaneous tumors in mice J, Exper, Med. 29; 31 5 1919 Grafts were removed from spontaneously appearing tumors in mice and the animals were then exposed to high, dry heat. After temperatures were elevated, tumor tissue grafts were trans- planted. In 36 of 61 test animals tumor growth ceased 1 all tumors were retarded in the remaining members of the group. Successful Inoculation and consistent growth of tumor tissue was seen in 28 of 29 control animals, 88, RHYMER, P. Ueber Milchlnjektiontheraple (On milk Injection therapy) Bor Bl, f , Schwelz, Aerzt. 49^1337, I919 Pyrogens, and not the proteins of milk, are responsible for the fever seen after milk injections. Fresh, sterile milk does not produce temperature elevations. 30 - 1 9 1 9 - 89 » WALKER^ I. C. The treatment of bronchial asthma with vaccines Archo Int. Med„ 23? 220-234, 1919 A group of 178 patients received bacterial vaccines In the treatment of bronchial asthma. Of these, 28 were found to be sensitive to bacterial proteins and were treated with vaccines prepared from organisms to which they were sensitized « The remainder were treated with vaccines from organisms found in sputum or nasal secretions. Sensitized patients treated with vaccines received much benefit from this type of therapy (75 per cent relieved, 21 per cent improved). Vaccines prepared from organisms grown on plain agar were somewhat less effective (46 per cent of the patients so treated were relieved; I6 per cent only Improved), When dextrose bouillon was used for culture of streptococci, 37.5 per cent of the patients treated with a vaccine prepared from the cultures were freed from symptoms, and 25 per cent showed some improvement. Combinations of the two types of vaccines were least effective. - 1 9 2 - 90, BARBOUR, H. G. and HOWARD, H, G, Coll fever and blood volume (in dogs) Proco Soco Exp, Biol, Med, 17s 148-150, 1920 The antipyretic effect of Intravenous dextrose is not noted in the healthy dog, but in febrile conditions produced by Injections of E. coll organisms. It exerts a distinct fever-reducing effect. The mode of action of dextrose is not clear; It may give osmotic support through increasing the fluidity of the blood at a rapid rate. Such an alteration would aid in the elimination of heat. When subcutaneous injections of killed colon becillus prepara- tions were given, sterile abscesses developed in the dog. The blood solids Increased at a rate parallel to Increases in body temperature; the hemoglobin was concentrated. Loss of blood fluidity In fever reduces blood volume and lowers the rate of heat elimination. 31 - 1 9 2 - 91. BARBOUR, H. G. and HOWARD, H. G, Dextrose plethora and its antipyretic effect In coll fever Proc. Soc, Exp. Biol, Med. 17:150-15^, 1920 In infections produced by E, coll organisms, a higher percentage of water is held in the tissues. The action of sugars is a hygroscopic one. Withdrawal of water from the tissue spaces Increases blood v.olume. 92. JOAMOVICS, G. Zur Wirkung fermentativ gewonner Spaltungsprodukte aus Geweben und Bakterien (Action of split products obtained by digestion of tissues and bacteria) Wiener klin. Wchnschr, 33:649, 1920 Human tumor tissue was digested and sterilized, and its products injected into patients bearing malignant neoplasms. There was proliferation of connective tissue and the area became flbrotic; smaller tumors decreased in size. Split products obtained by the digestion of bacterial cells possessed similar properties. Such products are heat stable (15 minutes at 100° C.) and do not pass through the Reichel filter. 93. SCHERBER, G. Zur der Bakterienspaltungsproduket (On bacterial split products) Wiener klin, Wchnschr. 33:654-55, 1920 Superficial epithelioma appeared to be improved by injections of Joannovic's tumor tissue and bacterial split products. The product was administered both intravenously and subcutaneously. For other types of neoplasms, surgical intervention is advised. - 1 9 2 1 - 94. COWIE, D. M, Non-specific protein therapy in arthritis J. A.M. A. 76:310-311, 1921 32 - 1 9 2 1 - sterile albuminose, horse serum and bacterial proteins were used In the treatment of arthritis. The bacterial products were the most satisfactory and typhoid vaccine Is the usual choice. No Increase In antibody production followed such therapy. The question as to whether or not arthritis Is an Infectious process remains unanswered . 95". CULVER, H. Protein therapy In dermatology J. A.M. A. 76:311-13^ 1921 Mixed i'esults followed the use of foreign protein therapy in dermatologlc conditions. Typhoid vaccine was used in one case of psoriasis. In certain chronic conditions, such therapy may be beneficial. 96. DUBOIS, E. P. The basal metabolism In fever J.A.M.A. 77:352-355, 1921 In fever the standard normal metabolism is much increased. With a reading of 40° C, the acceleration was plus 32 per cent in tuberculosis and plus 48 per cent In typhoid. In malaria and 'foreign protein infection' the increases in metabolic processes may reach plus 60 per cent. A straight line function could be demonstrated in accordance with van't Hoff's law. Reduced heat loss played no part in causing body heat elevation; this was caused solely by increased heat production through metabolic breakdown. When normal metabolism has been calculated by the surface area method, 13 per cent must be added for each degree of temperature above the normal (7.2 per cent per Fahrenheit degree) . To this 10 per cent additional must be added In extreme cases of fever or when the food Intake is larger than normal; for the restless patient the same increment should be added to calculations. 97. GOVAERTS, P. Action du serum antiplaquettelque sur la elimination des microbes Introduits dans la circulation. II. Effets de la injection de plaquettes (Action of antiplatelet serum on the elimination of bacteria introduced into the circulation. II. Effects of plate- let injection 33 - 1 9 2 1 - Compt. rend. Soc. de biol, 85:667-668; 745-7^^7, 192I Intraperitoneal injection of 1 or 2 cc. of washed antiplatelet serum was followed by an injection of either B. coli or E. typhosa organisms. Within 30 minutes the temperature had risen; there were fewer organisms present yet mortality was even higher than that of the control groups. Washed guinea pig platelets markedly reduced the number of organisms (E. typhosa ) in cir- culation, and activity exceeded that seen after erythrocytes were injected. 98. GRAY, P. P. Use of vaccines in prevention and treatment of influenza and its sequelae J. A.M. A. 76:2H, 1921 A single vaccine prepared from organisms believed to be causa- tive or conjunctive in influenza, or typhoid protein preparations may be used with good effect. Many excellent reports have been made of good results from the use of a mixed vaccine containing those organisms most frequently found in fatal cases (Pneurnococci, Streptococci , Staphylococci and B , influenzae ) . 99. HIRSCH, E. P. Changes in the leukocytes and the alkali reserves of the blood in experimental infections J. Infect. Dis. 28:275-278, I92I Intravenous Injection of bacteria caused leukopenia and alkali reserve depletion for about 2 hours afterwards. The normal alkali reserves parallelled the return of leukocytosis. 100. MILLER, J. L. Foreign protein therapy in acute infections J. A.M. A. 76:308, 1921 Foreign protein modified the course and mortality rate of typhoid fever. Approximately 40 per cent of patients recover after 2 or 3 injections; the disease terminates by crisis or by lysis. For at least 20 per cent of the patients, such injections shorten the period of illness. "In sepsis and septic endocarditis the blood became sterile within 24 hours after the febrile reaction. 3^ - 1 9 2 1 - but was not rendered free from bacterial multiplication. In acute alcoholics, foreign protein therapy may be dangerous. IGl. PETERSEN, W. P. Non-specific reaction J.A.M..A. 75:312, 1921 Nonspecific protein therapy develops resistance to toxic or proteln-spllt products, thereby Increasing tolerance. The enzyme systems mobilize and leukocytes are Increased. Anti- body production may be Increased. Treatment should begin early In the course of Infection. At this time, cellular permeability is increased, and a local inflammation reaction appears. Later cellular resistance to intoxication is active, but cellular permeability decreases. 102. PETERSEN, W. F. Protein therapy and nonspecific resistance New York, 1922, p. 90 The author quotes Luke on the favorable effects which pyrogen injections afford in infectious processes. Stimulation of thermal centers in the brain produces a mobilization of antibody defenses which are progressively reduced in progressive infections 1C3. PRINZ, A. Oral Reizetherapie (Oral Stimulative therapy) Munch c med. Wchnschr. 68:1215-1217, 1921 The Initial leukopenia and succeeding leukocytosis after paren- teral injection of "foreign" proteins may be noted likewise when methylene blue (or yatren) is administered orally. 35 - 1 9 2 2 - 104. BARR, D, P,, CECIL, R. L. and DUBOIS, E, F. Clinical calorimetry, XXXIII. Temperature regulation after the Intravenous injection of proteose and typhoid vaccine Arch. Int. Med. 29:6o8-6lO, 1922 Heat production In human beings Increased from 75 to 200 per cent during the chill produced by proteose or typhoid vaccine. Heat elimination did not increase. Equalization with the en- vironmental heat followed, and elimination was from 20 to 40 per cent above the basal levels. After heat production ceases, elimination continues, producing lower values. That a rapid consumption of glycogen occurs during febrile phases may be ascertained from records of respiratory quotients made during the chill phase. Fever is not caused by failure in the elimination of water. The velocity of chemical reactions follows van't Hoff 's law (30 to 6o per cent Increase for each 3 C, rise be- tween 37 and 40° C . ) . 1C5. PENPOLD, W. J. and ROBERTSON, D. G. Haemolytic and water fevers Med. J. Australia 1:129, 1922 The role of bacteria and bacterial products in the production of 'water' fever is discussed. -19 2 3 FTJRTH, 0. and LANDSTEINER, K, On precipitable substances derived from Bacillus typhosus and Bacillus paratyphosus B, J. Exper. Med. 47:171-176, 1923 Extraction of a culture of E, typhosa through the use of boiling 75 per cent EtOH yielded an antigenic precipitate, insoluble in water, but soluble in weak alkali. It contained traces of phos- phorus and 15.7 per cent nitrogen (ash-free preparation). After hydrolysis for five hours, there is little reduction of Pehllng's solution. Tryptic digestion alters antigenic activity. A second fraction was obtained by extracting cells with saline and preci- pitating with 95^ alcohol. The fraction had a high nitrogen content. Again tryptic digestion destroyed antigenicity. 36 - 1 9 2 3 - Prom an alkaline extract of the cells held at room temperature, i an alcoholic precipitate was secured and redlssolved In alcohol. On ac^'dlflcatlon a final precipitate was obtained which contained little or no protein, a considerable amount of phosphorus, and 39.^ per cent reducing sugar (after 5 hours hydrolysis). This "C" fraction could also be isolated from paratyphosa B organisms; it contained 63.8 per cent reducing sugar. Elemental analysis showed 43.8 per cent carbon and only I.85 per cent nitrogen, 107. SEIBERT, P. B, and MENDEL, L, B. Protein fevers with special reference to casein Amo Jo Physiol,, 6?; 105-110, 1923 A study of the fever-producing powers of pure native proteins was undertaken in an effort to determine whether or not bacterial contamination of such solutions produced febrile effects in the rabbit. Each protein was dissolved in freshly distilled water before Injection; controls were given the solvent only. All of the 21 protein solutions gave positive reactions, except where the protein was soluble only In alcohol. Casein, on purifi- cation, was found to be nonpyrogenic, but could be rendered pyro- genic when it was kept under non-sterile conditions. Nearly sterile milk was pyrogenic in quantities greater than 1 cc , Sterile egg albumin did not produce fever; the egg proteins, edestln and hemoglobin were likewise nonpyrogenic when prepared under sterile conditions. "Protein per se may,„cnot be the cause of fever In the so-called 'protein' fevers." 108. SEIBERT, P, B. Pever-producing substance found in some distilled waters Am, J, Physiol, 67:90-104, 1923 The author eliminated, in turn, all possible sources of fever production by parenteral infusion solutions. All experiments were repeated twice and in the same manner. Eliminated as pos- sible causes of fever were: rate of injection; hypersensltlve- ness or immunity (of the rabbit); hemolysis (in blood); pH of solutions; specific effect of ions; impurities from glass, cork or laboratory gases. Non-pyrogenlc water could be produced by distillation through an all-Pyrex apparatus. The pyrogen was present in many distilled waters kept more than 4 to 5 days under unsterlle conditions, and could be destroyed only by long and drastic heating, Sm.all rod -like gram-negative organisms were Isolated from several pyrogenic waters, "The pyrogen is a filterable product produced by a specific bacterium..," 37 -19 2 5- HEIDELBERGER, M,, GOEBEL, W. F, and AVERY, 0. T, The soluble specific substance of a strain of Friedlander ' s Bacillus Jo Exper, Med, ^2:701-707, 1925 Isolation and chemical analysis of a nitrogen-free specific polysaccharide from the E strain of Friedlander ' s bacillus are described, > LING;, Co Yo The mechanism of reaction of nonspecific protein agents in the treatment of disease. I.. The influence of various agents on temperature and leukocyte counts in normal persons and In rabbits, II. The influence of various agents on the mobilization of blood antibodies. III, The influence of various agents on the mobilization of blood enzymes in normal persons and in rabbits. Arch. Int. Med. 35:598-608; 790-795, 1925 Therapy through induced fever is complicated by the fact that leukocytes do not play the principal role in body defenses, in spite of their phagocytic activity. These cells release endo- lysins, which, like bacteriolysins, are bactericidal, and elaborate protease and peptidase likewise. The rise in the leuk- ocyte count is caused by an accelerated production 6f myeloid elements; it varies with the agent employed and the degree of infection present. Seven foreign proteins and distilled water alone were administered to rabbits and to human beings. Typhoid vaccine (0,2 cc , per kg, of body weight), containing 100 million organisms per cc, anu market milk were responsible for the production of more intense pyrexia than other proteins used. Bacterial products increased titer against E, typhosa and Staphylococcus aureus in unsensltized indi- viduals. Complement in serum was depressed, but natural anti- sheep hemolysin was not affected. The slight trauma and bleeding seen in injection has, in itself, a slight nonspecific stimu- lating effect. The production of large amounts of proteolytic enzyme after foreign protein injection may be either an elabor- ation by tissue cells in defense or acceleration of the lymph flow from the intestinal tract, or both. Detoxification through the digestion and elimination of bacterial, toxins may occur. Pro- teolytic activity was much Increased when typhoid vaccine was injected; it decreased steadily after the initial dose. Peptone decreases proteolysis initially, but a rise takes place soon after. Lipolytic activity in serum was temporarily increased. 38 - 1 9 2 5 - 111. MENTEN, M. L, and MANNING, H, M, Relationship of enteritldis - paratyphoid B infections to hyper- glycemia in rabbits J. Infect. DiSo 37:400-410, 1925 Rabbits were subjected to adverse environmental conditions for one year. During this period all blood sugar changes were recorded. Bacterial cultures were made of heart blood and organs of all animals dying or killed within stated periods. Agglu- tination tests with antisera obtained by rabbit inoculation with these isolated bacteria followed; all organs were examined. In addition the effects produced by both killed and living bacteria were observed in the rabbit and dog^ A general seasonal variation in temperature was noted; the blood sugar levels were found to be in reverse relationship to temper- ature. Hyperglycemia was seen in cold weather. Most marked hyperglycemic values were found after spontaneous infection with enteritidis-paratyphold B groups. Hydropic degeneration of the islets of Langerhans was noted only in prolonged hyperglycemic conditions. Blood changes and histologic alterations were simi- lar regardless of whether or not the injected organisms were viable. The dog exhibits a natural resistance to the organisms used in the study. 112. MULLER, E. P. The involuntary nervous system: An important factor in the body's resistance Arch, Int. Med. 35:796, 1925 The theory is presented that the route or site of injection and not the substance injected produces the phenomena seen in paren- teral therapy. Dilution in peripheral vessels alters the leukocyte concentration. An overbalance of parasympathetic tonus follows with stimulation of myeloid tissue. This may be the result of kinetic response of the involuntary nervous system. Intradermal water, milk or salt solution (or air) caused rapid leukopenia and a high concentration of leukocytes in the liver. Peptone injection produced a migration of leukocytes away from the periphery toward organ storage centers. 113. PRIBRAM, B. 0. Proteintheraple und chirurgische Therapie des Magen-und-duodenal- geschwurs (Protein therapy and surgical treatment of stomach and duodenal ulcers) 39 - 1 9 2 5 - Deutsch. med. Wchnschr. 51:l4l, 1925 Pain in peptic and duodenal ulcer was reduced, and some healing of the lesions was demonstrated roentgenically when surgical procedures and nonspecific protein therapy were used in con- junction. 11^. SEIBERT, F, B. The cause of many febrile reactions following intravenous in- jections Am. Jo Physiol, 71:621-651, 1925 Pyrogens in distilled waters were injected in the rabbit. After sensitizing doses, typical anaphylactoid reactions followed the provocative injection. Febrile reactions were most intense after intravenous injection but could be obtained by use of the subcutaneous and intraperitoneal routes. Non-chromogenic bac- teria appear to produce the pyrexial substance, which is des- troyed by heat, only after treatment with strong acid or alkalis, Some nitrogen is found, but the content appears to have little correlation with pyrogenic activity. 115. ZIMMER, A. and BUSCHMANN, P. Vermeidung und Verhandlung von Schaden die durch Protein-Korper- therapie hervorgerufen werden (Avoidance and palliation of illness through so-called protein therapy) Zeitschr, f, artzl, Portbild , 22:513, 1925 For chronic conditions the best results with protein nonspecific therapy are those secured without the appearance of fever. In acute illness or infections a febrile reajction appears to be more satisfactory, 11:6. ZECKWER, I. T. and GOODELL, H. Blood sugar studies, I, Rapid alterations in the blood sugar level of rabbits as the result of intravenous injections of killed bacteria of various types J. Exper. Med. ^2:43-56, 1925 Heat-killed, l8-hour cultures of B. proteus , B. coli , and paratyphosus A and B, produced changes in blood sugar levels after Intravenous injection into the rabbit. The saline sus- pension contained 2 billion organisms , Marked hyperglycemia was 40 19 2 5 paratyphosa noted after Injections of B. proteu s, j^. '.^oli ard par B. Slight and irregular increases were ceen after B. A and B. enteritidis solutions vjere injected. Leukopenia ac- companied hyperglycemia and persisted after the blood sugar had returned to normal levels. No relationship could be traced between temperature fluctuation, blood sugar increases and the leukocyte count. B. faecalis alkaligenes , Str . hemolyticus or viridans . Staphylococcus aureus , B. pyocyaneus and B. typhosa , in similar preparations, had little effect on blood sugar levels. -1926- 117. BARBOUR, H. G, Heat regulation and water exchange. XI. Blood and plasma changes in cocaine and B. coli fevers and aspirin antipyresis . J. Pharm. & Exper. Therap, 29:^27-440, I926 When fever of a mild grade is produced in dogs through injection of B. coli , blood plasma is slightly reduced. Blood solids rise. Fluid loss may be the result of increased capillary permeability with escape of plasma into tissues from the general circula- tion. Increased venosity may be seen. The alkaline content of the blood falls. When a synthetic antipyretic is administered, the fall of temperature is closely related to the return of fluid into the blood stream. 118, BOSHAME, R. K, Thrombopenia of infective diseases and of protein injections Folia Haemat. 33:105-121, I926 Thrombocytes play an important role in immunity. Their normal activities include agglutination of bacteria and removal from the blood stream. When thrombocytes are destroyed, the bacteri- cidal factor is liberated into the serum. Thrombopenia is the result of an exhaustion of activity and may be seen after the injection of parenteral protein, living or killed bacteria, toxins and in hemorrhage. Splenectomy prevents exhaustion. 119. CANNEYT, J, VAN Action du Bacillus subtilis et de ses secretions sur le bacille de la tuberculose (Action of B. subtilis and its secretion on the tubercle bacillus) 41 - 1 9 2 6 - Compt. rend. Soc. blol. 95:878-881, I926 Inocula of preparations of B. subtllls overran the growth of the tubercle bacillus on potato cultures and exhibited a pre- ferential selection between the mycobacterium and other con- taminants. Cultures of B. mesentericus vulgaris had similar activity. The activity appears to be antibiotic in nature and not merely one of competition for growth elements, 120. CONSOULOPP, S. Theoretical experiment in curing by increased temperature and relation to the cancer problem (Translated Title) Ann. Univ, of Sofia Sci, 22:1-2^^, I926 The spirochaeta of syphilis are sensitive to high temperatures] other parasitic organisms may be similarly affected. Human cellular tissue is passively stimulated by fever. These two facts explain many of the benefits derived from bacteriotherapy. Applications of these findings to cancer therapy are discussed. 121. DREYFUS, G. L, and HANAU, R. Grundsaetzliches uber die verwendung des neuen Piebermittels Saprovitan in Neurologie (Fundamentals of the application of the new fever producer, Saprovitan, in neurology) Deutsch. raed. Wchnschr. 52:1381-1383, 1926 122. PAHRAEUS, R. Physikalische Gewebsveranderungen bei Pieber und Hyperpyretischen (Physical tissue alterations through fever and hyperpyretics) Acta med . Scand . (Supplement) l6:6o8-6lO, I926 A preliminary report on the alterations seen in tissues during fever in infections and that induced by hyperpyrexial agents. 123. PAHRAEUS, R. Uber Anderung des Aggretszustandes lipoider Substantzen bei Pieber u. d. hyperpyretischen Temperaturen (Changes in the aggregate condition of lipoid substances in fever and hyper- pyretic temperatures) Skand. Arch. Physiol. 49:125, 1926 (Abstract) 42 -19 2 6- 12i^. KRAUSS, E. Untersuchungen liber den mlnlmalen elxvelss Gebrauch des Menschen unter gesunden und krankhelten Bedingungen (Minimal protein requirements of man in healtn and disease) Deutscho Arch. klin„ Med » 150:13-59, I926 Nitrogen excretion is increased after the injection of bacterial and other 'foreign' proteins only when fever is produced in the sensitized animal. In some types of tissue destruction urinary N remains near the minimal point because of the reuse of protein in metabolism. Minimal total N is placed at 1.0 to 1.1 Gm. per square meter of body surface. 125. OKURA, Y, Influence of toxic substances on nitrogenous and purine meta- bolism in dogs: Influence of pyrogenous substances (Translat( Title) Jap. J. Med, Sci, (Tr. IV, Pharmacology_ 1:65-71, 1926 The acceleration of catabollc processes and the influence of the tissue destruction on toxicity must be considered when the effects of fever are evaluated. 126, REICHE Toxlsches oder dynaraisches Elweiss Pieber (Toxic or dynamic protein fever) Ztschr, f. Kinderheit, 410:96, 1926 Addition of a protein concentrate to a milk formula increased body temperatures of healthy infants. Breast milk (or formula alone j were not pyretic agents. Split products of protein digestion may be absorbable in the digestive tract or Intestine. 127. SOLOMON, H. C, BERK, A., THEILER, M. and CLAY, C, L. Use of soduku in the treatment of general paralysis. A pre- liminary report Arch, Int. Med. 38:391-404, I926 The excessively high fever and distinct lymphaglnltis which follows the experimental use of 'rat -bite fever' therapy appears to in- fluence the centtal nervous system and produce favorable changes in progressive paralysis. 43 -19 2 6- 128. TOMCSIK, J. On carbohydrate-like specific substance in the colon-Aerogenes group Proc, Soc. Expero Biol, & Med, 2^:810, 1926 A method is given for separation and purification of the specific polysaccharides of B. lactis aerogenes, encapsulated B. coli strains and five other Aerogenes organisms. Dissolu- tion of the capsule occurs through treatment with KOH; alco- holic precipitation follows. On repurlfication, the nitrogen content could not be reduced below 0.9 per cent. The poly- saccharide was not antigenic for the rabbit, was specific for its own parent strain and gave no cross reactions with immune sera, 129. VON TUKACS, J. Protein Korpertherapie und Vegetatives Nervensystem (Non- specific protein therapy and the autonomic nervous system) Wiener med , Wchnschr, 39:885-888, I926 Nonspecific protein therapy develops a stimulatory effect in the sympathetic system, with the initial reaction one typical of sudden sympathetic response. Within a few hours, the opposing parasympathetic system is likewise stimulated; this effect is more prolonged and therapeutically important. - 1 9 2 7 - 130. ANDREWS, E,, PETERSEN, W, F, and BOIKAN, W. Observations of eviscerated dogs (Effects of bacterial proteins) Proc. Soc, Exp, Biol. Med, 25:109-110, 192? The response of febrile agents may be conditioned by the effects of stimulation in splanchnic organs. When the proteins of B. coll organisms are administered to the eviscerated dog', neither chills nor fever follows. hh -1927- 131. BRANHAM, S. L. and HUMPHREYS, E. M. Soluble antigens of B. enterltidls J. Infect. Dls. 40:5l6-524, I927 Bacteria -free filtrates from B. enterltidls were concentrated in vacuo and the properties of the opalescent supernatant fluid and grey precipitate observed. The precipitate was chiefly polysaccharide. Dialysates from the supernatant fluid con- tained less than 1/4,000,000 Gm. of protein, but were superior to living bacterial emulsions as antigens. 132. EVANS, C. LOVATT and ZECKU^ER, I. T. On the nature of the hyperglycaemic response to injections of certain killed bacteria Brit, J, Exp. Path, 8:280-288, 1927 A hyperglycemic response follows the injection of B, coll and B, proteus killed cells in rabbits. Splanchnic nerve stlmula- tion appeares to initiate glycogeno lysis; removal of the thyroid decreases it, but thyroid preparations given orally increase the response. When the adrenals are inactive, hypoglycemia may reach lethal levels. Sectioning of the vagus nerve does not prevent reduction in blood sugar, 133. GOEBEL, W. F. and AVERY, 0. T. The soluble specific substance of Friedlander ' s bacillus . III. On the isolation and properties of the specific carbohydrates from types A_ and C Friedlander bacillus J. Exper. Med, 46:601-607, 1927 Two specifically-reacting N-free polysaccharides were isolated from strains of types A anc C Friedlander ' s bacillus . While chemically they possessed individual properties, the following similarities were noted: high specificity; non-reducing in pure form; reducing sugars found on hydrolysis; strongly acidic with glucuronic acid or its Isomer within the molecule. The specific function and carbohydrate structure were apparently inseparable. 134. HEIDELBERGER, M. The chemical nature of im.mune substances Physiol, Rev. 7:107-128, I927 The author presents a summary of the current information on the 45 - 1 9 2 7 - actual chemical nature of immune substances. He discusses in turn proteins and their derivatives, the lipoids and carbohy- drates, 135. HOWARD, Ho J, Nonspecific protein therapy in eye inflammations with specific reference to the use of typhoid vaccine China Med, J. 41:395-^07, 1927 Typhoid vaccine arrests inflammation in uveal infections; bene- fits are proportional to the fever produced o Milk and protein split products may be used, but typhoid vaccine is the selection of choice, 136, LILIENTHAL, H, and COLEY, Wo B, Mediastinal sarcoma treated with coley's fluid Ann. Surgo 85:615, I927 Three years after treatment with Coley's fluid, of a child for whom a diagnosis of inoperable sarcoma of the posterior medias- tinum had been made, no residual, physical or roentgen evidence of the existence of the tumor could be demonstrated. A series of six patients with inoperable sarcoma of the spine responded to mixed toxins with remarkable 'clinical remission,* Successful results may be expected in approximately 10 per cent of cases treated by this method. 137 MATSUNAMI, Y„ Experimentelle Untersuchungen uber das Verhalten der Leukocyten (Experimental investigation on relations of leukocytes) Okayama Iggakkuai Zasshi 39:622-625, I927 Protein, carbohydrates and fat have widely differing effects upon leukocytes. On intravenous injection, protein acts most intensely on the neutrophils, to a lesser degree on lymphocytes and affects eosinophils moderately. Carbohydrates stimulate neu- trophil production, decrease the lymphocytes and infrequently alter the ratio of eosinophils. Only after the injection of fat is lymphocyte activity heightened; production continues for a considerable period „ Inorganic stimulants differ in activity from those of organic ori- gin. The luekocytes are little influenced by the parenteral in- jection of metals. The salts have least activity and the alkalis the greatest. Eosinophils are increased in blood after injec- tion of metallic colloids. 46 19 2 7 138. MUELLER^ E. P. Nonspecific protein therapy: Its action and its application Wisconsin M. J, 26:287-288, 1927 In nonspecific protein therapy the V3getative nervous system alters and produces early changes tnrough the splanchnic areao Major internal organs are mobilized into rhythmic action, followed by reflex action at the periphery which decreases capillary capacity. 139 o SEIBERT^ P. Bo II '* Welche substanzen erzeugen Pieber nach intravenoser Injektlon (What substance produces fever after intra^/enous injection?) Arch. Exp, Path. Pharmakol. 121:247-249, 1927 The author opposes the theory of Donath and his school, holding that fever after intravenous injection of distilled water is caused, not by nucleic acid, but by a metabolic product of the bacterial contaminants. 140. STOKES, J. H, Modern Clinical Syphllology Philadelphia, W. B. Saunders Co. 1st Edition, 1927, pp. 177; 346 The "water error" (Wasserfehler) is commonly found on large dermatologic services where large amounts of distilled water are prepared in advance. Showers of reactions, with chills and fevers were noted Mondays on the author's clinic. The 'tubing reaction', first described by Stokes and Busman, is character- ized by the appearance, within 30 minutes after an injection, of malaise, pain in the lumbar region, nausea and diarrhea with tenesmus. The chill may be the first symptom. With repetition of the rigor, sharp rises in temperature may be seen. There is often prostration and emotional disturbance. The fever may persist beyond the usual 8 hours. Profuse outbreaks of herpes have followed the reaction. Leukocytosis (with 96 per cent polymorphonuclear cells) is present. The use of nuclein in neurosyphilis, advocated by Pischer and by Meyer, is discussed at length. Pischer observed remissions 47 - 1 9 2 7 - In 58 per cent of the patients treated. He found sodium nuclelnate to be a useful substitute. The Initial dosage used was 2,5 to 3 cc o of a 10 per cent solution j Interrupted treat- ment was the most successful. The marked leukocytosis, not fever produced., received credit for therapeutic benefits, Meyer J, in comparing nucleln with tuberculin and arsephenamlne alone, reported successes in 42 to 50 per cent of cases treated with the former. Tuberculin produced remissions in but 25 per cent of the cases treated; arsephenamlne, in 7.0 to 7.5 per cent, 141. TEISSIR, P., REILLY, J, and RIVALIER, E. Recherches experlmentales sur 1' infection chancrelleuse. I. Preparation d ' une antigene Streptobaclllaire soluble (Ses Effets sur 1' animal et I'homme) (Experimental ini/estlgatlons on chancroid infection, I, The preparation of a soluble antigen Streptobacillln . Effects in animal and man.) J. Physiol, et Path. 25:268-282, 1927 "Streptobacillln " a homologous vaccine-type extract, was prepared from Ducrey's bacillus. A mixture of nucleoproteln-globulln complexes, it is non-toxic to mice, guinea pig or healthy humans in the ordinary dosages. On intravenous injection certain reactions associated with protein 'shock' were noted. The sub- stance may be used by subcutaneous or intradermal Injection, as well. The preparation appears to have sensitizing activity; marked reactions occurred when injections were given to persons already Infected with the bacillus. There was no complement fixation or inactivating ability in serum after the use of the extract, the precipitin reaction was feeble, and no bactericidal activity could be demonstrated. 142, TEISSIR, P., REILLY, J„ and RIVALIER, E, Recherches exper^mentales sur 1' infection chancrelleuse, II. Les prlncipes genf^raux d ' une vacclnotheraple speclfique (Experi- mental investigations on chancroid infection, II. General principles of specific vaccine therapjr) J. Physiol, et Path, 25:319-338, I927 The respective values of specific vaccine therapy and nonspecific protein therapy for the treatment of chancroid were compared, A homologous vaccine "Streptobacillln" was administered to persons infected with Ducrey' s bacillus and the therapeutic results ob- tained appeared to parallel the degree of sensitization, most marked in conditions of long standing. The results would suggest a provocation of inflammatory processes, favoring leukocytosis and phagocytosis. 48 -19 2 7- 143. VON EULER, U. If Uber Hyperadrenallnamie bel Pleberzustanden (On the Increased blood adrenalin in fever conditions) Pfluger's Arch. ges. Physiol. 217:699-716, 1927 - 1 9 2 S - 144. ALLEN, A„ W. and SMITHWICK, R. H. Use of foreign protein in the treatment of peripheral vascular disease J, A.M. A. 91:ll6l, 1928 Typhoid vaccine, containing 125 to 300 million bacilli per dose, was used in the treatment of Buerger's disease, in gangrene of arteriosclerosis and simple vasomotor types of vascular occu- lusion. The result of this treatment was most promising. It is believed that tht benefits are chiefly derived from vaso- dilatation, which brings relief of vasospasm and increases capillary circulation. 145. BORCHARDT, W. Zur Physiologic des Piebers Uber die Bedeutung von Schildruse und Nebennieren fur das Pieber (Physiology of Pever. On the impor- tance of tbyroid and adrenals in fever) Arch. Exp. Path. u. Pharmakol, 137:45-70, I928 In an exhaustive study of the fever produced by bacterial, chem- ical and mechanical stimulation of the midbrain, a primary action upon the heat centers was noted. This can be delayed by denervation of the liver. The presence of thyroid and adrenals is important. The adrenals are not necessary to fever production, but after removal, susceptibility to fever is increased. However, no rigor follows when adrenals are removed. When adrenals are intact, puncture of the heat center of the brain alone leads to marked leukocytosis. ^9 19 2 8- 146, BORCHARDT, W. Neutrophile Leukocytosis und Nebennieren (Neutrophilia, leukocy- tosis and adrenals) Klin. Wchnschr. 7 :2H 0-2442, 1928 147. CENTANNI, E, Die Reversibllitat in der antibakteriellen und antitumoralen Vaceinebehandlung (Reversibility in antibacterial and anti- tumor vaccine therapy) Deutsch. med. Wchnschr. 7:519-530, I928 148. CHRISTIAN, S. L. and PALMER, L. A, An apparent recovery from multiple sarcoma, with involvement of both bone and soft parts, treated by toxins of erysipelas and Bacillus prodigiosus (Coley) Am. J. Surg, 4:188-197^ 1928 A case report is presented involving myelosarcoma of the femur, with wide-spread metastases and recurrence at the stump after mid -thigh amputation. The diagnosis was microscopically and roentgenologically confirmed. The neoplastic area regressed and finally disappeared after a series of treatments with Coley' s mixed toxins. Two years later, the patient was reported to be in good health. 149. COLEY", W. B. End results in Hodgkin's Disease and lymphosarcoma treated by the mixed toxins of erysipelas and Bacillus prodigiosus , alone or combined with radiation. Trans. Am, Surg. 46:331-357, 1928 The author discusses the theories prevailing on the etiology of Hodgkin's disease and the manner in which differentiation may be made between this condition, lymphosarcoma and other members of the lymphoma group. An impressive number of cases of Hodgkin's disease and lymphosarcoma have been treated with the combined toxins of erysipelas and B, prodigiosus alone or in conjunction with radium and X-rays, Five-year survivals in this group have been frequently attained. 50 -19 2 8- 150. HESSE, E. and TAUBMNN, G. Untersuchungen uber das Fleber nach Heulinfus (Inquiry Into fever after hay Infusion) Arch. Exp, Path, u, Pharmakol, 136:239-256, I928 Extracts of decomposed hay, injected parenterally, caused temperature increases. Analyses of these 'pyrogens' revealed that humic acid was present. Like the humic acid from turf and peat, it produced fever and leukopenia. 151. KUTNEZOWSKY, N. Uber die Einfluss lokaler thermischer Reize auf den Speicherungs- prozess in den Lymphknoten (The influence of local hyperemia upon the storage process in lymph nodes) Ztschr. ges. Exp. Med, 62:44-61, I928 In the stimulation of the reticuloendothelial system, the route of introduction of various substances may be of great im- portance. Storage of substances directly introduced into the blood stream takes place in the reticuloendothelial cells of the blood vessels; if the material is introduced into the lymph gland, storage occurs in the cells of the lymph nodes. When colloids are injected subcutaneously, storage is seen in macro- phages of the connective tissue. It is possible to influence the character of distribution of colloids through local hypere- mia; storage thereafter takes place much earlier and in larger amounts than is seen in unstimulated tissue. Heating of the. lymph nodes before injection of a dye hastened the rate of storage. 152. SHWARTZMAN, G. Studies on Bacillus typhosus toxic substance I. The phenomenon of local skin reactivity to B. typhosus culture filtrate J, Exper, Med. 48:24?, 1928. See also: Proc. Soc. Exper. Biol. Med. 25:560, 1928 Toxic filtrates were obtained from tryptic digest broth cultures of E. typhosa strains. In rabbits intracutaneous injections of a sensitizing dose, followed in 24 hours by a provocative in- jection, produced hemorrhagic -necrotic skin lesions at the site of the initial injection. From 78 to 79 per cent of normal rabbits were sensitive to this reaction, which was not dependent on the amount of filtrate used. No relationship was shown 51 - 1 9 2 8 - between the degree of erythema after preparatory Injection and the intensity of the hemorrhagic reaction produced by Intra- venous filtrate. Skin preparation with nonspecific irritants did not render tissues responsive to subsequent injections of filtrate. Neither did the Injection of the bacterial filtrate into the skin provoke the hemorrhagic -necrosis phenomenon, which is not related closely to bacterial hypersensitivity„ The filtrates themselves resisted inactlvation by heat at a range of pH between 4oO and 9oOo 153. TOMCSIK, J. and KUROTCHKIN, T„ Jo On the role of carbohydrate haptens in bacterial anaphylaxis J. Exper, Med, 47:379-338, 1928 Carbohydrate haptens obtained from B, lactis aerogenes , the pneumobaclllus and from a yeast were found capable of producing anaphylactic shock in vivo and in vitro In guinea pigs passively sensitized with immune rabbit sera. Toxic and minimal shock - producing doses were found to have a wide margin, corresponding to those noted in protein anaphylaxis. Active sensitization could not be produced with these substances. -19 2 9- 154. BREUER, S. Insullnartlge Substanzen aus Bacterium coll und Rauschbrand- bakterien (Insulin-like substance from^„ coll and Blackleg bacteria) Munch, med, Wchnschr, 76:741-742, 1929 Filtrates from two cultures of B, coll were Injected into the rabbit, A severe hypoglycemia followed, similar to but less marked than that produced by Insulin; it was relieved by the administration of sugar. The filtrates from cultures of Clos - tridia chauvoei vjere four times as active as those prepared from B, coll but were orally inactive. When concentrated through use of acid alcohol, the potent principle was thermostable. 52 -19 2 9- 155. FREMONT -SMITH, Lo, MORRISON, R. L., MAKEPEACE, A. W. Capillary flow in man in typhoid vaccine fever J. Clin. Invest. 7:^89, 1929 Changes in the capillary blood flow appear in three stages. At the onset of fever complete stasis begins, with cyanosis appearing at the height of the reaction. As fever mounts, the blood flow is increased. The typical flush is seen near the peak of febrescence; it continues throughout the succeeding fall in temperature and, occasionally, for some hours thereafter. Stasis is initiated by a rapid constriction of the terminal arterioles and is prevented by the local application of heat. It also can be abolished once it has begun by the same means. Constriction in renal blood vessels leads to water retention and a subsequent dilution of blood, producing diuresis in the later stages of fever. 156. GROLLMAN, A. Variations in the cardiac output 6f man. Vo The cardiac output of man during the malaise and pyrexia following the injection of typhoid vaccine J. Clin. Invest. 8:25-32, 1929 The cardiac output, pulse rates, blood pressure, temperature and oxygen consumption of 8 individuals were studied after the intramuscular injection of typhoid vaccine. Soon after injection the cardiac output was increased to a significant degree, but at the height of malaise and fever, the output was somewhat reduced. Pulse rate and oxygen consumption parallelled the degree of malaise and of fever. 157. HOFP, P. Ueber den Einfluss von Baktierieneiweiss auf das Blut (Influence of bacterial protein on the blood) Verho Deutsch, ges . inn. Med, ^Ist Kong. Inn. Med. 208-211, I929 The influence of bacterial protein on cellular and chemical elements, volume and rate of flow of the blood is discussed. 53 -19 2 9- 15S. URBANEK, J. Die Bedeutung der Tuberculos e fur die entzundllchen Erkrankungen des Uvealtraktus (The Importance of Tuberculose for Inflammatory ailments of the uveal tract) Berlin, S. Karger, 1929 Extracts from cultures of human tubercle bacilli and pure bact- erial proteins from organisms with specific activity were combined and used In treating 500 patients with uveal Infections seen on the services of the Meller Clinic, Vienna, After 0.1 mg, was administered as a sensitizing dose, injections were continued, with the range of dosage from 0,0001 to 0,1 mg. The toxicity associated with tuberculin was absent in this pre- paration. WAGNER, W. Untersuchung der Bakterizlden Bestandtelle des B. pyocyaneus . . (Investigation of the bactericidal constituent of B. pyocyaneus .) Zeltschr. Immunltats, forschung., 63:483-491, 1929 A highly potent bactericidal and detoxifying solution was prepared from cultures of B. pyocyaneus and pyocyanase. -19 3 0- CARTER, E. B, A proposed chemical test for pyrogen in distilled water for intravenous injections J, Lab. Clin. Med, 16:289-290, 1930 If pyrogens are not present, the color of a sample of distilled water, to which H2SO21. (10 cc) and O.O5 N KMnOi^ (O.l cc.) have been added, remains unchanged after boiling. HAMEL, J. Die Behandlung des Trippers bei Frauen mlt Pyrifer (Treatment of gonorrheal infections of women with pyrifer) 54 - 1 9 3 - Dermat, Ztschr. 60:404-4l2, I93O Specific vaccines were added to pyrlfer and administered to 15 patients with gonococcal Infections, The treatment was success- ful for 73.3 per cent of the group, Pyrlfer alone. In dosages calculated to Increase the body temperature to 40° C, brought relief to 34,8 per cent of the patients In a second group,, The values of adjuvant therapy are discussed, 162. HARRISON, P. C, TARR, H. L. A. and HIBBERT, H, Factors relating to carbohydrates and polysaccharides, XXXIIIo Synthesis of polysaccharides by bacteria and enzymes Canad, J, Res, 3:449-463, 1930 163, KRUIffiRUCH, 0, Pyrlfleberhandlung bel leulschen Nervenkrankhelfcen (Pyri(fer)- fever treatment In neurosyphllltlc conditions) Deutsche Med. Wchnschr, 56:2170-2173, 1930 A preparation produced by Rosenberg of Freiburg (Pyrlfer) has been used for therapeutic fever production in the Psychiatric and Neurologic disease Clinic of the University of Gottingen. As prepared from the killed bacteria of the colon group found in milk, pyrlfer gives rapid elevation of temperature, occa- sionally chills, and a strong leukocytic response. It is utili- zed in seven different strengths containing from 50 to 5OO million bacterial 'units' and is usually administered intravenously, although more protracted fever follows intramuscular injections. Leukocyte values rise to 20,000 or 25,000 total counts, with neutrophils of Immature type accounting for tnost of the increase; lymphocytes are decreased in number. Eight of 13 tabetic patients treated with pyrlfer improved. Paralysis with tabes is less favorably influenced than pure para- lysis with neurasthenic complications. Optic atrophy may be hastened by fever therapy. There is speculation as to whether or not heightened blood circulation may be credited for the benefits received from this type of therapy. 55 - 1 9 3 - 164. RADEMKER, L. The cause and elimination of reactions after Intravenous infusions Ann, Surg, 92:195-201, 1930 Two specimens of distilled water, one known to contain pyrogens, were carefully studied* In the pyrogenic solution, total and organic solids, ammonia and an ammonia fraction were increased. The residue produced fever in animals. The bacterial count was high in both pyrogenic and non-pyrogenic waters but the pyro- genic specimens contained only one-third as many organisms as the nonpyrogenlc , The use of water traps in the distilla- tion step and immediate sterilization and sealing of solutions were advocated as measures against contamination of products destined for intravenous injection. 165. SPINELLI, A. Una substanza ipertermlca nella levodura (A substance producing hyperthermia coi tained in yeast) Blochem, terap, sper. 17:397-401, I930 Autolyzed yeast produces a pyrexial substance after standing at room temperature for I5 to 25 hours. On injection, this material, in amounts of 0.7 to 0.8 cc, increased body temper- ature in the rabbit to 41,8° within 5 or 6 hours. 1660 STETNER, E. Uber die Wirkung von Bakterieneiwelss ein Spritzungen bei Kindern, mit besonderer Beruchslchtlgung des Gelemrheumatlsmus (Zur Frage der Herpes sentstehung) (The action of bacterial protein, etc, on the arthritis of childhood, with special attention to the question of the appearance of herpes) Ztschr, f, Kinderh, 48:623-639, 1930 167. WESTPHAL, K, and WEGSCHEIDER, K, Zur Pyriferbehandlung der Tabes und Tabo paralyse (Pyrifer treat- ment of tabes and tabetic paralysis) Deutsch, Med, Wchnschr. 56:1731-1733, 1930 56 - 1 9 3 - Excellent results were obtained by the use of pyrlfer in classic tabes, with lightning pains, gastric crises and "girdle pain". It was less effective when ataxic complications were present (5 of 13 patients improved). The improvement of psychic symptoms in tabes is most spectacular. In one instance, improvement was seen in sexual impotency. The authors review the literature on the use of pyrifer. They find 8? per cent of tabetic patients exhibited improvement, while in paralysis, 45 per cent in a large group (104 persons) were benefited. -19 3 1- 168, ARNETH, Jo and ALBACHT Uber das qualitative und quantitative (reaktive) Verhalten der Leukocyten bei der Piebertherapie mit Neosaprovitan B (Quali- tative and quantitative proportions of leukocytes in Neosaprovi- tan B fever therapy) Ztschr, f, ges. Exper. Med „ 77:641-688, I931 Neosaprovitan B, a vaccine prepared from saprophytic organisms, exerts a profound effect upon blood-forming organs through the mediation of the vegetative nervous system. Leukocytosis appears early, while lymphocytes increase within 24 hours after in- jection. Suggestions are made for its application to tabes dor- salis and multiple sclerosis therapy. 169. DAVESME, .J._,and HABER, P. L' influence de 1' hyperthermic, de I'acide et de I'alcalose sur la production des agglutinins (Influence of alkalosis and acidosis and the thermal reactions (produced by a vaccine) on the produc- tion of agglutinins) Compt. rendo Soc, blol, 100:1053-1054, I93I A preparation which contained the endotoxins of histolytlc bacillj, produced fever in rabbits upon intravenous injection. When acld- , osis or alkalosis appeared during pyrogenlc fever, the production of agglutinins was unchanged* 57 -19 3 1- DELAPIELD, M. E, A comparison of the changes In the blood sugar and blood phos- phorus In rabbits following the Injection of suspensions of Bact . aertrycke J. Patho Bacto 3^:177-19^, 1931 Hyperglycemia appeared in rabbits after injections intravenously of suspensions of Bo aertrycke or filtrates from such suspen- sions » Hypoglycemia and death followed. Elevated blood sugar levels and inorganic phosphorus bore inverse relationships to each other; increases above initial values of P were seen during the hypoglycemic phase^ Organic acid-soluble blood phosphorus rose and fell with the carbohydrate content. Diphtheria toxins did not alter blood sugar and phosphorus in the same way; the latter reached a high level two days after the injection of toxin. Bo aertrycke cells were active after autoclaving, although their enzymic activity was reduced. Alcohol and ace- tone extraction did not alter their capacity for changing blood sugar and phosphorus ratios, L71. DIETEL^ Pc Pieberbehandlung rait Pyrifer (Pever therapy with pyrifer) Medc klin, 27:622-624^ 1931 A bacterial preparation (pyrifer) had been used in over 600 cases of gonorrhea and in psoriasis. The dosage was not easily deter- mined, since the febrile reaction was not a prerequisite for therapeutic response. Good results were also obtained by its use in progressive paralysis, tabes and vulvovaginitis, r2, EVANS, A, C, The effect of bacterial by-products on leukocytes J, Bact, 21:42-43^ 1931 Certainty-products of bacterial culture growth were com^pared with known toxins (tetanus and diphtheria). The phagocytic acti- vity of leukocytes was not impaired by washings from cultures of S 'reptococci scarlatinae . Organic acids and free H ions im- paired leukocytic functions , 73 » PINKELSTEIN, H, and WEIL, E, Zur Kenntnis des alimentarien Piebers, IV, Das Kochsalzfieber (Information on alimentary fevers, IV, Saline fever) Ztschr, Kinderh, 50; 259-287, 1931 5S - 1 9 3 1 - Saline 'fever' may appear after a single dose of hypertonic so- lution given orally or after repeated oral administration of hypotonic or isotonic solutions. Amounts as small as 50 cc. per kilogram of body weight may bring temperature increases. Ringer's solution has similar hyperthermic effects. The pattern of reac- tion is one of defense against disturbance of normal tissue con- centrations of salts; the reaction diminishes the pressure grad- ient with the production of fever. This last-named phenomenon may be the culmination of tissue activity directed toward dehy- dration. 17^ c FINKELSTEIN^ H, Zur Kenntnis des alimentarien Piebers, VI o Hyperthermie Oder Fieber? (information on alimentary fevers, VI, Hyperthermia or fever?) Ztschr, Kinderh. 50:637-650, 1931 When body cells are forced to 3;leld intracellular water, fever appears. Protein and sodium chloride retain water and are addi- tional factors in its diversion from its physical destination. Desiccation of the liver during periods of high body temperature produces profound alterations in body chemistry^ and colloid chem- ical changes are seen in the body cells, "The, , .theory df pyro- genous substances or protein split products as basic causes of temperature elevations, , ohas inadequate background. Presence of neither, , ecssential for fever production, " . o « o 175. PINKELSTEIN, H. and WEIL, E. Zur Kenntnis des alimentarien Piebers V, Zur Pharmakologie des Eiweiss-und Kochsalzfiebers (Information on alimentary fevers, V Pharmacology of protein and saline fevers) Ztschr, Kinderh, 50:268-291, I931 No distinction between hyperthermia and 'true' fever was found. 176, GOLD IE, H, Les substances antlhemolyses (antihemo lytic substances) Compt, rend, Soc. blol, 109:7-9, 1932 Thermostable and filtrable disaggregations of the products of cul- ture filtrates of Streptococci , Staphylococci , E, typhosa and E„ Goli exert a marked antihemolytic influence on ^he blood. While the substances appear to be related to antibiotic and immunologic factors in the bacteria, they are not present in very young or •very old cultures. Purified products are crystalline NHg compounds. 59 - 1 9 3 1 - 177. HEIDELBERGER, M. and KENDALL, P, E, Specific and nonspecific polysaccharides of type IV pneumococcus J. Exper. Medo 53:625-639, 1931 Three N-containing polysaccharides were isolated from autolyzed cultures of Type IV, pneumococci. One was a type-specific carbohydrate, which was separated with difficulty an^t -r^e- quired more alcohol for precipitation than the Specific polysaccharides of Types I, II and III. A serologically in- active substance allied in structure to chitin was found. The "C" substance of Tillett, Goebel and Avery was present. The inactive fraction had the lowest optical rotation value and the highest carbon content. It was least soluble in alco- hol or acetic acid and contained a small amount of nitrogen. On hydrolysis it yielded crystals which exhibited the optical rotation characteristics of glucosamine. The reducing sugars accounted for 55 per cent of all chemical constituents; total N was 5.9 per cent. Like chitin and chitosan, the in- active polysaccharide was partially hydrolyzed by snail juice. 178, KROMAYER, E, Uber Fieber Behandlung mit Pyrifer (Pever treatment with pyrifer) Dermat, Wchnschr, 93:15^7-1550, 1931 A preparation from the sterilized protein of killed bacteria from milk (pyrifer) produced fever of 39-'^0° C , in 1 to 2 hours after Injection, and chills in 6 to 10 hours. Its use in buboes, gonorrhea, balanitis, psoriasis and staphylococcic infections 60 - 1 9 3 1 - Increased leukocytes in the blood and produced other changes indicative of an action upon heat-regulating nervous centers. Some benefits were noted in all ailments treated, with the exception of psoriasis. The preparation is Ineffective when given intramuscularly. Headache and herpes labialis were listed among the side effects. 179. LEUDEL, E. and DUTT, J. N. The influence of elevated temperature on the reaction curve of endocrine glands (Translated Title) Permentsforsch. 12:335-340, 1931 Febrile conditions, whether produced by infections or through the injection of pyrogens, increase the interferometer reading for the Abderhalden reaction. The functions of the suprarenals may be widely altered in fever, iSO. LUSTIG, B. and LANGER, A. Ueber die Bestimmung und den Gehalt der freien, Eiwelss und gebundenen nichteiweiss Kohlenwasserstoff s im norm und patholo- gischen Seren (Determination and content of free, protein- bound and non-protein carbohydrate in normal and pathologic serum) Biochera, Ztschr, 242:320-337, 1931 High values were found for sugars associated with protein in the serum during febrile infections. The highest values were recorded in carcinoma, sarcoma and pneumonia. No increases were noted in chronic conditions in which fever did not appear. I3l. NEITBERGER, J. Elnbllck in die Wirkungsweise einer Pyriferkur (Glance at the manner of action of pyrifer therapy) Med, klin, 27:954-956, 1931 The action of pyrifer on neurosyphilis was observed in patients treated on the services of the State Hospitals in Berlin, Temperature seldom rose above 40*^ C. and local reactions were Infrequent. Pyrifer gave a stronger therapeutic reaction than either specific or nonspecific protein therapy. The leukocyte and differential counts were altered; the white cell count rose to 16,000 in many cases, occasionally as high as 33;iOOO. The 61 -19 3 1- decrease began 6 to 7 hours after adroinistratlono A sharp. Initial leukopenia sometimes antedated leukocytosis; where this occurred, stab cells made up approximately 50 per cent of the total leukocyte count. Although It is an active hematopoietic agent, pyrifer is not a cure in the final sense. In neurosyphi- lis, it is a valuable adjunct in combined therapy. 182. SABIN, A. R, and WALLACE, G. Bo On the nature of the chill-producing principle in anti- pneumococcus serum J, Exper„ Med. 53:339-362, 1931 A chill may occur 30 to 60 minutes following the injection of anti-pneumococcus serum. It is accompanied and followed by a rise in temperature which is prolonged for several hours. Since the same reaction has been noted after intravenous injec- tion of other solutions and in transfusion, a study of its properties and origin was made. The influence of drugs upon the chill-producing factor was ascertained. No relationships between the chill, anaphylaxis or the toxic effects of drawn blood were noted. The principle appears to be formed in blood after standing; it is not removed from solution by anticoagulants, dialysis, filtration or moderate heat. It was independent of the formed elements, the lipids or fibrinogen. Fractionation methods, utilizing the changes in pH and NaCl con- centration, removed acid and alkaline globulin fractions from antibody solutions. The acid globulin apparently acts as an adsorptive carrier for +-he chill-producing fraction, while the alkaline globulin serves as a vehicle for the antibody substance. 133. SHWARTZMAN, G. Phenomenon of local skin reactivity to bacterial filtrates in the treatment of mouse sarcoma I80 Proc. Soc. Exper, Biol. Med, 29:737, 1931 Agar washings of Meningococcus 44D group I were filtrated and injected intravenously into mice bearing sarcoma I80. Doses ranging from C.25 to 0.5 cc, were given singly, as repeated injections, and at varied time intervals during tumor growth. The m.ajority of neoplasms responded with prompt hemorrhage followed by complete regression or regression succeeded by slow regrowth. The effect appears to be selective. The sub- stance was highly toxic. -19 3 1- l8i^* SOLARI, L. A. Temperature et reactions thermiques chez les chiens hypo- physoprlves ou i tuber llse (Temperature and thermal reactions In hypophysectomlzed or tuber-injured dogs) Compt. rend, Soc. biolo 108:125, 1931 185, SPEIRER, C, Die unspezif Ische Behandlung des Gonorrhoe mlt Pyrifer (Non- specific treatment of gonorrhea with pyrifer) Dermat, Wchnschr, 92:13-17, 1931 Immunologic mobilization^, and not natural resistance^ are cardinal features of all nonspecific 'fever' therapeutics. The authors found a death point fdr gonococcl in vitro at 4^0 to 41° Coj others, particularly Koch, have noted no absolute destruction through heat in vivo „ A bacterial protein material from apathogenic colon type bacilli (pyrifer) was used in treatment in all seven strengths (50 to 500 million organisms) Pyrifer fever resembled that of malaria. Most frequently encountered reactions were those of head- ache, muscle pain and herpes lablalis. While pyrifer has a place in the therapeutic armentarlum, it is not a panacea, 186. WOLFF, L. K. and RAS, G. Uber unspezif Ische Theraple II. (On nonspecific therapy, II.) Ztschr, ges, exp, Med, 75^719-736, 1931 A nonspecific bactericidal effect was found to be common to or- ganic compounds (31), inorganic salts (12), biologic proteins (12) and suspensions of dead bacteria (14), when these materials were injected intravenously into the rabbit. When tolerance to histamine developed, there was tolerance to all other materials injected. Appearance of a tolerance to gram-negative bacilli produced similar tolerance to all other gram-negative organisms, but none to gram-positive bacterial preparations. When the materials were Injected in a reverse order, the tolerance exhibited likewise was in reverse. Subcutaneous Injection itself is bactericidal. When leukocytes were destroyed by coagulation, the blood and serum of the rabbit exhibited bactericidal properties. 63 -19 3 1- 187- ZOZAYA, J< Serological study of polysaccharides of meningococcus , B, anthracls, B, proteus , B. subtllls and Bo mesenterlcus J. Expero Medo 5^:725-732, 1931 - 1 9 3 2 - 188. BANUS, Mo G. and GINSBURG, E„ Changes In blood associated with fever Induced by killed B. coll Amo J. Physiol o 101:106-114, 1932 Vaccines of B. coll or typhoid organisms, or the suspensions of B, coll , produced a very marked alteration in the blood of the dog. A series of injections of increasing strength was more effective in producing high temperature levels than was a single dose» The concentration of the blood increased? hemoglobin and oxygen capacity were increased together. The alkali reserve declined o The reactions observed Included the appearance of bloody stools and diarrhea, nausea and vomiting. 169. HARTMAN, P. A» and SCOTT, W, J. M, The protection of adrenalectomlzed animals against bacterial intoxication by extract of adrenal cortex Jo Exper, Med, 55^63-65, 1932 Adrenalectomlzed rats were given preliminary injections of cortln or equivalent volumes of saline solution until body weight appeared to be standardized. Surviving animals were divided into groups two weeks iQter; one group received standard typhoid vaccine followed by 0.5 cc . of cortln or saline, respectively; injections were continued until death ensued or animals recovered from the intoxication produced. A second group received injec- tions of saline or cortln daily with Increasing doses of killed Staphylococcus aureus organisms (2 to I6 billion) . Acute intoxication from killed E, typhosa and chronic intoxica- tion after Injection of Staphylococcus aureus were resisted by those animals protected with cortical extracts. Larger amounts were necessary for protection during the peak of the intoxication The authors believe that inadequate production of cortln may be one factor in prolonging severe pyogenic infections which endure over two to three weeks. 64 -19 3 2 190- HENCH, P. S. Usual and unusual reactions to protein (fever) therapy- Arch. Int. Med, 49:1^ 1932 Physiologic changes during the "protein" reaction Include those In basal metabolism and blood pressure, peripheral and splanchnic vasomotor mechanisms and in size and permeability of the arter- ioles and capillaries o Fluctuations In renal function are seen. There may be pH, N, P, urea and uric acid, albumin and allantoin concentration alterations and the amounts excreted may vary. Immunological phenomena may be observed (antibody and complement fixation) and the flow of bile, lymph, saliva, breast milk or menses may be Increased. The activity of liver, gastrointestinal tract and spleen may vary from the norm. Of physical changes observed in blood, those of volume alteration, specific gravity, freezing point and viscosity are most evident. There are certain cellular blood characteristics which reflect the results of temp- erature elevation; platelet fragility is increased and the con- tent of fibrinogen may vary. Sedimentation rate may be affected. Chemically, COg tension and combining power of plasma and total NPN of whole blood and serum may reflect the general state during fever. Sugar tolerance and the ratio of albumin to globulin have shown variation in hyperpyrexia , 191. MURRAY -LYON, R, M. Nonspecific protein therapy in rheumatism Edinburgh M. J. 39:619-627, 1932 In chronic arthritis, typhoid vaccine or protein preparations bring a temporary response only. In the subacute arthritic conditions, typhoid vaccine may be beneficial. Its action on collagenous tissue has not been explained, 192 , NOUVELAS, P. A. Plrogenos; Mode de producto (Pyrogen production) Siglo med. 89:77; lOSO; I63, 1932 65 - 1 9 3 2 - 193. VON PAP, Z. Neosaprovltan Arch. f. Psychlat. 97:^50-460, 1932 194. ZOZAYA, J. Carbohydrates adsorbed on colloids as antigens J. Exper. Med. 55:325-351, 1932 Bacterial polysaccharides, including dextran, are non-antigenic when administered in small doses alone. When adsorbed on a colloid carrier, as haptens, their antigenicity appears. The possibility is considered that anticarbohydrate antibodies are produced. - 1 9 3 3 - 195 » CANZIANI, G. and LONGO, V. Donaggio's 'inhibition phenomenon' in the urine and spinal fluid of neuro- and psychopathic patients (Translated Title) Boll. soc. ital. biol. sper, 8:1476-1478, 1933 The Donaggio 'inhibition phianoraenon' does not appear in the normal individual after induced fever unless mental symptoms appear; it is not seen in neuropsychopathic or schizophrenic subjects. During epileptic seizure, the reaction is positive and may be a useful diagnostic sign, 196, CARMINATI, V. Influenza di culture di germi lattacidogeni sulla crescita del cancero del topo (Influence of lactic acid bacilli on mouse cancer) Boll. d. Inst, sierotherap, 12:205-220, 1933 The author injected cultures of termobacterium bulgaricus in milk serum into mice bearing cancer implants, with inconclusive results. 66 - 1 9 3 3 - 197. DONAGGIO^ A» Curves showing the 'Inhibition phenomenon' in urine and spinal fluid under various febrile conditions (Translated Title) Bollo soco ital. blol, sper, 8:l459-'1^62, 1933 Hyperpyrexia Induced by injections of pyrogenic substances (proteins and vaccines) does not cause immediate changes in the urine and spinal fluid. Resistance is exhibited in a latent period p extending 12 to 24 hours after the onset of ordinary fever^ and to 36 hours after injection of pyrogens. No lag is seen when fever Is Induced by physical means. Fever provoked by the injection of malarial parasites is preceded by alterations in urine and spinal fluid before the rise in temperature. The inhibiting substance can be removed from fluids by dialysis or by adsorption with bone charcoal or kaolin, followed by filtration o 198, DURAN-RFfNALS, P, Reaction of transplantable and spontaneous tumors to blood -carried bacterial toxins in animals unsusceptible to the Shwartzman phenomenon Proc, Soc, Exper, Biol, Med, 31^341, 1933 The tumor hemorrhage and necrosis which follows the Intravenous injection of bacterial filtrates of B, coll was studied in rats and mice, animals normally unsusceptible to the Shwartzman phen- omenon. The majority of animals carried rapidly growing, malig- nant tumors, a smaller proportion bore slower-growing spontaneous or transplanted malignant growths, em^bryomas or granulomas, A strongly positive hemorrhagic reaction was seen in the group bearing rapidly growing transplanted tumors; the larger the tumor the greater, in general, was the reaction. Slower growing and less malignant tumors were not affected. Animals bearing regressed tumors were resistant to regrafted tumor tissue. Toxic effects of the filtrate appeared to be related to the size and age of the tumor. The investigators found only tumors showing malignancy and rapid growth were capable of response to bacterial toxins, 199- GIAJA, J. and DIMITRIJEVIG^ I. La thermoregularisation sur la flevre (Thermoregulation during fever) Arch, int, pharmacodyn, 45:3^2, 1933 67 - 1 9 3 3 - Fever caused by Induced Pyocyaneus Infection In rats did not inhibit the temperature regulating apparatus of the brain centers. The temperature remains high during wide variations in environmental temperature. 200^ GORDON, R. E. and STARK, C. N. The toxicity of young cells of S. paratyphi A and B when lysed by bacteriophage. J. Infect. Dis. 62:45-47, 1933 Young bacterial cells did not yield toxic fractions after auto- lysis and f iltration^ but a slight toxicity was shown by prepara- tions made from S. paratyphi A and B cells 6 or more days old. The maximal toxicity was present between 8 and 14 days of age. Aging again reduced the toxic factor. At room temperature for 2 months toxicity was gradually lessened. Filtration, additional bacterial inoculations and low temperatures did not reduce activity. 201 . HSAIO -CH ' lEN , CHANG Gastric secretion in fever and infectious diseases J. Clin. Invest. 12:155-169, 1933 Gastric acidity falls during febrile conditions and finally reaches levels 66 per cent below the normal. Chloride ion concentration falls with the volume of secretion. The decreases are In direct proportion to the degree of fever. 202. HEUBNER, W. and SILBER, W. Der Bestimmung der antlpyretlschen Stoffen (Testing of antipyretics) Arch, Exp, Path. Pharmakol, 169:530-536, 1933 The most regular and enduring fever reproducible in rabbits is seen after infusion of hay extracts. If subcutaneous injections are used, no ill effects follow high temperature elevations. The method may be employed for testing antipyretic drugs. - 1 9 3 3 - 203. LEVINE, P. and PRISCH, Aa W, Further observations on specific inhibition of bacteriophage action Proc, Soc, Exper. Biol, Med, 31:^6, 1933 Specific inhibition of bacteriophage by two extracts from or- ganisms of the Salmonella group was reported (Proc, Soc, Exper. Biol, Med. 30:993^ 1933). In addition, the specificity of the inhibition was determined through isolation of specific phages for B, paratyphosa B and B, suipestifer from chicken stool filtrates. The extract of B. suipestifer had only a feeble influence on anti-B, paratyphosa phage, while the latter was inhibited markedly paratyphosa B« extract. The latter was only slightly specific for antl-B, suipestifer phage; its homologous extract was far more potent as an inhibitor. The order of acti- vity of extracts did not run parallel to living bacillus phage titer, 20^. LEWISOHN, R, and ROSENTHAL, N. Prevention of chills following transfusion of citrated blood J. A.M. A, 100:^66-^69, 1933 Transfusion reaction rates were reduced 1 to 12 per cent by care- ful preparation of solution and rigorous antisepsis of apparatus used in transfusion. Pyrogen reactions are reduced to a mini- mum by such precautions. 205. RADEMAKER, L, The cause and elimination of reactions after intravenous infusions Surg, Gynec. and Obst , 56:956, 1933 Pyrogenic reactions are produced by toxic by-products elaborated by the bacteria and not by bacterial components. Careful dis- tillation, immediate sterilization and cautious attention to the prevention of later contamination will reduce pyrogens in fluid. 69 -19 3 3- 206. THOMPSON, S. A. Preparation of dextrose and saline solutions and apparatus for intravenous and subcutaneous use Am. J. Surg. 22:127, 1933 In a committee report on the causes of reactions following intravenous infusions, the presence of bacterial pyrogens in improperly distilled water, is considered to be the most important cause of the twelve listed. The correct method of distillation is described, and a permanganate color test is recommended for use. Techniques for the preparation of glu- cose, normal and 2 per cent saline solution are presented. 207.. WAELSCH, H. and WEINBERGER, E. Das Gehalt des glutathiones im Blut (Glutatione content of blood) Arch. exp„ Path. Pharmakol. 169:625-632, 1933 Glutathione and ergothionine in human blood are Increased during pyrexia produced by injections of pyrifer, milk protein or bacteria. Glutathione alone does not influence the temperature of the normal rabbit nor in animals after the removal of thermo- regulatory organs. - 1 9 3 ^ - 208. BANKS, H. M. A study of hyperpyrexia reaction following intravenous therapy Am, J, Clin. Pathol. 4:260-291, 1934 Organisms Isolated from various pyr6genlc waters were identified as Pseudomonas sclssa and Ps. ureae. A suspension of killed organisms elicits a fever of 3 to 4^ P, in the rabbit, but no immunity or hypersensitivity was noted after repeated injection. Bacterial suspensions of the two organisms were Injected sepa- rately in patients with advanced neurosyphilis, dementia paraly- tica and tabes dorsalis. Central nervous system disturbances began to clear within three weeks; the psychiatric symptoms abated to a considerable extent. 70 19 3 4- 209 e BIERRY^ H. L' action specif ique et la structure chimlque (Specificity and chemical structure) Compt, rend, Soc » biolo 115:1168-1170, 1934 The role of carbohydrate and protein in determining specificity of reaction to living or killed bacteria is briefly discussed, 210. BLUM^ D, N. and COLEY, W. B. Large malignant tumor (sarcoma) of the uterus with multiple bone metastases (femur, pelvic bones and skull) Am. J, Surg, 1:47, 1934 ' A patient with a malignant myoma and multiple skeletal metastases received a series of injections with 'Coley's toxins' after total hysterectomy. No return of malignancy was evident six years after treatment. j 211. BURNET, P. M. The phage-inactlvatlng agent of bacterial extracts Jo Path, Bact, 38:285-299^ 1934 The findings of Levine and Prlsch that bacterial extracts may be capable of inhibiting activity of phages lysing parent strains are confirmed. Extracts from resistant strains fail to inhibit phages to which bacteria themselves are resistant. Homologous antibacterial serum destroys the phage inactivating power. 212. CECIL, R. L, The medical treatment of chronic arthritis J. A.M. A. 103^583, 1934 Small intravenous doses of streptococcus vaccine, given four to live days apart, and subpyrexial in dosage (50, 000-100, OOOj 000 organisms) brought some Improvement In chronic arthritis. At the time of writing, the author preferred this type of treatment. 71 -19 3 4- 213. DARROW, K. E. Revlev.' of causes of reactions following intravenous injections of glucose and normal saline (with special reference to pyrogen containing distilled water as a cause) yy^^&^n Journal -Lancet 54:65-66, 1934 214. DELAPIELD, M, E.- Blood sugar changes and toxic effects produced in rabbits bv certain fractions derived from B. aertryke Brit. J, Exper. Pathol. 15;130, 1934 Fractions prepared by the method outlined by Raistrick and Topley were capable of producing hyperglycemia and toxic effects in the rabbit. Antibacterial and antitoxic immunity production in mice by means of these fractions appeared to parallel their toxicity for the rabbit. The active fraction of B. aertryke is precipitable in alcohol (50-63^ by weight), a second inactiv e iraction is obtained by use of excess alcohol. The alcohol- soluble material is also inactive. The hyperglycemic effect can be removed from the precipitable active fraction by acidic or alkaline hydrolysis. Repeated injections of this fraction produces tolerance to the chemical response, 215. GOUGH, G. A. C. and BURNET, P. M. The chemical nature of the phage -inactivating agent in bacterial J. Path. Bact. 38:301-303, 1934 The phage-inactivating agent of bacterial extracts is a poly- saccharide which can be converted into a hapten by alkaline treatment. The poiver to inactivate different phages is lost by degrees during degradation by either heat or alkali. The investigators consider the specific somatic antigen of dysentery and Salmonella bacilli to be a labile polysaccharide and to be responsible for serological properties and phage susceptibility 01 the bacteria. ° t- j - 1 9 3 4 - 216 « HOOPER, P. E., RENFREW, A. G. and JOHNSON, T. B. The chemical study of bacteria,, Studies on the complex car- bohydrates isolated from the culture medium and the ultrafll- trate after the growth of tubercle bacilli Am, Rev, Tuberc . 29s66-72, 193^ A fraction secured by the hydrolysis of a culture of tubercle bacilli 6 weeks old contained d-galactose, d-mannose and d-arabinose with a small amount of uronic acid. The nitrogen- free ultraf iltrate contained a polysaccharide with identical specific reactlvitys The polysaccharide did not contain phos- phorus . 217, HOWIE^ J, E, Observations on the use of pyrifer Jo Ment, Sci. 80s 521 -525, 193^ Pyrifer is a preparation produced from killed colon bacilli and prepared in seven strengths, containing from 50 million to 500 million bacteria per cc. The initial dosage recommended ranges from 25 to 50 million bacteria. The intravenous route is preferred The febrile reaction begins one-half to 1 hour after administration and reaches its height in 3 hours, falling by l7/sis, A secondary rise follows with lower maxima; there is complete recovery in 2k- to 48 hours, A regular fever rhythm appears, usually after the 3rd treatment. Side effects are moderate in degree and, unlike malarial or cabinet therapy, the treatments can be given to patients with serious cardiac lesions without adverse effects. The successive phases of leukocytosis and lymphocytosis resemble those seen in other types of nonspecific therapy, Howie administered pyrifer to 15 patients with advanced general paralysis, all too feeble for malarial therapy. Six were improved, 2 discharged as cured. The average duration of treatment was between 3 and 6 weeks. In schizo- phrenia (15 cases) improvement was seen in 5, The treatment was ineffective for chronic manic states, Pyrifer reduced seizures in one epileptic patient from 32 in 3 weeks to 16 in the same length of time. Nc permanent remission could be obtained . 218, LANPRANCHI, F, Ricerche sul plrcgene batterlco : influenza degli amino acid mel mezzi sintetlci, sulla produzione del pirogene (investiga tion on bacterial pyrogens: Influence of synthesis of amino acids In media on pyrogen production) 73 - 1 9 3 ^ - Ann. igiene 44:443-^169, 1934 219. NEDZEL, A. J. A study of muscle temperature during bacterial chill Proc. Soc. Exper. Biol, Med. 32:279, 1934 The muscular tremor observed during bacterial chill was not accompanied by an Increase in temperature in the skeletal muscles. Such muscular activity differs from that of muscular work which is accompanied by increased heat production. 220. (COUNCIL ON) PHARMCY and CHEMISTRY, AMERICAN MEDICAL ASSOCIATION Erysipelas and prodigiosus toxins (Coley) J. A.M. A. 103:167, 1934 The Council briefly reviews the literature on the use of the mixed toxins of Coley. Its members conclude that "...the com- bined toxins of erysipelas and B. prodigiosus may sometimes play a significant role in preventing or retarding malignant recurrence or metastasis (and) occasionally they may be curative in hope- lessly inoperable neoplasms. Probably their value is strictly limited to tumors of entodermal or mesodermal derivation, and more particularly in the case of bone tumors, to those exhibit- ing little or no osteoplasia," For these reasons, the Council retained the toxins of Coley in New and Non - official Remedies with p view to facilitating their further study, particularly for a prophylactic use in conjunction with conservative or radical surgery, 221. PIOTTI, M. Terapia pirotogena in casi di ebefrenia iniziale (Pyrogen therapy in cases of early hebephrenia) Schlzofrenie 4:443-447, 1934 222. RAISTRICK, H, and TOPLEY, W. W, J. Immunizing fractions isolated from B, aertrycke Brit, J, Exp. Path, 15:113, 1934 The preparation of an immunizing fraction is described. 74 -19 3 4- 223. WRIGHT, I. S. The modern medical treatment of diseases of the peripheral vascular system. Med. Clin, No Amer. 17:1429, 1934 Leukocytosis or immobilization of immune bodies may account for a portion of the benefits secured through the use of 'fever therapy' o Vascular changes bring relief from spasm in partially occluded vessels; local capillary dilatation brings an improved blood supply to ulcerated areas and healing is promoted « - 1 9 3 5 - 224o APITZ^ Ko Studies on the chemical nature of Shwartzman-active substances Jo Immunol. 29:343-358, 1935 The nucleoproteln fraction of bacteria, obtained by autolysis or extractlonj is Shwartzman-active, The potency is increased in alkaline solutions, A metabolic fraction can be isolated from agar washings through alcohol precipitation; it contains a highly unstable Shwartzman-active fraction, not identical with type-specific carbohydrates. It may be dialyzed slowly from filtered washings but resists tryptic digestion. 225, DURAN-REifTNALS, F, Reaction of spontaneous mouse carcinomas to blood -carried bacterial toxins Proc, Soc, Exper, Biol, Med, 32:1517, 1935 Previous experiments had revealed the insusceptibility of slow- growing malignant carcinomas of the mouse to the tumor-necrotic action of certain bacterial filtrates. Highly toxic agar wash- ings of human typhoid bacilli, of mouse typhoid II and the less toxic filtrates of two other types of mouse typhoid bacilli (I and III) were injected, separately and in combination, in mice bearing mammary carcinomas. The highest incidence of local reaction, as well as the most Intense effects, were seen in larger tumors after large doses 75 - 1 9 3 5 - of the toxins. Mortality was higher. Partial or total inhibi- tion of tumor growth was higher in the group bearing smaller tumors and receiving smaller doses of the toxins. It is be- lieved that newly formed vessels are most susceptible to toxins. 226, CECIL, R. L. Nonspecific protein therapy. J. A.M. A, 105:1846-1854, 1935 The history of nonspecific protein therapy is reviewed. In- cluded are the following sources of therapeutic preparations: native proteins; serums; protein-split products; enzymes; tissue extracts; bacterial extracts and vaccines. Differences between nonspecific reactions and focal processes are probed. The possibility that all types of 'protein' therapy may be specific in calling forth body defenses is presented. The therapeutic usefulness of leukocytosis is still unexplained. The author notes that gram-negative bacteria and their products cause febrile reactions more often than gram-negative organisms. Application of this type of treatment to specific disease con- ditions is evaluated. 227, GIEHM, G. Die moderne Therapie der Schlzophrenle (Modern therapy of schizophrenia) Med. Klin, 31:547-549, 1935 A suspension of bacterial albumins (pyrlfer) was used in the therapy of schizophrenia. Bacterial proteins from non-pathogens may prove efficacious in selected cases, 228, HEKTOEN, L. Nonspecific proteins J.A.M,A. 105:1765-1767, 1935 Foreign proteins united with body fluids are taken up by body cells, particularly those of the reticuloendothelial system; humoral and Intracellular alterations follow. The products of these processes affect the entire organism in a complex fashion. Resultant phenomena are partially temporary in effect, partially permanent. The temporary effect is that exercised on the autonomic or sympathetic nervous system. An increase 76 - 1 9 3 5 - in chemical activity accompanies fever. Capillary walls and cells of the reticuloendothelial system are important sites of chemical activity. Proteolytic and lipolytic enzyme output is accelerated. Fibrinogen and complement are decreased initially, then increased. The colloid stability of plasma is lessened. Altered metabolism is shown in the Increased NPN of the blood. Histamine and choline are released as secretory stimulation follows dilatation in the splanchnic area, A local edema may be an outward manifestation of detoxification, 229. KOPP, I. Metabolic rates in therapeutic fever Am, J, Med, Sci, 190:491-49^^ 1935 Fever was induced by physical means and by mixed typhoid vaccine in 7 patients with neurosyphilis. One patient received fever therapy by all five methods employed. Various combinations of fever production were studied. Metabolic rates at fixed temperature levels were higher during periods of elevation than during periods of falling temperature. Rapidity of fever pro- duction did not affect the results; no differences in basal metabolism could be traced to the technique by which fever was produced , 230. MENZIES, A. W, C. Pyretotherapy in Dementia Praecos Lancet 2:99^-996, 1935 Dmelcos ( Ducrey bacillus atoxic vaccine) intramuscularly or sulfosin produced improvem.ent in 26 schizophrenic patients and a complete remission for four of these. The recovery rate cannot be altered by this type of fever alone; accessibility of the patient to psychiatric treatment was increased and the psychic pattern was broken. 231, PINKSTON, J. 0. Peripheral circulation during experimental fever Am. J, Ihysiol, 110:448, 1935 Sympathectomy delays initial vasoconstriction seen in peripheral vessels following the Injection of typhoid -paratyphoid vaccine. In the normal. Innervated ear of the rabbit, constriction begins 77 - 1 9 3 5 - within 10 minutes after injection and persists until the fever raaximum is attained. After sympathectomy, vasoconstriction is noted in 50 per cent of animals and ^ in the majority of these, delayed vessel constriction occurs, Inactivation of the adrenals may abolish the early responses of the vascular sys- tem. In the general peripheral vasodilation after febrile maximal points have been reached, the sympathectomized ani- mals show a similar delay in vessel dilatation. 232. PINKSTON, J. 0.* Experimental fever in sjrmpathectomlzed animals Am. J. Physiol. 111:539, 1935 Complete removal of sympathetic chains from the stellate to the pelvic ganglia brings a profound delay in both the initial febrile reaction and in the attainment of maximal temperature levels. The fever curves are flattened. With splanchnic section or adrenal inactivation only, the behavior of the curve in Induced fever approaches that seen in the normal febrile ani- mal, 233. SHWARTZMAN, G. Hemorrhagic necrosis and regression of sarcoma l80 Science 82:201, 1935 The lethality of E. typhosa filtrates was much reduced when cer- tain proportions of homologous antlsera were combined with the material. Single intravenous Injections of either antlserum- filtrate mixtures or filtrate alone were administered to sarcoma- bearing mice. The marked reduction in lethality which followed did not affect the hemorrhagic -necrotic action of the filtrates on tumors. Regression was prompt when a mixture of 200 neutra- lizing units of antityphoid serum was mixed with 300 reacting units of E, typhosa . 234. WALTER, C. W. Economical intravenous therapy. J. A.M. A. 104:1688-1790, 1935 Physiologic reactions ranging from fever and chills to cyanosis, diarrhea, nausea, vomiting and collapse have been seen after intravenous infusions of saline solutions contaminated from impurities in distilled water, chemicals rubber tubing and glass- ware. While individual susceptibility, velocity of injection. 78 - 1 9 3 5 - Its volume, and the temperature and pH of the solutions must be considered, pyrogens In water take first rank as causative agents In a reaction. The methods by which Infusion materials may be rendered pyrogen-free are outlined In detail. -19 3 6- 235. ANDERVONT, H. B, The reaction of mice and of various mouse tumors to the Injec- tion of bacterial products Amo J„ Cancer 27:77-83, 1936 Bacterial filtrates obtained from meningococcus and B. coll cultures were used to determine their toxicity for mice, using changes In cutaneous tumors as a standard for Judging activity of the filtrates. Toxicity was greater for tumor-bearing mice held at 37° C, than when room temperature was used; the same was true for the normal animal. Normal mice were more resis- tant to toxic filtrates than were the tumor-carrying animals. The route of injection was not Important. Certain stralr dif- ferences In susceptibility to toxic filtrates were shown. Spontaneous mammary carcinomas were resistant to B. coll fil- trates while chemically-induced tumors responded with regression. 2360 ANDERVONT, H, B. and SHEAR, M.J. Production of Shwartzman reaction in rabbits with purified fraction of B, coll filtrate Proc, Soc. Exper, Biol, Med, 3^:673, 1936 The original filtrate and a purified fraction from B. coll were capable of eliciting the Shwartzman reaction and producing tumor hemorrhage in the mouse. The minimal effective tumor-hemorrhage dose of the original filtrate was 0.2 cc . of the 1:50 dilution. When the purified fraction was used, the minimal effective dose for tumor hemorrhage and that eliciting a positive Shwartzman were of the same magnitude. 237. GENTANNI, E. Sulla prezenza di un prlnciplo plrogene e antlpirogene nella cultura batterica (On the presence of a pyrogenlc and antl- pyrogenlc principle in bacterial cultures) 79 -19 3 6- Bagllvl 2:241-253, 1936 238. CO TUI, McCLOSKEY, K. L., SCHRIPT, M. H. and YATES, A. L. Filtration studies on reactive infusion fluids Proc. Soc. Exper. Biol. Med. 35:297, 1936 The pyrogenic substance found in infusion fluids is of a parti- culate nature, with a diameter somewhat larger than 50 milli- microns. 239. FOGG, L. Co Effect of certain bacterial products upon the growth of mouse tumor Pub. Health Rept. 51:56, 1936 A small gram-negative bacillus was Isolated as a contaminant of mouse sarcoma I80 tissue cultures. When injected intraven- ously into mice bearing sarcoma I80 growths, tumor regression appeared in 20 per cent of the animals, and hemorrhage and ne- crosis in 28 per cent. However, mortality reached 45 per cent and the use of immune sera did not alter the mortality rate. An alcohol preclpitable fraction was prepared which, on in- jection, produced complete tumor regression in 42 per cent of the mice, and necrotic changes in 22 per cent. Mortality was reduced to 33 per cent. Addition of bacterial vaccine or this fraction inhibited in vitro tissue cultures of sarcoma I80 but did not injure normal tissues. 240. GIUPFRE, I. II trattaraento ipertermico con 'pyrifer' nella terapia della schizofrenie e della demenza paralytica (Hyperthermic treatment with 'pyrifer' in therapy of schizophrenia and paralytic dementia) Arch, gen. di, neurol., psichiat. e psichoanal. 17:223-246, 1936 Two patients were cured and one notably improved after injections of a bacterial protein secured from a nonpathogenic strain of Bo coli . Temporary remissions of hebephrenic behavior followed therapy in two other instances. Three failures are reported. Malarial and sulfur injections were ineffective in these conditions , 80 -19 3 6- 241. JACOBI, M, The effect of the Shwartzman reaction with bacterigQ. filtrate on transplantable tumors In animals Am. J, Cancer. 26:770-774. 1936 The Shwartzman. phenomenon was provoked in experimental animals bearing mouse sarcoma l80, Plexner-Jobling rat carcinoma. Walker rat carcinosarcoma and Rous chicken sarcoma. Both preparatory and provocative injections of E. typhosa filtrate utilized the undiluted toxin. Preparatory injections were given intratumorally. All tumors responded with violent hemorrhage and necrosis after the provocative Injection, complete sloughing and healing followed In some, slow regrowth of tumor tissue in others. When the injections were made only into tumor tissue or only intraperltoneally, no hemorrhage occurred o 242. MORGAN^ W. T. J, Studies in imraunochemistry, I. The preparation and properties of a specific polysaccharide from B, dysenteriae (Shiga) Blochem, J, 30s909-925> 1936 A polj/saccharide containing 97 per cent reducing sugars on acid hydrolysis was isolated from the 'smooth' form of B. dysenteriae . Strongly dextrorotatory, it contained but 1 per cent of nitrogen, all in the form of acetylated amino groups. It accounts for the serological specificity of the bacterium. The occurrence and significance of certain nonspecific polysaccharides are discussed. 243. SHEAR, M, J. Chemical treatment of tumors, IV. Properties of hemorrhage- producing fraction of B, coll filtrate Proc, Soc, Exper, Biol, Med, 34:325-326, 1936 The hemorrhage-active fraction of B. coll filtrate previously describedwas further purified by methyl alcohol precipitation. The minimum dose for hemorrhagic activity was 0.2 cc, of a 1:500 dilution. After solution in water the fraction gave a strongly positive Molisch test and a negative biuret test; it exhibited no selective absorption peak. Activity was demonstrated after storage for 8 weeks in cold temperatures. In biologic tests, normal tissue capillaries were not rendered more permeable after injection of the fraction. 81 - 1 9 3 6 - 244. SHEAR, M. J. and ANDERVONT, H. B. Chemical treatment of tumors. III, Separation of hemorrhaee- produclng fraction of B. coll filtrate Proc. Soc. Exper. Blol„ Med. 34:323-325, I936 A method Is described for the separation of the tumor-hemorr- hage producing fraction of B. coll filtrate from toxic and Inert contaminants. The method Involves centrlf ugatlon, filtration, alkaline precipitation, and the removal of calcium by acidi- fication with HCl and precipitation with alcohol. The final product was a water-soluble fraction, highly potent for the production of mouse tumor hemorrhage In amounts as low as 0.1 cc, of a 1;100 dilution of a stock solution containing 22 mg. per cc. of the active fraction. 245. SHWARTZMAN, G. Reactivity of malignant neoplasms to bacterial filtrates. II, Relation of mortality to hemorrhagic necrosis and regression elicited by certain bacterial filtrates Arch, Path. 21:509-524, I936 Mice bearing 12-day-old sarcoma I80 implants were injected intra- venously, intra-oeritoneally or subcutaneously with one of the following bacterial filtrates: meningococcus "agar washlngs'j B. enteritidis . B. coll , E, typhosa , Staphylococcus aureus . Streptococcus hemolytic us and the tubercle bacillus. The ability of the preparations to elicit the Shwartzman phenomenon in rabbits was determined shortly before parenteral injection. E. typhosa and meningococcal filtrates were more toxic for the tumor-bearing mouse than for normal animals; filtrates of B, enteritidis were toxic for both normal and tumor-bearing test animals. All three were potent agents for tumor destruction. Bo coll , Str, hemolytlcus and tubercle bacillus filtrates pro- duced only slight changes in tumor tissue. Staphylococcus aureus filtrate produced no changes. Since all filtrates were highly toxic, it was evident that the lethal effects and tumor-des- tructive activity exist Independently, In certain given proportions, serum-E, typhosa mixtures protected animals against the lethal effects, while tumor hemorrhage, necrosis and re- gression proceeded unchanged. 82 - 1 9 3 6 - 2^6. WALTER,. C. W. Preparation of safe intravenous solutions Surg., Gynec, & Obsto 63:643-646, 1936 Pyrogenic bacterial substances are the chief offenders in pro- ducing the reactions noted after intravenous therapy. Proper preparation of solutions and careful cleaning of transfusion or infusion equipment eliminates many of the hazards attending parenteral therapy. 247. WITEBSKY, E. and SALM, H. Hemorrhagic necrotic skin lesions in rabbits produced by Hemo - philus influenzae and Hemophilus pertussis Proc. Soc. Exper, Biol. Med. 34:351, 1936 Skin areas of the rabbit, prepared with intradermal injections of living H, influenzae 24 hours before the intravenous injec- tion of the same suspension or E. typhosa agar washings filtrate, responded with hemorrhage and necrosis within 3 to 6 hours. The response to intravenous H, influenzae exceeded the one noted after injection of H, pertussis . Sites prepared with H, per - tussis were unchanged by intravenous challenging doses. Heat killed H, influenzae were likewise effective in producing hemorr- hagic necrosiL in sites previously prepared by the intradermal injection of the same organism or E. typhosa ' agar-washing' f il- trate. -19 3 7- 248. ABERNBTHY, T, J. and FRANCIS, T., JTt. Studies on the somatic C polysaccharide of Pneumococcus . I, Cutaneous and serological reactions in pneumonia J. Exper, Med. 65:59-74, I937 The intracutaneous Injection of pneumococcal somatic polysac- charide produced a characteristic skin response in patients ill with pneumococcal lobar pneumonia , Certain patients ill with non-pneumococcic febrile diseases gave similar responses. The response was not present during convalescence. No skin reaction could be obtained in 7 fatal cases. 83 - 1 9 3 7 - 249. BOYLAro, E. and BOYLAND, M. E. Studies In tissue metabolism. IX. The action of colchicine and B. typhosus extract Blochem. J, 31:454-460, 1937 Agar washings of E. typhosa cultures were injected to deter- mine the effect, of tumor hemorrhage produced by such means upon tumor, liver and intestine ascorbic acid content. Colchicine was Injected and its toxicity for normal and tumor-bearing mice, capacity for hemorrhage production in the transplanted tumor or the mouse and rat and tissue metabolic changes were determined, in vitro and in vivo. The effect of colchicine upon the as- corblc acid content of tumor, liver and intestine and its ability to produce the Shwartzman phenomenon in the rabbit were observed. Both colchicine and E. typhosa agar washings were capable of producing tumor hemorrhage and reducing ascorbic acid content and metabolism in grafted tumors, but dosages necessary to ini- tiate these effects were close to the toxic levels. Tumor- bearing animals were more sensitive to the toxic effects of colchicine than normal animals. The size of the tumor and the survival rate were significantly related. Ascorbic acid content of the rat and mouse intestine diminished after colchicine; liver metabolism was not inhibited. Colchicine did not elicit the Shwartzman phenomenon, nor did it produce hemorrhage in the liver, 250. CO TUI, McCLOSKEY, K. L., SCHRIPT, M. and YATES, A. L, A new method of preparing nonpyrogenic Intravenous infusion fluids, based on removal of pyrogen by absorptive filtration Ann, Surg. 106:1089-1094, 1937 Adsorptlve filtration, followed by ultrafiltration, is advocated for the preparation of pyrogen-free Intravenous solutions. The sterile solution is passed through the compressed Seltz EK (serum) type asbestos filter and the 200-second Zsigmondy mem- brane filter. The Jena, Berkefeld, and 42-second Zsigmondy type filters are not effective for this purpose. It is be- lieved that the pyrogen particle diameter lie between 50 milli- micron and 1 micron. 8^ - 1 9 3 7 - 251, CO TUI, SCHRIPT, M. H, and RUGGIERO, W. P. A new method of preparing infusion fluids J. A.M. A, 109:250-252, 1937 Filtration through adsorptive filters and a 200-second Zsigmondy filter will render saline and dextrose solutions pyrogen-free. The Seitz serum #3 was employed . 252, CO TUI, SCHRIPT, M, Ho McCLOSKEY, AND YATES, A. L. Filtration studies on pyrogenic inulin Proc, Soc. Exper. Biol, Med. 36:227-230, 1937 Dahlia inulin, given intravenously, produced fever and leuko- penia. The pyrogen particle resembles that found in infusion fluids and can be adsorbed by standard methods. 253, DENNIS, Eo W, and SENEKJIAN, H. Typhoid leucociden Proc, Soc. Exper. Biol. Med, 36:6l, 1937 The activity of a typhoid toxic fraction, leucociden, on normal rabbits' blood and non-immune human blood, was manifested by a reduction in the number of leukocytes present as the concen- tration of toxin was increased. Only the granulocytes were affected. Neutrophils which survived showed degenerative changes The alcohol precipitate was stable for oneyear or more without loss of potency. An Incomplete inactivation could be produced by heat. Specific immune globulin (Pellx anti-typhoid serum) neutralized the toxin. One preparation of leucocidin contained 19.9 per cent of carbohydrate calculated as glucose. 254, FEVER THERAPY (A symposium) New York, Paul Hoeber, Inc., 1937 Therapeutic fever production by physical and bacterial agents was considered by International authorities, A discussion of the antichanchrold vaccine of Rimbaud was included. 85 - 1 9 3 7 - 255. GERBER, I, E. and BERNHEIM, A. I. Histological studies of tumor reactivity to bacterial filtrates Am. J, Pathol, 13s 67.3, 1937 (Abstract) A single intravenous injection of 20 to 100 reacting units of meningococcus 'agar-washing' filtrate produced severe degenera- ti\.'e changes in sarcoma l80 of the mouse., Vascular engorge- ment, edema and necrosis of the tumor cells preceded regression (or regrowth) of the tumor. Hemorrhage was seen in the early stages of chang-e and vessel lesions and thrombi were absent^ The filtrate appeared to affect tumor cells directly. The reaction "is analogous to and Is elicited by the bacterial active principles of the Shwartzman phenomenon". No prepa^'a- tory local injection was required. 256. HJORTH, P. Investigations of a thermostable bactericidal substance in human serum, demonstrated particularly in the serum of fever patients Acta Path, et mlcrobiol, scand, 14 s 412-426, I937 The serum of patients with febrile conditions contains the thermostable, bactericidal substance previously described by Wulff(J, Immunol, 27^451, 1934, Fever alone does not lnf'lu^'n<^« production of the bactericide. In undulant fever and influen- zal pneumonia, the sera were not bactericidal, whereas Inacti- vated sera from patients with cancer, cirrhosis and nephritis. In which temperatures were normal or only slightly iP'-reased, were high potent. This substance was active against meningococd. , gonococcl, and gram-negative cocci; Staph ylococcus aureus growth was not inhibited. The serum~^idnot Iose~poiiFcy com- pletely until after exposure for one-half hour to 68° G. Minute amounts of active serum restored bactericidal effec- tiveness. The properties of the substance resemble those cre- dited to beta-lys.tn by Petterson (Microben. (Jena), 1934). 257. MILLER, P, R. The induced development and histogenesis of plasma cells J. Exper, Med, 645 333-347, 1937 The mechanism by which the injection of tuberculoprot^in stimu- lates plasma cells after Intravenous or intraperitoneal injec- tion was studied at length. Plasma cells were found in normal connective tissue. Genesis proceeds, it is believed, in lympho- cytes or mesenchymal cells. The Russell body cells constitute 86 - 1 9 3 7 - the end point in the evolution of these cells. The greatest concentration was found in those organs closely concerned with detoxification, as the omentum and lymph nodes parti- cularly after the injection of bacterial proteins „ They are noted in spleen, liver, the body wall of the cecum, Polyblasts in the 'milkspots' of the omentum were precursors of these cells. 258. OLITZKI, L. and AVINERI-SHAPIRO, So The hypothermic factor of B, dysenteriae Shiga J, Exper. Path. l8:3l6-321, 1937 In B. dysenteriae Shiga , and in other organisms, a hypothermic fraction may exist. Hyperthermic reactions may precede and follow the drop in temperature. The lipoid and carbohydrate fractions of the organism considered in this study produced temperature increases only; the hypothermic activity was closely associated with the protein f inaction which may produce hyper- glycemia and leucopenia. 259. OLITZKI5 L., LEIBOWITZ, J. and BERMAN, M. Further investigations on the chero.lstry, toxicity and other bio- logical properties of different fractions of dysentery bacteria Brit, J. Exper. Path, lS:305-3l6, 1937 Bacterial antigens, on injection, have the ability to produce hyperglycem.ia combined with a fall of inorganic blood phos- phorus and followed by hypoglycem-ia and rising phosphorus index. The relationships of these alterations to the rise and fall of leukocytes were determined , Fractions obtained from Bo dysenteriae Shiga , Flexner , and Y (fractions of Purth and Landsteiner) as well as the hapten were injected intravenously in test animals. Blood sugar and leoKocytes were examined. Changes in body weight were recorded. Toxic symptoms were ob- served, A leucopenic factor was present in PI and P2 fractions; a slight leucopenic effect was observed after administration of the C fraction. The hapten did not effect leukocytes. In PI, C and the hapten a glycemlc factor occurs; It was present in unpurified polysaccharide 2 but not in the residue after alcohol extraction, P2 was strongly toxic, but fraction C and the hapten were non-toxic. The glycogen in liver tissue, gal- actose tolerance and diastase in blood were altered during the hyperglycemic reaction. Spleen and bone marrow changes took place during the period of leukopenia. Antileucopenic and anti-glycemic immunity existed independently. 87 - 1 9 3 7 - 260. PYRIgER Ge^^es Codex, (Dresden), 1937* Po 1350 A temperature-increasing bacterial product from apathogenlc colon bacteria grown in milk„ It is marketed in seven strengths, ranging from 50 million to 500 million bacterial cells per cc. Three types of packaging are obtainable. It has been used extensively in paresis and other luetic conditions involving . the central nervous system^ but uses in other types of in- fection have been reported. The beginning dose is 0.5 to 1.0 cc. of strength I, with gradual increases to maintain desired reactions. 261. SHWARTZMAN, G., MORELL, S., and SOBOTKA, H. Chemical investigations on the active principles of the phen- omenon of local skin reactivity to bacterial filtrates I. Purification by dialysis and attempts at fractional precipi- tation Jo Expero Med. 65^323-337, 1937 The active principles in the phenomenon of local skin reactivity (Shwart.em.an reaction) are retained by cellophane membranes. This method effects considerable purification, for culture filtrates of E. typhosa, B. coli and meningococcus , increasing reactive potency about three-fold. Fractional precipitation of concentrates of these filtrates, using acid, dilute alkali or alcohol, was not successful in this study. 262. WECHSLER, Z. Der Elnfluss der pyrifer fiebers auf die Blutliquorschranke xra Tieversuche (Influence of pyrifer on plasma barriers in animal investigations) Schwelz. med , Wochenschr, 67; 1048, I937 88 -19 3 8- 263. ALDER, A, PleberlDehandlung der epldemischen Kinderl^hmung mlt Pyrlfer (Fever therapy with pyrlfer In poliomyelitis) Med. Klin. 34:1527, 1938 The development of pyrlfer and of Its application is discussed. The case histories appended would indicate some usefulness for such bacterial substances in the therapy of poliomyelitis. 264. CHASIS, Ho, RANGES, H. A., GOLDRING, Wo and SMITH, H. W. The control of renal blood flow and glomerular filtration in normal man J. Clin. Invest o 17:683-697, 1938 The diodrast, Inulln and phenol red clearance of the human renal tubule was studied under a variety of experimental con- ditions. The physiologic regulation of renal blood flow and glomerular filtration rate was examined during the pyrexlal reaction Induced by Intravenously administered typhoid vaccine, during water diuresis, and when certain stimulants and diuretics were administered. The action of typhoid vaccine was initiated with a rise in blood pressure during the period of chill ac- companied by efferent arteriolar constriction and decreased renal plasma flow. The renal ischemia gave way to hyperemia In the febrile period; the filtration fraction Increased, indicating a dilatation of efferent structures. The filtration fraction varies inversely to the renal blood flow, while the filtration rate tends to be Independently maintained. 265. CONWAY, E, A. Reaction of lymphatic tissue in early stages of Bacterium mono - cytogenes Infection Arch, Patho 25:200, 1938 After Infection with B, monocytogenes a rapid mobilization of the pre-existing lymphocytes takes place. Intensified production in lymphatic nodules of the mesenteric lymph node and splenic periarterial tissue begins. The free stem cell from which the monocyte develops in diffuse lymphatic tissue, the mesenteric node and spleen, is morphologically identical with lymphocytes found in these tissues. 89 - 1 9 3 8 - 266, GERBER, I. E. and BERNHEIM, A. I. Morphologic study of the reactivity of mouse sarcoma l80 to bacterial filtrates Arch. Path. 26:971-983, 1938 In the mouse bearing growing tumor implants, the injection of meningococcus filtrate, capable of producing local reactivity, produced hemorrhage, engorgement and edema in tumor tissue within k- hours after administration. Cellular necrosis followed, but capillary rupture, thrombosis and other vascular changes were not seen. The amount of degeneration noted in tumor tissue appeared to be a function of the amount of filtrate injected. Large doses (100 rabbit-reacting units) brought complete slough- ing of malignant tissue with healing o With smaller dosages, the undestroyed residuum contained peripheral neoplastic cells, and regrowth was more commonly seen. Carcinoma was unaffected, and some hemorrhage and necrosis took place in tumors produced by dibenzanthracene, 267. GORO, M. Action of various substances on the secretion of gastric Juice Jap. J. Med. Scl. (IX) 5:3^1-342, 1938 The oral administration of a 10 per cent solution of either mono- or polysaccharide diminished gastric secretion in the dog. A weaker polysaccharide solution, averaging from 1 to 2 per cent, stimulated the secretory powers of the mucosa, 268, KOSTYAL, L. Wirkungswelse der Eiweisskorper (Foreign protein action) Ztschr, Immunltats. 92:3l8-335> 1938 The antitoxic action of the blood in diphtheria was Increased by intramuscular injections of omnadin, Pyrifer and milk, similarly administered, reduced such action. The activity is related to an alteration in colloid stability and of the globulin fractions, particularly pseudoglobulln I and 11. Euglobulin may enter into such activities. 269. PASCHKIS, K. and MARTOS, K. (The central nervous regulation of the blood) Arch, Int. pharmacodyn, 58:432-436, 1938 Phenobarbltal, administered before pyrifer, prevents the expected leukocytosis. If given before nucleic acid, phenobarbltal 90 -19 3 8- depresses leukocyte genesis and produces a leukopenia. Both pyrifer and nucleic acid stimulate leukocyte production. 270. RANSOM, S. W. JR. Fever Induced by the intravenous injection of typhoid -paratyphoid vaccine Arch. Int. Med. 61:285-296, 1938 The reaction of the normal cat to Intravenous typhoid -para- typhoid vaccine, is one of cyclic stimulation, first, heat con- servation, sympathetic stimulation and heat production and, secondly, a period of heat loss and parasympathetic stimula- tion. The cycle of these alternate reactions is repeated three times. The heat preservation mechanism predominates, and the end result appears to be sustained hyperthermia. Anaesthesia appears to affect either the mechanism of heat preservation and loss or a coordinating control of these phenomena; etherization of cats before vaccine injection re- sults in hypothermia and parasympathetic response to the bacterial material. In typhoid fever. Intravenous typhoid vaccine brings forward similar mechanisms. 271. ROBERTSON, R. C. and YU, H Leukopenia and the toxic substances of B. typhosus J. Hyg. 38:299, 1938 The intraperitoneal or intravenous Injection of toxic fil- trates from several strains of E. typhosa provoked, in the rabbit given sublethal doses, sharp leukopenia . The leuko- cytosis which followed persists two days. In vitro mixtures of the filtrate and blood produced no pronounced leukocyte changes. Histologic section? from lung, liver, spleen and bone marrow displayed an accumulation of neutrophils in these organs . The constant liberation of toxic substances in human typhoid fever is believed to be responsible for the leukopenic response, 91 - 1 9 3 8 - 272. SEVAG^ Mc G,^ LACKMAN^ D„ B., and SMOLENS, J. The Isolation of the components of streptococcal nucleo pro- teins in serologically active form Jo BlOo. Chemo 12^tk25-^36j, 1938 From hemolytic streptococci of Lancefleld group A^ new antigenic substances, designated labile antigens, were isolated. Both nucleic acid and protein have been liberated from the complex structure., through hydrolysis, chloroform extraction, and a foam -reducing agent c 273, WIEN, K. Glucose tolerance and lactate utilization during fever Quarto Jo Pharm, Pharmacol, 11; 34-45, I938 When fever was induced in rabbits through subcutaneous injections of a B, coli vaccine, oral glucose tolerance was lowered. Peak levels of blood sugar far exceeded those normally present. After glucose infusions, intially high levels appeared, but normal blood sugar values quickly re- turned. Lactate utilization was im.paired in such febrile states, and the ability of the liver to form glycogen after the administration of sodium dl-lactate was inhibited. Insulin injections did not increase glycogen reserves in the liver. - 1 9 3 9 - 27^. ANDERSON, C. G., HAWORTH, W. N., RAISTRICK, H. and STAGEY, M, Polysaccharide synthesized by microorganisms. IV. The molecular content of luteose Biochem. J. 33;272-279^ 1939 Luteose, a neutral polysaccharide remaining after removal of the malonic acid content of luteic acid, is composed of beta-glucose units linked through the 1,6-posltions. The molecular structure may be of the closed-chain type. Luteic acid fe a metabolic pro- duct of penicillin luteum (Zukal), 275. ANDERVONT, H, B, and SHIMKIN, M. Bo The effect of ascorbic acid upon the hemorrhage produced by bac- terial filtrate in transplanted tumors Am. J. Cancer 362 451-^59* 1939 Minute intraperitoneal injections of a bacterial filtrate of B. prodigiosus into tumor-bearing mice (Sarcoma #37) were followed by intracutaneous injections of neutralized or unneutralized ascorbic acid. Similar experiments tested the effects of ascor- bic acid and bacterial filtrate in combination against Sarcoma 180 and Lung Tumor F transplants. Ascorbic acid prevented the appearance of hemorrhage and regression of tumors after injection of the filtrate from Bo prodigiosus . Acidity was unrelated to hemorrhage prevention, but reducing power of ascorbic acid was apparently involved in the phenomenon » Hemorrhage Inhibition was directly proportional to the amounts of filtrate and ascorbic acid used. The route of administration appeared to be unimportant A theory is advanced that the bacterial filtrate may produce hemorrhage in tumor tissue through sudden lowering of tumor as- corbic acid content, thus weakening the capillaries and permitting hemorrhagic extravasation. 276. GO TUI, BENAGLIA, A. E., RUGGIERO, W„ F, and YATES, A. L. Study of the fever -producing principle in the typhoid vaccine Proc. Soc. Expero Biol. & Med. 41:272-275^ 1939 There is a close relationship between the fever-producing sub- stance found in vaccines from B. typhosus cultures and pyrogens isolated from contaminated waters" and Infusion solutions. Initial leukopenia, rise in temperature and chills are identical; either may produce transient gastrointestinal disturbances. 93 - 1 9 3 9 - 277. CO TUI and SCHRIFT, M, H„ Production of pyrogen In sera by bacteria Proc. Soc, Exper. Biol. & Med. 42:5^9-552, 1939 Normal horse serum was inoculated with cultures of Pr, vulgaris, B. coli . Staphylococcus aureus , B. su btilis and two unidentified organisms isolated from water. Following Incubation periods of varying duration, the culture fluids were filtered and injected intravenously in the dog, A pyrogenic symptom-complex which included fever, leucopenia, occasionally chills, and gastrointes- tinal disturbances, was noted, Pr, vulgaris, B. coli and Staphy - lococcus aureus filtrates produced severe reactions. Pyrexia was insufficient after B. subti lis injections, but leucopenia was present, "On the basis of these experiments it is suggested that the chill and fever-producing substances in sera may be pyrogens, caused either by direct bacterial growth, or by pyrogen already present in chemicals used in the purification and concentration of therapeutic sera." 278, no TUI, SCHRIPT, M. H, and RUGGIERO, W. F, Production of pyrogen in gum acacia by bacteria Proc. Soc. Exper. Biol, & Med. 41:533-535, 1939 Pyrogen-producing bacteria (B. subtili s, two unidentified water organisms and Staphylococcus "alFus ) grown In gum acacia solutions produce an "active" a"cacla capabre of eliciting febrile responses after injection. Leucopenia and other changes seen with reactive inulin and typhoid vaccine follow. 279^ DENNIS, Eo W. and SENEKJIAN, H. A leucocidal toxin extracted from typhoid bacilli Am. J. Hygiene 30:103-11, 1939 A crude extract of typhoid bacilli presents two active factors: a leukocidal factor with selective lethal effect on the pseudo- eosinophilic granulocytes and a toxic somatic antigen. The former loses activity on purification by trichloracetic acid, but the latter increases in potency during the same process. Leuko- cidin can be demonstrated in extracts of S. typhimurium, S, schottmuleri,^ S, sulpestifer (voldagsen strain), S. enterTtidis , S. gallin arum and S. paratyphi, listed in decreasing order of activity. - 1 9 3 9 - 280. GARDNER^ R. Ec, BAILEY, G. H. and HYDE^ R, R. Hemorrhagic activity of toxic carbohydrate complexes from bac- teria on a transplantable rat tumor Am. Jo Hygiene 29Bsl-1^5 1939 The theory has been presented that generalized vascular shock following injection of bacterial filtrates or specific substances initiates tumor hemorrhagic processes o Such materials were injected into rats bearing transplanted Walker tumor No, 256, all cutaneous^ and approximately 10 days old. Controls were used for comparison.. Non-bacterial carbohydrates and a yeast were also injected o The yeast carbohydrate produced acute systemic reactions and a hemorrhage in tumors which differed from that occurring after use of bacterial filtrates o A polysaccharide-free component of the soluble specific substance from So enteritides also had activity and produced a severe reaction. Most marked results were obtained with fractions isolated from the cultures of enteric organisms, particularly those endogenous in the rat. However, other bacteria, including Ko pneumoniae , had distinct activity, 281. HARKAVY, J, and ROMANOFF. A« Local hemorrhagic -necrotic skin reactions in man (Shwartzman phenomenon) Jo Allergy 10;566y 1939 A comparison is made between mechanisms of the Shwartzman and Arthus phenomena, and three case histories are presented for illustration. Each presented skin lesions fulfilling all criteria for Shwartzman reactions. The provocative factor which precipi- tated lesions may be either a parenterally introduced antigen from a bacterium or a product derived by an interaction between an injected foreign protein and a preformed homologous antibody. 282. IVANOVICS^ Go Chemische Untersuchungen liber de Polysaccharide des Milzbrand- bacillus (Chemical studies in the polysaccharides of the anthrax bacillus) Zentr, Bakto parasitenk, I, Abt„ l4ifj 2^4-246, 1939 The water soluble precipitate produced after concentration and purification of a culture of avirulent anthrax bacilli contained 95 - 1 9 3 9 - 0.6^ nitrogen and 60^ reducing substances. 83, IVANOVICS, G. Das Schlcksal der Kapselsubstanz der Mllzbrandbaclllen im Organlsmus (Fate of the anthrax bacillus capsular substance In the organism) Ztschro f. Immunltatsforschung, u. Exp, Therap. 96:4o8-4l2, 1939 34. IVY, A. C. and GRAY, J. S. The application of recent contributions in basic medical sciences to surgical practice. Reactions to intravenous therapy Inter, Abstr, Surg. 69:4l4-4l6, 1939 A brief review of major milestones in the literature of pyrogens since I9II. 285. MASUCCI, P. Antigenic polysaccharide complex from cocci U. S. Patent #2,166,963, July 25, 1939 A method of extracting and precipitating antigenic polysaccharides from cocci. 586, MIELNIK-KOSMIDERSKI, S. fiber Der Elnflussung der Phagozytose durch die Bakterienkapsel und Bakterlelle Polysaccharide (Influence of phagocytosis of bacterial capsule and bacterial polysaccharide) Ztschr. f . Immunitatsforshung, u. Exp. Therap. 95:203-217, 1939 Free or somatic polysaccharide from the capsule of scleroma bac- teria enhances phagocytosis of uncapsulated bacteria to a degree limited by the number of bacteria and of leukocytes. Very small amounts of polysaccharides decrease phagocytosis below normal levels. The amount of polysaccharide released around bacteria by antibody may increase (or decrease) phagocytosis. 287, MORGAN, H. R, and BECKWITH, T. D. Immunological relationships of polysaccharides of mucoid organisms of typhoid -salmonella groups 96 - 1 9 3 9 - J. Bacto 372 389-399* 1939 Protein-free polysaccharide extracts from Eo typhosa . So para - typhi 5 A^ Bo and C, So enterltldes , aertrycke , sulpeFFlfer or So pulloruiD f gave rise to precipitins for polysaccharides and agglutinins for the organisms after testing with antisera produced in the rabhito Both immunized and non-immune animals were inoculated Intracutaneously with the polysaccharide, and sterile abscesses were produced in both, 288. NELSON, CM. The cause of chills following intravenous therapy aj JoA.M.A. 11221303-1306, 1939 Extremes in temperature of solutions Intended for venoclysls, the amount of solution,, rate of administration, concentra- tions, preparation of glass and tubing of equipment and pH were all eliminated as factors in producing rigors after Intravenous administration o Contamination of distilled water^ when Immediate autoclaving is neglected; was the primary cause of reactions o Aging alone in properly autoclaved so- lutions does not produce reactive solutions » 289. flANSON, S. Wo, JRo, CLARK, Go and MAGOUN, H, Wo The effect of hypothalmic lesions on fever induced by intravenc injection of typhoid -paratyphoid vaccine Jo Lab, & Cllno Med o 25;l60-l68, I939 Injection of typhoid -paratyphoid vaccine in the cat stimulates both the mechanisms for heat conservation and those govern- ing heat loss. The stimulation of the sympathetic system was expressed by febrile reactions in the normal cat; with chronic lesions of the hypothalamus prolonged temperature reduction^ enduring as long as twenty hours, followed the Injection of typhoid vaccine and this was accompanied by other signs of para sympathetic overaetlvityCdefecation, urination and sallvatlori). The portion of the heat loss mechanism which is stimulated by pyrogen lies caudal to the hypothalamus, 290, SMITH, Eo V. The effects of injections of toxic extracts of the typhoid bacillus on the blood picture in rabbits Am. Jo Hygiene 29215-23^ 1939 97 - 1 9 3 9 - Extracts from the cappola strain of the typhoid bacillus were injected intravenously in the rabbit in dosages ranging from sublethal to highly toxic amounts. Single and repeated in- jections were administered; the extract was also prepared with fresh normal, inactivated normal and immune serums. The severe systemic reactions, extreme leucopenia and tendency toward pro- longed coagulation time were observed after typhoid extract administration. The systemic reactions were dependent upon the dose and independent of the dose for blood changes. The systemic effects appear to become less intense after repeated injection; no complete immunity could be demonstrated, and the changes in blood cellular components were not effected. Mixtures of ' serum and toxic typhoid extract produced symptoms characteristic of small sublethal doses of the extract when given alone. 291. SMITH, H. W. Physiology of the renal circulation The Harvey Lecture Series 35:200-203, 1939-19^0 In a review of known facts on renal circulation, it is stated that the only known method of inducing renal hyperemia is by the use of pyrogens "either as present in typhoid vaccine or in pyro- genic inulin," Hyperemia is manifest at the time of the chill phase and continues for several hours. The relative increase depends upon the control level and is ".,,in general.,, from 36 to 60 per cent above the control levels''. Antipyretics have little influence. The dilatation is centered in the efferent arteriole; the filtration fraction is decreased, but the rate of filtration is essentially unchanged. 292. TERRY, G. G, Fever and Psychose s New York: Paul B. Hoeber, Inc., 1939 Biologically induced fever (through the use of organic, bacterial and "foreign" agents) produces some evidence of improvement in manic-depressive states, but only a few benefits in schizo- phrenics. It has been stated that Coley's fluid has therapeutic usefulness in the manic-depressive states, 293. WALKER, E. L. and HANDMAN, M. S. Biological reactions of malignant neoplasms. I. The reaction to bacterial fractions 98 - 1 9 3 9 - J. Immunol. 375 507-524, 1939 After a brief review of the use of bacterial products In the therapy of malignant neoplasms and of methods for their prepara- tion, details of a comprehensive study of the fractions obtained from Salmonella typhimurium a re appended. Crude fractions, nucleoproteins, nucleic acid and p61ysaccharldes were tested ^s preparatory or provocative agents incthe Shwartz- raan reaction; all were found suitable for either role. Several strains of transplanted sarcoma or carcinoma were allowed to multiply for 10 to 21 days in the rat; intra-abdominal injections of the bacterial fractions were then administered in 1 to 6 doses at the tolerated levels. There were intervals between doses which ranged from 3 to 7 days. Tumor hemorrhage, necrosis and regression were seen in Sarcoma l8o on injection of taucleoprotelna polysaccharides or fractions containing one or both of these constituents. In a maximum percentage of rats sublethal doses of these active fractions produced total regression. Pew car- cioma strains underwent complete regression without recurrence. The authors do not find a single special bacterial substance responsible i'or activity in the Shwartzroan phenomenon and against malignant neoplasms, but find that the ordinary proteins and carbohydrates of the bacterial cell carry the hemorrhagic -ne- crotic functions. I 99 -19^0- 294. ANDERVONT^ H. Bo Effect of colchicine and bacterial products on transplantable and spontaneous tumors in mice J. Nat, Cancer Inst.^ 1^361-6^ 1940 This study was undertaken to compare the effects of bacterial products and colchicine in inducing tumor hemorrhage and affecting tumor growth. Young mice bearing either Sarcoma 37 or Carcinoma P as transplantable tumors or mammary carcinoma as a spontaneous tumor, were given colchicine solutions or B. coll filtrate, in varying dosages, intraperitoneally. The effective dose which elicited tumor -hemorrhage without killing the animals was determined by injection of single doses at various levels of potency. Injections of colchicine in varying doses were repeated at differing time intervals. In order to determine whether or not colchicine and filtrate have a supplementary effect on each other, separate injections were made of each substance at practically the same time. The effective dose of colchicine, 0.1 mg. was close to the lethal dose and was no more effective than bacterial filtrate which has a much wider range of potency. Repeated injections of colchicine In doses too small to elicit tumor hemorrhage had no Influence on tumor growth; while injections of hemorrhage-producing doses were toxic to the majority of animals. Both substances were supplemen- tary to each other In eliciting hemorrhage In transplanted tumors, but their combined action was no more effective than either alone In treatment of spontaneous tumors. Tumor P, after the 17th serial passage, became susceptible to hemorrhage Induction by bacterial filtrate. 5. ASHENBURG, N. J., SANDHOLZER, L, A,, SCHERP, H, W. and BERRY, 3. P. The influence of bacterial and nonbacterial polysaccharide upon bacterlophagy J. Bact., 39s71-72, 194o In an investigation of the effect of capsular polysaccharide (from Aerobacter) upon the activity of a bacteriophage to which strains of Aerobacter are susceptible, inhibition of lysis was noted. Non-bacterial polysaccharide (starch glycogen and gum arable), and polysaccharide from a bacteriophage-resistant strain inhibited lysis to an equivalent degree. "The results did not support the hypothesis that susceptibility to bacterlophagy depends upon immunological specificity," 100 - 1 9 4 - 296. BEESON^ Po Bo and HOAGLAND, C„ Lo The use of calcium chloride in the treatment of chills N. Yo State J. Med. 40r803-804^ 1940 Intravenous administration of calcium chloride in humans aborts the chills due to malaria, blood transfusions, and typhoid vaccine. Relief of the typhoid chill appeared to have no effect on the sub- sequent elevation of the body temperature. 297. CAMERON, G». R., DELAPIELD, M. E. -and WIISOII, J. Pathological changes produced in rats and mice by a toxic fraction derived from Bacterium typhimuriuffl ■ J. Pathc Bacto 51s 223-233^ 19^+0 . A non-dialyzable protein-polysaccharide fraction from B. typhi - . murium ' was injected intrapei^itoneally, in doses ranging from O.O5-I0O mgc into 95 mice and 54 albino rats. The animals were sacrifleed at | hour to 6 days following injection, and various tissues were stained for microscopic study. Forty mice were injected with living B. typh imurium and their livers examined microscopically at in¥ervaTs^ varying from 1922 days following the initial injection. Blood sugar and hepatic glycogen content were also determined in animals injected . with the bacterial fraction. . A profound disturbance of the carbohydrate metabolism was shown by the histological and chemical results. The liver showed marked portal congestion associated with hemorrhage, thrombosis, and ., necrosis; the spleen and lymph glands exhibited necrosis of Malpighian bodies and lymphoid follicles. Infection of the animals with living B. typhimurium produced similar resiilts of more severe degree. ■■ Liver glycogen in rats and mice, and blood sugar in mice were rapidly <3ecreased in amount following initial injection. Carbo- hydrate disturbances are primarily of hepatic origin. 298. CENTANNI, E. Weitere Beitrage zur Kenntnis des pyrogenen Wlrkstoffs des _/>.\-; ; Fiebers (Further studies toward knowledge of active pyrogenic > materials of fever) I Deutsch. med. Wchnschr. (Anal. Series) 10; 263-265, 1940 The chemical character of the pyrogenic active material formed in the decomposition of bacteria was studied. It is reported that 101 -19^0- the pyrogen Is not a polypeptide or an organic base. It is in- soluble in fat solvents and not reduced by common hydrolytic enzymes. Stability during autoclaving or treatment with strong acids has been confirmed = It is divisable by specific precipi- tants and adsorption agents, but is non-dialyzable, 299. DE RENZI, S. and GRASSELINI^ A, Blood sugar in provoked hyperthermia (Translated Title) Bollo soc. ital. biol, sper, 13; 802-803;, 19^0 Hyperthermia induced by injection of killed bacteria increased the blood sugar in both normal and diabetic individuals. Glucose or galactose administered during fever brought blood sugar to peak levels. During hyperthermia^ adrenalin and insulin produced only insignificant changes in blood sugar o 300. EHELSON, L, M. The inability of desoxycorticosterone acetate to protect the adrenalectomized rat against typhoid vaccine. Endocrinology, 27:340, 19^0 Since adrenalectomized animals are protected against typVioid vaccine by cortioo-adrenal extracts, it was of interest to note whether synthetic cortlcoids were equally efficacious, Wistar rats vjere' adrenalectomized, and on the day after operation were given corticosteroids; 20 rats were given 2 mg. of desoxycorti- costerone acetate daily; 20 rats were given 2 cc of adrenal cortex extract daily; ^■ rats v/ere given 4 mg<, of the syrithetic daily. After 5-10 days of such treatment, typhoid vaccine was given Intraperitoneally in doses varying from 0.5 to 0.8 cce Treatment with adrenal substance was continued in those animals that survived an observation period of 3 weeks, A few of the anim.als in each group were given second vaccine injections 24 to 48 hours after the first. The synthetic product is unable to protect the adrenalectomized rat against typhoid vaccine, while the natural substance increases the resistance of such animals. 301. PREEIvIAN, G, G., CHALLINOR, So W. and WILSON, J, The use of a synthetic medium in the isolation of the somatic antigens of Bact . typhimurium and Ba c t . typhosum. Biochera. J, 34:307-324, 1940 -19^0- Antigenlc fractions from B» typhlmurlum and Bo typhosum have been prepared by 3 methods j {sT"^ development of the tryptlc digestion method of Raistrlck and Topley, (b) Bolvin's method of extraction with cold trichloracetic acid, and (c) extraction with organic solvents such as ethyleneglycol and diethyleneglycol Morgan f 1937") and the products have been compared by chemical analysis and determination of toxicity in mice. The purest pro- ducts obtained by these methods show a similarity of properties. It may be concluded that, by any of these methods, the essential antigenic complex of the bacteria may be obtained in a state approaching chemical homogeneity o On the grounds of yield and suitability for use in extracting large quantities of bacterial bodies, the tryptlc digestion method and Bolvin's method are to be recommended. 302, GRAY, J. S.J, CULMER, C. U., WIECZOROWSKI, E. and ADKISON, J. L;' Preparation of pyrogen-free urogastrone Proco Soco Exper. Biol, and Med. 43:225-228, 19^0 Extracts of normal human male urine were prepared by 3 methods: the benzoic acid adsorption procedure of Katzman and Dolsy; further purification procedures Involving neutral acetone fraction- ation. Assay of the gastric inhibitory factor was performed in 6 Heldenhaln pouch dogs in,jected subcutaneously with histamine; rectal temperatures and percentage inhibition of free acid secre- tion were recorded after injection of the extract. Pyrogen assays were also made by recording rectal temperature curves for a group of 5 rabbits. The pyrogenlc effect of the extracts was progressively lost with the use of the more purified materials, though gastric inhibition was not materially affected. Utilizing the acid acetone fraction- ation procedure, the gastric inhibitory factor was obtained free from pyrogen. "The results indicate quite clearly that the gastric inhibitory factor is separate and distinct from the pyrogenlc factor in extracts of normal male urine. Until such time as the gastric Inhibitory factor is definitely identified, we propose to call it urogastrone." 303. GRAY, J. S., WIECZOROWSKI, E., CULMER, C. U. and ADKISON, J. L. The presence of pyrogen in urine and its separation from urogastrone, Amer. J. Physiol., 1292589-596, 19^0 103 _ 1 9 4 - This study was undertaken to determine whether the gastric in- hibition produced by urine extracts was due to pyrogenic sub- stances. Six Heidenhain pouch dogs were used for assay of the gastric inhibitory factor under controlled conditions; the potency of the injected material was measured by percentage decrease in mgm, of free acid secreted. Pyrogen was assayed by rise in rectal temperature of the pouch dogs and in rabbits. Crude urine extracts were prepared by several modifications of the benzoic acid adsorption method of Katzman and Doisy (methods given) . Purification of the crude extracts was accomplished through fractionation with acetone. It was found that the major portion of the pyrogen in the crude extracts originated in bacterial contamination; measures which minimize bacterial growth permit preparation of crude extracts containing no more pyrogen than equivalent amounts of fresh urine o Fresh, untreated urine from healthy human subjects xvas found to contain small and variable amounts of pyrogenic substance » Purifi- cation of crude extracts relatively free of pyrogen consistently yielded products exhibiting high urogastrone and little or no pyrogenio potency c It was concluded that urogastrone is not pyrogen. In disease the quantity of pyrogen in the urine is increased. 304. LEES, J. C. and LEWY, G. A. Emergency preparation of pyrogen-free water Brit. Med. J., 1;430, 19^0 A method is described for removing pyrogens from contaminated water, thus rendering it suitable for intravenous use. The method consists of shaking the water with powdered charcoal (1 part per 1,000) for fifteen m.inutes, then allowing to stand for several minutes after vjhich the charcoal is readily removed by decanting through a filter paper. 305. MORGAN, H, R. Preparation of antigenic material inducing leucopenia from Eber - thella typhosa cultured in a synthetic medium Proc. Soc, Exp, Biol. Med. 43:529-532, 1940 Small amounts of antigenic substance isolated from cultures of E. typhosa induce fever and leukopenia in the rabbit while larger amounts are lethal to both mice and rabbits. Leukopen.ia was the result of the disappearance of neutrophils from the blood. The toxic properties of the antigen remain after 30 minutes boiling. 104 - 1 9 4 - 306. MOROAN, W. T. J. and PARTRIDGE, S. M. Studies In iininunochemlstry - the fractionation and nattire of antigenic material isolated from Bacto dysenteriae (Shiga) Biochem. J. 34sl69-19l5 19^0 A polysaccharide, a phosphollpin and a polypeptide -like component were isolated from the antigenic complex of "smooth" (Shiga) B. dysenteriae « Dissociation of the complex is described and a hypothetical structure suggested. 307. NISI, NAOTO Physiology and pathology of the hypophysis temperature-regulatory function J. Chosen Med. A. 30;1-21, 19^0 In rabbits, completely hypophysectomized or with only the anterior lobe removed, central pyrogenlc stimulants do not act, but peri- pheral stimulants like tet-rahydro-beta-naphthylamine or adrena- line are effective, although the response gradually decreases. The abnormal responses return to normal if the anterior lobe is Implanted or its extract 5.n jected . 308. OMITI, M. The influence of artificial fever on the nonspecificity in the syphilis reaction. IIIo Experiment with pjrrifer. Mittc med, geSo Okayaraa 52:2413-2432, 19^0 (English version) A comprehensive study of the effects of pyrlfer on the globulin- albumin alterations in serum, 309. PALMER, J. W. and GERLOUGH, T, D, A simple method for preparing antigenic substances from the typhoid bacillus Science 92s 155-156, 19^0 The capsular polysaccharides of pneumococci may be separated from their associated proteins by extracting the latter with phenol. In which polysaccharides are Insoluble. Fractional precipita- tion of polysaccharides by alcohol or glacial acetic acid may follow. After drying with acetone, a white powder is obtained (substance A)o Phenol extraction may likewise be used for the product obtained by tryptlc digestion; the product (substance B) resembles substance A in both appearance and antigenic properties. 105 -19^0- Both substances, obtained In yields of 10 to 15 per cent of the weight of dried typhoid organismsj give negative or faint biuret reactions and a strong Molisch reaction o Nitrogen content, corrected for ash and moisture, is from 3.^ to 4.6 per cent. Hexosamine, if present, accounts for less than 10 per cent of total N. Both substances give stroiig precipitin reactions with antityphoid rabbit serum, PARTRIDGE,' S. M. and MORGAN, W. T. J. Immunization experiments with artificial complexes formed from substances isolated from the antigen of Bact . shigae Brit. J. Exp. Path, 21:l80-195> 19^0 A specific polysaccharide component of the antigen of B, shigae failed to induce iiftmune bodies in the rabbit. The polypeptide component of the same complex produced low titer homologous precipitins but no agglutinins, A synthetic 'complex' built from these components in combination induced the formation of potent immune bodies, agglutinated B. shigae at high titer and precipi- tated with the specific polysaccharide. The complex fixed comple- ment when Shiga antibacterial sera was added „ SHAPIRO, C. J. The effect of toxic carbohydrate complex from S. enterltides on transplantable rat tumors in tissue culture Am. J. Hygiene, 31:SeG, B. 114-26, 19^0 Tissue cultures of rat sarcoma #10 or Walker carcinoma #256 were maintained in vivo in healthy rats as intradermal, subcutaneous or intramuscular growths. On plasma growth medium they were ex- posed to a toxic carbohydrate complex derived from S. enterltides , capable of causing tumor hemorrhage and necrosis in doses as small as 0.0005 mg. Control tissue tumor cultures were maintaine'd in the growth medium and saline. Doses of 2000 to 50OO provocative units of polysaccharide were used in all in vivo experiments. No effects were noted in vitro . It is believed that the plasma of a tumor-bearing host does not interact with the hemorrhage -pro- ducing agent to form a substance toxic to either young or sensi- tive cells of these neoplastic growths, SHEAR, M. J. and TURNER, F. C. Studies on the chemical treatment of tumors. V. Separation of the hemorrhage-producing fraction from. Bacillus prodlgiosus filtrates -19^0- J. Biol. Chetn„, 133:Lxxxvil, 19^0 (Abstract) Methods which had been used to separate hemorrhage -producing fractions from Bo coli were applied to broth cultures of B. prodiglosus . An untreated broth culture filtrate contained 330 mouse tumor units per cc of active principle. In a commercial sample of Coley's mixed toxins, 100 units per cc, were present. Further treatment of the above filtrate gave a concentration which contained 20,000 mouse units per cc. In studying growth on simple synthetic media, it was noted that filtrates had the same potent quality as those from broth cultures. On treatment with CHCI3, an emulsion was obtained which possessed most of the activity of the filtrate, A water-soluble precipitate remained after CHCI3 was removed and C2H5OH employed, A solution of this concentrate had a potency of 133*000 mouse units per cc „ and contained 0.2 gamma per mouse tumor unit. Lethal dosages of these concentrates ranged from 100 to 1000 times the minimum effective dose. The active principle was nondialyzable through cellophane and was heat-stable. Large scale preparation techniques are given in detail, SUTHERLAND, A, M, and WOLPP, H, G„ Experimental studies on headache; Further analysis of mechanism of headache in migraine, hypertension and fever Arch, Neurol, and Psychiat, 44^929-949, 1940 In twelve patients with chorea or rheumatoid arthritis, fever therapy was induced by intravenous typhoid vaccine, A tambour was placed on the temporal artery and the pulsations recorded. Photographic records of the pulsations of the cerebrospinal fluid were made from a needle introduced into the lumbar sac and connected to a Prank capsule. Control records of temporal artery and cerebrospinal fluid pulsations were made simultaneously. Then an appropriate dose of typhoid vaccine was given intravenously; and estimates of the degree of headache, determinations of blood pressure, and pulsations of temporal artery and cerebrospinal fluid were made at frequent intervals. Increased amplitude of pulsations of temporal artery and cerebro- spinal fluid in all instances was found to be followed by onset of headache or sensation of head fullness. Exacerbations and re- missions of the headache were found to closely parallel the in- crease or decrease in amplitude of pulsations. The headache ended with the ultimate decrease in amplitude. These findings are similar to those seen in histamine headache. Increasing the intracranial pressure decreased the intensity of the headache. 107 -19^0- 314. WALTER, C. W. The relation of proper preparation of solutions for intravenous therapy to febrile reactions Ann. Surg. 112:603-625, 1940 While the bacterial pyrogens of water, apparatus and rubber tub- ing are believed to be the principal causes of febrile reactions during intravenous therapy, in dextrose solution the dehydration products should also be eliminated if possible. Such products of molecular interaction include hydroxymethylf urf ural and levulinic acid. The alkaline film following sterilization of soft glass may cause some polymerization of dextrose during sterilization. The intravenous kit itself should be carefully sterilized if re-use contemplated . 108 -19^1 315. ABERNATHY, T. J. and AVERY, Oo T. The occurrence during acute Infections of a protein not normally present in the blood. I, Distribution of the reactive protein in patients' sera, and the effect of calcium on flocculation reaction with C polysaccharide of Pneumococcus J. Exper. Med. 73; 173-182, 1941 Sera obtained from both humans and monkeys during acute in- fections contained a protein which was precipitated by the C polysaccharide of pneumococci. C-precipitable substance was Inactivated by exposure to temperatures above 63^ C, or the range of temperatures in which protein is denatured. After ammonium sulfate separation, the reactive material was found in the albumin fraction. Decalcification by additions of potassium oxalate and sodium citrate inhibited precipitation from reactive serum; the inactivation is reversible through the addition of minute amounts of Ca, The reactive protein is non-specific with respect to the inciting cause of the infection, 316. DELATMAY, A., LEHOULT, Y., and SARCIRON, R. Recherches sur le chlmiotactlsme leueocytaire,pouvoir chimi- tactique des antigenes glucido-lipidiques (Investigations on the chemotaxis of leukocytes. The chemotactic power of glucido- lipoid antigens) Compt. rend. Soc. blol. 13521529-3532, 19^1 Autolyzed typhoid bacilli, in suspensions diluted from 1:10 to 1:1000, were injected in the guinea pig. Each of the 4 doses given contained 0.5 cc. of the diluted suspension. Microscopic examination of the injected tissue showed an Invasion of neutro- phils disseminated in the hypodermls. When the glucido- lipoid antigen of the typhoid bacillus was injected alone, it consistently produced the leukocyte migration, and antigens of a number of other bacteria (E. coll , the Flexner , para - t yphoid B. and Slajte a organisms) have identical activity. Maxima for leukocyre migration lie between 1:100 and 1:1000 dilutions and stronger doses have lower chemotactic power. The importance of the colloid structure in immunology is emphasized . %■ 109 -19^1- 317. ELLIS, E. L. and SPIZIZEN, J, The rate of bacteriophage inactivation by filtrates of Escherichia coll cultures J= Gen, Physiol. 24:^37-445, 19^1 The antl- coll phage Is inactivated by culture filtrates of B, coll in a pattern influenced by the temperature at which the reaction occ-urs. The rate of inactivation at 37*^ Co is proportional to phage concentration and filtrate con- centration; at 0° C, the rate is proportional to the square root of the concentration of the filtrate c Coll -phage is in- activated by other colloids (starchy inulin, gum arable); the inactivation is delayed by either very high or very low salt concentrations , 318. PELDMAN^ J. and GELLHORN^ E. The influence of fever on the vago -insulin and sympathetico- adrenal systems Endocrinol, 29il41-l43, 1941 Typhoid -paratyphoid vaccine was injected Intraperitoneally (0,7 cc , per kg,) into the normal rat and into adreno-demedul- lated or vagotomlzed animals. One group received vaccine after extirpation in toto of adrenals^ and medulla, and sectioning of the vagus nerves. The vaccine produced hyperglycemia in the normal animal, hypoglycemia in the adreno-demedullated animals but no alterations in blood sugar after vagus section in adreno- demedullated rats, Hjrperthermia appeared in the normal and vagotomlzed rat; removal of adrenals and medulla produced hypothermic reactions. In the vagotomlzed animal^ both hyper- thermia and high blood sugar levels persisted much longer than in the normal animal. The excitation of autonomic centers may affect discharge over the vago-insulin system as well as in the sympathetico-adrenal network, 319. FREEMAN, G, G, and ANDERSON, T, H, The hydrolytic degradation of the antigenic complex of Bact . typhosum Ty 2 Biochera, J, 35:564-577, 1941 Dissociation by slow hydrolysis of the antigen of B. typhosa Ty 2 yielded the following components: a polysaccharide, consti- tuting 50 to 60 per cent of the total; an insoluble polypeptide 110 -19^1- fractlon (l6 per cent), a soluble nitrogenous material (from 10 to 20 per cent) and a small amount of lipid » The poly- saccharide was highly dextro-rotatory, ketose and pentose- free, but contained d -galactose, d-mannose and d -glucose. There were no uronlc acid residues. Identical polysaccharides have been prepared from the dried organisms directly. The polypeptide component was insoluble in water, soluble in dilute alkalis, and contained 8o2 per cent N, partly as tyro- sine and arglnine units o Approximately 50 per cent of the total nitrogen appeared as free amino -groups after acid hydrol- ysis. The nature of the soluble nitrogenous component was not determined. 320. GOLDRING, W., CHASIS, H. ^RANGES, H. A., and SMITH, H. W. Effective renal blood flow in subjects with essential hyperten- sion J. Clin, Invest o 20:637-653, 19^1 Filtration rates, diodrast clearance, and maximal rate of tubu- lar excretion of diodrast were determined in 6o patients with essential hypertension. The results were compared with those obtained from a previous study of the normal kidney. The effective blood flow per unit of functional renal tubular tissue was usually below normal, the filtration fraction elevated, and the maximal rate of diodrast excretion far below normal. Small doses of pyrogenic Inulin resulted in renal hyperemia and a fall in the filtration fraction. In some patients, the maximal rate of diodrast excretion in the tubule increased during hyperemia. 321. HARTWELL, J. Lo, SHEAR, M. J,, KAHLER, H. and TURNER, P. C. Properties of the fraction of B. prodigiosus which produced hemorrhage in mouse sarcomas Cancer Res. l:74l, 1941 A summary is given of the methods now used to determine the properties of the hemorrhage -producing filtrate concentrate of Shear. Protein content was below 1 per cent; the biuret, ninhydrln, xanthoproteic and Millon's tests were negative. High molecular weight components were present as shown by dia- lysis of the filtrate. The Molisch reaction was positive, while iodine-iodide and Benedict tests gave negative results. Freezing of active solutions destroyed most of the potency. All fractions appeared to be equally toxic to tumor tissue when a bioassay was made on mice bearing growing sarcomas. Two active fractions were obtained by ultra-centrif ugation and electrophoresis . Ill -19^1- 322. MACLEOD, C. M, and AVERY, Oc T. The occurrence during acute Infections of protein not normally present in the blood „ II, Isolation and properties of the reactive protein J, Exper. Med. 73:183-190, 19^1 The reactive protein present In the serum albumin fraction of blood and precipltable by the C polysaccharide of pneumococci^ becomes soluble in tap-water after removal of the alcohol- ether soluble lipids and is no longer precipltable by calcium in small amounts c It still retains capacity for precipitation with the C polysaccharide « 323. MORGAN, Ho R. Immunologic properties of an antigenic material Isolated from Eberthella typhosa J, Immunol e ^I:l6l-l80, 19^1 The py-rexlal substance from E„ typhosa is antigenic and elicits fever In the animal when circulating antibodies are present. Washed precipitates of antigen and excess antibody cause ele- vations in temperature and leucopenla. Leukocytosis follows. The factor is heat-stable c Activity remains in the acid- insoluble portion after acid hydrolysis. 324. MORGAN, W. To J, and PARTRIDGE, S. M. S todies in Immunochemistry, VI. The use of phenol and of alkali in the degradation of antigenic material isolated from Bact . dysenterlae ( Shiga ) Blochem. J. 35:ll40-ll63, 19^1 The antigenic complex of B, dysenterlae Shiga Is soluble in 90 per cent phenol solution^, partially soluble In aqueous alkaline solution. The 'smooth' variant yields the antigenic complex and nonspecific water-insoluble simple proteins, the 'rough' variant yields no antigenic material. Polysaccharide compo- nents can be isolated in a free state by dialysis of the phenol solution o This protein-free carbohydrate fails to Induce formation of specific 'Shiga' agglutinins or precipitins in the rabbit. The acidic (polypeptide-llke) protein component appears to be a conjugated protein, non-antlgenic when separated from the polysaccharide, but, on recombination with undegraded specific , polysaccharide, a powerful antigen. A simple protein isolated 112 -19^1- , by phenol or alkaline dissociation was a higher N content - and an optical rotation which differs from the conjugated protein o It does not form an antigenic complex when mixed with 'Shiga' polysaccharide in aqueous solution. 325. NISHISHITA, So Studies on the fluctuation of the lipoid content of the blood in the fever period Japc Jo Expero Med o 19:97-107, 19^1 In normal rabbits, the total lipids are reduced after induced fever o The drop may be as much as 30 per cent below normal levels o After 24 hours, normal levels reappear. Cholesterol is markedly affected. In infectious disease, blood lipids may be slightly lower during the febrile phase and rise above normal during convalescence. The cholesterol content varies over a wide range. In starvation, blood lipids increase in the early phases, fall slightly below normal in ten days; when fever accompanies starvation, cholesterol rises with lecithin and fatty acids, A rise of cholesterol of 155 per cent above normal was seen on the 6th day of fever and starvation. 326. OLITZKI5 L^, AVINERI-SHAPIRO, S, and BENDERSKY, I, The leucopenic action of different micro-organisms and the antileucopenic immunity J, Immunol, 4l;36l, 19^1 Heat-killed bacterial suspensions of various strains of Cocca - ceae , Bacteriaceae , Baclllaceae and the mycobacteria were injected into the guinea pig or rabbit to determine the effect of different antigens and of varying amounts of each, the development of antileukopenic immunity of both passive and active character, and its species or strain specificity. The leukopenic factor was present in certain groups of organisms only and qualitative differences due to their chemical compo- sition were noted. Within the same species of any one group, quantitative variations for leukopenic activity could be found. Bacterial vaccines or normal rabbit sera produced a nonspecific antileukopenic resistance lasting from 2 to 3 days, Anti-leukopenic immunity could be invoked by those bacteria which contain a common heat-resistant antigen, but passive immunity against leukopenia was conferred with difficulty. -- •' «-*»«-.*- 113 -1^41- 327« PASrtlCHA, C, Lo, MALIK, K, 3, flttd PAUL, Bo M, '^^Pyrogen' foimd In salines for Intravenous use Indian Med. Gaz, T6j216-218, 1941 The soluble, heat -stable pyrogens which develop in pai»ent©»al solutions through bacterial protein splitting are not easily detected by permanganate titer. Only extreme eare in pro- duction will prevent their appearance* but adsorption on char- coal will ustuaXly remove all traces. 328. SAHDERS, T, ««, Non-speciTio piMsein therapy In ocular disease J. Iowa Medo Soc, 31j51-54, 19^1 Use of foreign protein therapy materially shortens the course of noiny ocular infections and reduces permanent damage. It is particularly effective in the treatment of ocular trauma. Foreign protein therapy has been used, with more or less suc- cess, in typhoid feveiP, pneumonia, puerperal fever, arthritis, pelvic Inflammation, syphilis of the central nervous system, other nervous disorders, multiple sclerosis, peptic ulcer, dermatolog^Q eonditicms^ and in thxH>mbo -angiitis obliterans. 329. &AKDWEXSS^ D» J«, SUGARMAK, M. H., PRl^DMAlf, M. H. P., 3AL7Z- STEIN, H. C* and FARBMAN, A* A. The effect of «rlne extracts on peptic ulcer. An experimental and clinical study i Am. Jo Dlges. Dlse 8g3Tl-382, 19^1 Pregnancy turine and normal female urine appar^tly contain'' a principle capable of exercising a beneficial effect on peptic ulcer, as determined by the prolongation of life; spans of dogs with experimental ulcerf, bylv the fibroblastic proliferation and eplthelizatlon of ulcer craters. The action by which healing is initiated appears to be concerned with suppression of se- cretion, but healing appears through stimulation of fibroblastic and epithelial cells and formation of blood vessels, as well. When 14 patients with duodenal ulcer were given large doses {30 to 40 mg«| oi normal female urine extract, Subcutaneously or intramuscularly ft ftl1?e? injection of stimulating amounts of hlBtamine^ total volame, but fjot acidity, of gitstpic secretion decreased iter ©IsPonic peptic ulcer, a high peT*centage of re- miaslojss ai%d total improvement was obtained. Relapses within 6 raonthe w#^ less fs^uently seen than with other medicaments* 114 -19 4 1- 330. SHEAR, M. J« Effect of a concentrate from B. prod igio sua filtrate on subcu- taneous primary Induced mouse tumors Cancer Res. 1:731# 19^1 A nitrogen -containing polysaccharide, obtained as a concen- trate from broth cultures of B, orodliziosua . was injected In mice bearing primary chemically-induced tumors. Doses more than 500 times the minimum hemorrhage -producing dose -wtr* lethal for most of the tumor-bearing straing^but normal mice tolera- ted even larger doses » Severe hemorrhage was produced in a few hours in the primary spindle cell sarcoma, but regrowth was commonly seen. Mice with larger tumors usually succumbed to a given dose while those with small tumors survived. Repeated injections of gradually-increased small doses of the poly- saccharide produced tolerance to the lethal effect, but lethal- ity was always more pronounced for the tumor-bearing mouse. 331. WBISBEaG, Jo and GOLDSTEIN, H. H. Modification of the use of 1;yp^d vaccine in the production of hyperpyrexia Illinois M, I^ 79:139-140, 1941 The authors devised an expanding doaige method for the pro- duction of therapeutic hyperpyrexia. Typhoid vaccine was ad- ministered in a low initial dose until fever was produced; at the height of fever, a second larger dose was injected. Very high temperatures were secured by this method. A definite dosage schedule is appended to the article, 332. WIENER, A. S. DREMLAND, B. H., HYMAN, M. A. and SAMWICK, A. A. Transfusion reactions. Experience with more than 3000 blood ^ansfusions Am. J. Clin. Path. 11:102-121, 1941 In 1936, the incidence of chills and fever appearing after blood transfusion was 12 per cent, on the average, regardless of the method employed in transfusion. When the saline solution used was exchanged for another type, reactions dropped to 3.8 per cent and has continued to be between f and 3 per cent. 115 - 1 9 4 1 - 333. WRIGHT, I. S, The conservative treatment of occlusive arterial disease New England J. Med, 225t805-8lO, 19^1 Typhoid vaccine has been used intravenously in the treatment of thromboangiitis obliterans with highly satisfactory results The 'H' antigen of the typhoid bacillus v.'lll produce a thera- peutically useful fever without the distressing chill, 334. YAMAMOTO^ Ko Studien Uber die Bezlehung zwlschen der Virulenz und den giftigen Lelbessubstanzen der Maustyphusbazlllen (Studies on the relationship between virulence and toxic endogenous substances in mouse typhoid bacilli) Tohoku J. Expe Medo 41:69-91^ 1941 The less virulent strains of the typhoid bacilli have low percentages of polysaccharides and high protein content. Endogenous toxic substances ar*^ more readily Isolated from more virulent strains ^ v;hich yield larger amounts of the carbohydrate-protein complex. - 1 9 4 2 - 335. BLOOM, N, Treatment of peripheral vascular diseases Virginia M. Month, 79:273, 1942 The action of typhoid vaccine on the collateral vessels sup- plying the lower limbs with blood is one of vasodilatation and improved tissue nutrition. Buerger's disease is greatly im- proved by this type of therapy, 336. CENTANNI, E. Immunitats Erscheinung Im experlmentellen Fieber mit besonderen Seruchsichtigung des pyrogenen Stoffes aus Typhusbakterleren (Appearance of imm.unlty in experimental fever with particular emphasis on the pyrogenlc materials from the typhoid bacillus) X16 -19^2- Klln. Wchnschr. 21s 664-669, 1942. See also: Bull. Hyg. (London) 17:890, 1942 The pjrrogenlc decomposition product obtained from typhoid bacilli appears to exist as a prosthetic group on a large protein complex molecule. Agar cultures of the typhoid bacillus 1 to 2 days old are prepared by autolysis and either pepsin or papain digestion; trypsin Is less effective and acidic or alkaline hydrolysis Injures the pyrogen. The pyrogen can be boiled In neutral solution without damage. It even appears that through such action Its activity Is Increased, either through destruction of Interfering material or thro ugh.. liberation of., fever material," The large polypeptides and albumin may be removed through the use of trichloracetic acid or ammonium sulphate. Histamine hydrolysis and dialysis will remove materials of smaller molecular mass, Centannl preferred fractional precipitation with alcohol and glycol for further purification before filtration. The fever unit was 0.05 mg, A new substance appeared during a study of the method outlined above, a biological unknown related to the polysaccharides. It Is found In combination with the 'klastlns' or endotoxins which produce characteristic Immunity and certain toxic symp- toms, as fever and Inflammation. The pyrogenlc factor Itself contains both a hapten and a toxic group. The former pro- duces pure histologic Immunity through Its action as an antl- pyrogen, with a prevention of antibody formation. Through fractional adsorption on aluminum hydroxide, the hapten can be obtained In a fairly pure state and may be then used In Immunization against the pyrogenlc reaction. This, the 'Third Immunity' of Centannl, has Important potentialities in the treatment of disease. 337. CHAPMAN, C. J. Use of rabbits for the detection of pyrogenlc substances In solutions for intravenous administration. Quart. J. Pharm. Pharmacol. 15:361-366, 1942 Initial leukopenia, after the injection of pyrogen-containlng infusion solutions, may be used as a simple indicator of the presence of pyrogen. In the test rabbit, a drop of 4000 leuko- cytes per cmm, of blood or more is considerecl evidence of pyro- gen contamination In the injected solution. 117 -19^2- 338c CHASIS, H., GOLDRING, W. and SMITH, H, Reduction of blood pressure associated with pyrogenic reaction in hypertensive subjects J, Clin. Invest, 21:369-376, 19^2 No inherent vasodilator or depressor activity is known to reside in pyrogens, and the vasomotor responses noted are believed to be complex. The initial pressor phase is character- ized by vasoconstriction, probably neurogenic in origin; systolic and diastolic pressures are moderately reduced shortly there- after. A dual activity in pyrogens is suggested by the fact that the temperature rise may be blocked without altering the hypotensive action and renal vasodilation. Premedication with amidopyrine allows the hypotensive effect to be applied in hypertensive states, without a corresponding increase in body temperature c The delayed activity of the second phase of the hypotensive cycle after administration of pyrogens may, if dosage is not controlled, produce alarming circulatory crises. 339. CO TUI, and SCHRIPT, M. H. A tentative test for pyrogens in infusion fluid Proc. Soc. Exper. Biol. Med, 49; 320-323 ■, 19^2 These Investigators used, with success, a procedure which eliminated some of the errors commonly encountered in pyrogenic testing. Since the rabbit is responsive to other substances and has a highly labile thermoregulatory mechanism, the lack of response to pyrogen injection has more significance than the positive test. The dog is less sensitive to pyrogenic: materials; hence positive pyrogenic reactions in this animal are highly significants Preliminary tests on the rabbit are confirmed through injection of a test dose in the dog. The test dose Is graduated according to the sensitivity dis- played. The rabbit is 3 times, the dog 6 times less sensitive than human beings. In 214 tests, clinical and laboratory data have been in agreement, 340. CO TUI and SCHRIPT, M. H. Production of pyrogen by some bacteria J, Lab. Clin. Med. 27 "569-575^ 1942 In a study of pyrogen production in 18 strains of micro-organ- isms, representative of different genera, families and species 118 -19^2- pyirogen production was found to be common to many types of bacteria o It was not confined to organisms found in water, and was not associated with nucleic acid, with lack of affinity for the gram stain, pathogenicity, chromatin production, nor was it confined to lower biologic forms. Saceharomyces Fink wild yeast produces pyrogen. In this study, a new criterian was em- ployed in the Judgment of toxicity; the production of antibodies in experimental animals. 3^1. CO TTJI and WRIGHT, A. M. The preparation of non-pyrogenlc infusion^. and other intravenous fluids by adsorptive filtration Ann, SuPg. 116:412-^25, 19^2 The adsorptive filtration method, and a standardized apparatus, have been adopted for the production of non-pyrogenlc physiolo- gic salt, dextrose and sodium citrate solutions. The use of calibrated asbestos filter pads is a feature of the method. 3^2. DELATMAY, A. Recherche des constituents bacterlens responsables de I'appel leucocytalre (Investigation of bacterial constituents re- sponsible for the leukocyte response) Ann. Insto Pasteur, 68:72-74, 1942 Marked leukocytic response was produced by an autolysate of s t a phy lo cocci . Dealburalnized autolysates yielded an active, specific polysaccharide, capable of affecting the leukocyte count In concentrations ranging between 0.001 and 1.0 mg. The physiologic carbohydrate content is directly concerned In the stimulation of leukocyte production. Chemotaxis may be in- volved but this was not verified by a comparison with glycogen. Similar activity is shown by preparations prepared from ty- phoid, colon, paratyphoid B and Shiga organisms. It is believed that the active principle Ts a specific glucldo -lipid antigen, since local leukocyte response follows the injection of small quantities of the substance beneath the skin. 343. DIBOS, R. J., HOBERMAN, H. D. and PIERCE, C. Some factors affecting the toxicity of cultures of Shigella dysenteriae 119 -19^2- Proc. Nat. Acad. Scl. 28:^^53, 19^2 Conditions which favor aerobic metabolism greatly increase the toxicity of the cells in S. dysenteriae cultures, as well as the yield of dry material. When 1,5 mg, of cells grown under anaerobic conditions were injected into mice, all survived; 0.1 mg. of cells grown on silica gel plates killed all mice. Glucose in silica gel medium decreased the toxicity of cells. 'Smooth' and 'rough' varieties were similarly affected by environmental growth conditions. The toxic pi'lnciple was bound to the cell 'itself and released in solution through autolysis. It was vjater soluble, stable and resistant to proteolysis . 344. DUGGAN, W. F. Choroiditis centralis serosa: Diagnosis, patholgic physiology and therapy Arch. Ophthalmol. 27:123-133, 19^2 Bacterial body cellular elements and toxins produce a local ischemic condition after injection. As this is overcome by pyrexial factors, oxygen is increased in the area with bene- ficial effects. 345. FAVORITE, G, 0. and MORGAN, H, R. Effects produced by the intravenous injection in man of a toxic antigenic material derived from. Eberthella typhosa : Clinical, hematological, chemical and serological studies J, Clin. Invest. 21:589-599, 19^2 No marked changes in the total protein, urea nitrogen, creati- nine, chloride, glucose and C02-comblning power of blood appeared after a purified antigenic material obtained from E. typhosa was administered to human beings with neurosyphilis. Repeated injections produced antibodies in high titer. The leukopenia and leukocytosis usually noted after pyrogen Injections were present. The sedimentation rate rose after each injection. In animals receiving Intravascular injections of this substance, pathologic changes involving heart muscle, lung, liver and spleen tissue, the bone marrow and vascular bed were produced. 120 -19^2- 346. PEDOROV, N. A. and SHTH, E. L. The role of the viscera in regulating the temperature of the body of an animal under physiological and pathological condi- tions Am. J. Physiol. 137:30-38, 19^2 The sites of therinogenesis were studied in normal animals arti- ficially heated or cooled and febrile states after blood transfusion. All experiments were made on angiostomized dogs. In normal fasting dogs, lowest temperatures were found in the aorta, highest in the hepatic vein. Important thermo- genesis occurred in the intestines. Hepatic heat production rose rapidly during cooling of the skin and the reverse took place during heating. In transfusion and anaphylactic shock, variations were much greater in temperature, particularly with respect to visceral thermogenesis , Both liver and intestines participate in determining febrile reactions to foreign protein substances. 347. GERBER, I. E. and GROSS, M. Production of the Shwartzraan phenomenon with a sulfonamide con- jugate of a bacterial filtrate Proc. Soc. Exper. Biol. Med, 51:237-238, 19^2 In four experiments performed with the rabbit, the skin was pre- pared by an intradermal injection of meningococcal filtrate, and in f<>ur others, a conjugate of paraminobenzenesulfonylace- tylamide with bacterial filtrate was used for preliminary conditioning to the Shwartzraan reaction. Both filtrate alone and the conjoga'fee were injected 24 hours later. The filtrate was still €^|feto elicit the reaction despite conjugation. 348. HIATT, E. P. The effect of denervation on the filtration rate and blood flow in dog kidneys rendered hyperemic by administration of pyrogens Am. J. Physiol. 136:38-41, 1942 In order to determine whether or not the delayed renal hyperemia induced by pjn^ogens was under neural or humoral control, the ureters of two dogs were explanted to the exterior, 100 mg. of pyrogenic inulin administered, and urine from each kidney separately collected. The determinations of glomerular fil- tration rate and diodrast clearance weye repeated after 121 -19^2- denervatlon of the left kidney in each animal, Denervated kidneys functioned in the same manner as normal kidneys during the experiment. In response to pyrogen, a decreased filtration fraction and increased renal blood flow were obtained. The pyrogenlc renal hyperemia is apparent- ly humoral and not neural in nature, 349. HUTNER, S„ H. and ZAHL, P, A, The action of sulfanilamide compounds on the lethal factor of bacterial toxins Science 96:563-564, 19^2 Sulfanilamide exhibits a protective action on mice after ad- ministration of lethal doses of purified Salmonella endotoxin. The method may have useful application in the toxicity encountered after the induction of hemorrhage in tumors through bacterial fractions. The antitoxic effect is inhibited by para-amino- benzoic acid, 350. KNOPPERS, A, The rat tail as a part for temperature regulation (Translated Title) Arch, Neurl. physiol, 26:364, 19^2 Since the temperature of the rat tall rises after injections of pyrogens the rise in temperature may be utilized in testing for fever production. 351. KOPP, I, I. Plasma protein in therapeutic fever J, Lab. Clin, Med, 2?; 105^-1062, 19^2 Fever induced by malaria organisms produced plasma protein shifts in patients with general paresis. The globulin shifted, albumin was decreased c The fibrinogen content^ varied. In- jections of typhoid vaccine and physically-induced fever brought smaller changes. Destruction of red cells, as well as the in- fectious process itself, may account for plasma globulin increases in malaria. 122 -19^2- 352. KOPP, I. I. Relationship of the plasma protein to the corrected sedimen- tation rate J. Lab. Clin. Med. 27:1072-1077, 1942 As globulin in plasma increases in malarial or typhoid vaccine fever the sedimentation rate is proportionately height«ned. 353. MORGAN, W. T. J. and PARTRIDGE, S. M. An examination of the 0' antigenic complex of Bact . typhosum Brit. J. Exper. Path. 23:151-165, 19^2 A substance possessing the immunologic properties of the anti- gen of E. typhosa was prepared by diethyleneglycol extraction. Three components were found, a protein, a phospholipin and a specific polysaccharide. The protein component was chemically and immunologically similar to the conjugated protein found in B. Shlgae antigen. Toxicity of both antigenic preparations appears to reside in the undegraded polysaccharide component; degradation removes toxicity. 35^. NEAL, P. A., SCHNEITER, R. and CAMINITA, B. H. Report on acute illnesses among rural mattress makers using low-grade stained cotten J.A.M.A. 119:107^1082, 1942 An acute illness appeared among workers on a rural mattress project, in a cotton mill and in cottonseed -processing plants. High concentrations of stained cotton dust were found in the occupational environment. Samples of the cotton were given physical, chemical, mycologic serologic, biologic and bacterio- logic examinations. A gram-negative bacillus was found in stained cotton and cotton dust; the disabling illness, charac- terized by acute intoxication appearing shortly after exposure, could be reproduced by inhalation of dust containing the bact- erium. Aerosols of a sterile filtrate from cultures of the 'cotton' bacterium produced similar symptoms. 123 -19^2- 355. NECHELES, H,, DOMMERS, P», WEINER, M„, OLSON, Wo Ho and RYCHEL, Wo M. Depression of gastric motility without elevation of body tem- perature following the injection of pyrogen Am, J. Physiolo 137:22-29, 19^2 Pentnucleotide, yeast or thymus nucleic acid, peptone, B« coll vaccine or triple typhoid vaccine, a bacterial pyrogen, and tap water were administered in subfebrlle doses into unanesthetized fasting dogs in which continuous gastric motility had been pro- duced by prostigmlnee Pentnucleotide inhibited gaatric motility in all tests. The average duration of activity was 30 minutes. Yeast nucleic acid had deep depressive effects, thym$c nucleic acid none. Peptone, 5 and 50 mg., neither affected temperature nor motility, B, coll vaccine (12-1/2 million organisms) depressed gastrTc motility. The pyrogenic preparation depressed gastric motility profoundly. 356. OLITZKI, L., AVINERI-SHAPIRO, S. and KOCH, Po K, The hypothermic and adreno -hemorrhagic effects of bacterial vaccines J. Immunol. 45:237-248, 19^2 A large number of vaccines from a variety of bacterial species were tested for the following: hypothermic effects, adreno- heraorrhagic effectsj nonspecific resistance through treatment with bacterial vaccines; nonspecific resistance through treat- ment with serum or plasma, heterologous or homologous; active and passive immunization. Adreno -hemorrhagic, hypothermic and leukopenic reactions appeared to be associated and were produced only by vaccines from certain organisms, in the main, the gram-negative groups. Reactions were varied in intensity and occurrence and influenced by such nonspecific factors as amounts, age and weight of exper- imental animals^ and the species. Normal serum or plasma pro- duced a resistant period extending 2 to 3 days, vaccine, for 12 days. However, vaccine prevented leukopenia after injection of bacterial products for two days only. It did not protect against the adreno -hemorrhagic effects, nor did passive immunization. 124 -19^2- 357. RETES, P. P. Algunas alteraclones hematlcas provados par el pyrif er en los esquisofrenlcas (Some alterations in blood provoked by pyrlfer in schizophrenics) Rev. neuro-psiquiat. 5:381-413, 19-42 No differences in the kind, degree or duration of leukocytosis was observed in schizophrenic patient-s who received injections of pyriferj a small reduction in the heffloglobin content of the blood followed. 358. SCHRADE, W. Effect of bacterial substances (pyrogena) on blood lipldes (Translated Title) Ztschr, f. ges. exper. Med. 110:518-534, 1942 Blood fats, phosphatides and cholesterol are decreased after the injection of bacterial pyrogens in the dog. Free and total cholesterol is less affected. Catabolism of fat may be stimulated. Normal levels are resumed after pyrogen activity ceases. 359. SOLOMON, H. A. and SOMKIN, E, An improved method of obtaining controlled hyperpyrexia with triple typhoid vaccine Am. J. Med. Sci. 203:736-740, 1942 Continuous infusion of triple typhoid vaccine permits prolonged hyperpyrexia to be maintained. Only one chill phase occurs. The method is applicable to the oheraotherapeutic treatment of subacute bacterial endocarditis, pyogenic lung infections, chronic arthritis and ulcerative colitis. It may be used to augment the effects of sulfonamides. Calcium gluconate or chloride and morphine sulfate suppress hyperpyrexia. 360. WEINSTEIN, J. J. Reactions from the transfusion of unpooled liquid human plasma. Analysis of 1500 transfusions Med. Ann. Dis. Columbia ll;226-229, 1942 125 19^2- A total of 15 reactions ( 1 per cent Indidence) in I5OO trans- fusions were observed; all were mild. From the standpoint of precipitating causes, they were divided into 3 groups (1) those caused by agglutination (2) allergic reactions and (3) pyrogenlc contamination. The last-named was most frequently encountered. An outline is presented for the prevention of plasma reactions. 361. WINKELSTEIN, A. and SHWARTZMAN, G. The use of concentrated and purified antitoxic B. coll serum in the treatment of Indeterminate ulcerative colitis Am. J. Diges. Dls , 9:133-136, 19^2 Whole and concentrated horse serum^ strongly antitoxic, was prepared from immunizing doses of B, coll . Since this organism is considered to be a secondary invader in chronic ulcerative colitis, intramuscular injections of the concentrated Be coll antitoxin (Shwartzraan) were administered to 29 patients exhibi- ting chronic aspects of colitis. The results were encouraging, 22 in 29 patients were benefited by this type of therapy. 362. YOUNGNER, J. S. and NUNG ESTER, W. J. The effect of pneumococcus polysaccharide on the circulation of the blood in small blood vessels J. Bact. ^3:9^^ 19^2 (Abstract) Intravenous injection of various quantities of pneumococcus polysaccharide produced changes in the rate and uniformity of flow of erythrocytes. Increased sedimentation rates were observed. 363. ZAHL, P. A., HUTNER, S. H,, SPITZ, So, SUGUIRA, K. and COOPER, F. S. The action of bacterial toxins on tumors. I. Relationship of the tumor-hemorrhagic agent to the endotoxin antigens of gram- negative bacteria Am, J, Hygiene 36:223-242, 19^2 The antigenic endotoxin of Shigella dysenteriae , on extraction with cold ethylene glycol, yields three components: a phos- pholipid, non-toxic, non-antigenic and not a hapten; a poly- saccharide, comprising approximately 50 per cent of the endotoxin. -19^2- and haptenlc in structure but nontoxic; the toxic polypeptide fraction, non-antlgenic. The last-named fraction gives intense color reactions for tyrosine and arginine. It may be this type of fraction which produces tumor hem.orrhage. 364. ZAHL, P. A. and HTJTNER, S. Ho The action of bacterial toxins on tumors. II. Effect of sulfani- lamide on toxin-induced hemorrhage Proc. SoG. Exper. Biol, Med, 51:285-287, 19^2 The hemorrhagic factor found in Salmonella endotoxin is believed to be a component of the antigen and to exhibit parallel lethal effects in a manner common to most negative bacteria. The lethal activity is reduced in vivo by sulfanilamides, but the mode of action of such protection is not understood. It may. like ascorbic acid, affect the threshold of vascular re- sistance or participate in a toxlcity-reducing mechanism. - 1 9 4 3 - 365. DELAUNAY, A, Recherche sur la phagocytose, V, Chimotactisme leucocytaire et toxines microbiennes (Research in phagocytosis. V. Leuko- cyte cheraotactism and bacterial toxins) Rev. Immunol, 8; 30-45, 1943 Bacterial toxins with the characteristics of proteins were iso- lated from staphylococci , corynebacterla of the pseudotubercle type, and organisms of diphtheria and tetanus. On injection, they inhibited cheraotaxis of the leukocytes, preventing phago- cytosis. 366. DELAUNAY, A, Le pouvoir leucopeneant de I'antigene glucido-llpidique du Bacille d ' Eberth et la leucopenla dans la filbre typhoide (The leukopenic ability of the glucldo-llpid antigen of E. typhosa and leukopenia in typhoid fever) Compt. rend. See, blol, 137:540, 1943 127 -19^3- The leukopenic factor has been sought In E. typhosa ♦ It has been considered to be nonprotein (Morgan); the Molisch reaction is positive. Trichloracetic extracts of bacterial preparations produce leukopenia on injection. 367. DELAUNEY, A„ Mise en evidence d ' une nouvelle proprlete des antig^nes glucido- lipidiques; Leur pouvoir leucop^eant (A new property of glu- cido-lipid antigens: Their leukopenic ability) Compt. rend. Soc , biol. 137:589-590, 19^3 A new property of antigens^ the leukopenia -producing ability, appears when lethal doses of glucido-lipid antigens from colon or typhoid organisms are administered. The leukocyte count is depressed within one hour (from 10,000 to 25,000 initially to 5*000 or less). This is an early sign of intoxication. The leukocyte index is balanced by the increased mononuclear cells. In about 3 hours, the white cells increase. With more moderate dosages, the return to normal levels begins in 24 hours. Minute (gamma) dosages bring an early leukocytosis; the animal so treated remains in perfect health. This stim- ulation is believed to be a cheraotactic one. According to J. Jolly, leukopenia occurs when leukocytes are retained in viscera, liver, lung and spleen - only small numbers remain in tissues. Glucido-lipid antigens bring intravisceral mobilization as the leukocytes migrate inward from the peripheral areas. 368. EDELMANN, Ac, MAHANNA, D. L., LEWIS, L, A., THATCHER, J. S. and HARTMAN, F. A, The use of adrenal extract in fever therapy J. Clin, Endocrinol. 3:20-27, 194-3 369. GUERRA, P. and BARBOUR, H. G. The mechanism of aspirin antipyresis in monkeys J. Pharm. & Exper. Therap, 79:55-61, 1943 In normal monkeys aspirin produces only a slight decrease in temperature, but in fever produced by the subcutaneous inject- ion of yeast, it induces vasodilation and perspiration. 128 i - 1 9 If 3 - 370. HARRISON, Jo W,^ MYERS, Re J, and HART, D, So Purified mineral-free water for pharmaceutical purposes Jo Am. Pharra. Ao 32:121-128, 1943 By the use of Ion exchange resins, pyrogens In mineral-free water or? In solutions- Intended for parenteral use may be re- duced. The amount of pyrogenic material remaining does not produce temperature increases above 0.5° C. 371. HARTWELL, J. Lo, SHEAR, Mo J. and ADAMS, J. H., JTl. Chemical treatment of tumors. VII. Nature of the hemorrhage- producing fraction from Serratia mareescens ( Bacillus prodigiosus ' Jo Nat. Cancer Inst. 4:107-122, 1943 The active material contained 47.5 per cent C, ,7.1 per cent H, 2.2 per cent N, 1.1 per cent P and 2.2 per cent acetyl. Ash was 3.5 per cent. The minimal hemorrhage -producing dose contains about Ool gamma of total solids. Neither protein nor poly- peptide can be demonstrated after hydi^olysis; hexosamlne, methylpentose and a firmly bound phosphoiipld are present. Although stable at room temperatures, the potency is lost at increasing rates as temperatures increase between 60° C. and 100° Co 372. HARTWELL, J. L., SHEAR^ M. J. and ADAMS, J. R., JR. Nature of the bacterial polysaccharide which produces hemorrhage in mouse sarcoma Cancer Res. 3^122, 1943 "Further data were given on the material obtained from cultures of Bo prodigiosus " o The polysaccharide fraction had previously given negative results in tests for protein; in this study colorlmetric tests for tyrosine, arglnlne and hlstldlne gave positive results. The active agent could be separated from the protelnate material by tryptic digestion o Potency of the active portion disappeared when the acetyl content was lost during treatment with 0.1 N/i^aOH« By use of 0.1 N/MaHC03, the acetyl was removed with Injury to activity. Hydrolysis (1.5 N/HCl) pro- duced 60 per cent reducing sugars and 16 per cent of a water-in- soluble, alkali-soluble product containing N and P. The re- ducing sugar was approximately 30 per cent methylpentose. * 129 -19^3- Gluccsamine was about k per cent. No ketose or desoxy- sugars were noted; galactose, mannose and Inositol were not present, A small amount of uronic acid was measured. The end-point dose (producing hemorrhage in 50 per cent of tumors) v^?as about 0.1 gamma. 573. HUTNER, S. H, and ZAHL, P. A. Action of bacterial toxins on tumors. IV. Distribution of tumor-hemorrhage agents among bacterial species Proc. Soc. Exper. Biol. Med e 52:364-368, 1943 When 30 gram-negative and 7 gram-positive killed organisms, pathogenic or non-pathogenic, were injected in doses approach- ing lethal limits into mice bearing mouse sarcoma l80, repre- sentatives of gram-negative species induced tumor hemorrhage (with few exceptions). But one gram-positive bacterium ( Listeria monocytogenes ) possessed the capacity to produce vascular stasis in tumors. It is argued that tumor -hemorr- haging toxins may be bound in the somatic antigens, charac- teristic of gram-negative organisms. 574. KAHLER, H., SHEAR, M. J. and HARTWELL, J. L. Chemical treatment of tuitiO]?s. VIII. Ultracentrif ugal and electrophoretic analysis of the hemorrhage-producing fraction from Serratia marcescens ( Bacillus prodigiosus ) J. Nat. Cancer Inst. 4:123-129, 1943 Analyses of 3 preparations of the polysaccharide fraction from S. marcescens which produces tumor hemorrhage gave the following information: the non-dialyzable solids were approx- imately 1 per cent of weight o The partial volume of poly- saccharide by ultracentrifugal analysis was 0.75; the sedimen- tation rates differed. No polysaccharide component appeared to carry potency for other activities than that of producing hemorrhage in neoplasms. This potency was about equally divided between sediment and supernatant fluid. The electron micro- graph revealed that the active principle was a large symetrical particle with molecular weight somewhere between 3 and 30 million. It appears to remain in the material most easily sedimentable. The potency is lost rapidly at ordinary temperatures and pressures 130 -19 4 3- 375. KNIGHT, H. Co, EMORY, Mo L., and FLINT, L. D. A method of inducing therapeutic fever with typhoid vaccine using the intravenous drip technltjue Vener. Dis. Inform. 24:323* 19^3 The Infusion of a dilute solution of typhoid vaccine in 5 per cent glucose-saline permits control of fever levels with- out danger to the patient. Over 1^00 5>atients with gonorrhea of a resistant type were treated -by jaeans of an initial intra- venous 'shock' dose of concentrated material, followed in 1 or 2 hours by intravenous slow Infusion. I 376. HOROAN, flc R. Pathologic changes produced in ra'bblts by a toxic soiaatlc anti- gen derived from Eberthella t:yph6sa Am. J, fathol, 19s 135-1^3, 19^3 Marked inflammatory changes with later necrosis and fibrotic 'walling' of the area followed the injection in the skin of somatic fever-producing antigen of E. typhosa . When injected intravenously, it caused vascular damage and subsequent throm- bosis, ne(Ji»o3is of hepatic cells and changes in heart muscle, adrenals and bone marrow. The lymphoid tissue of the spleen may be injured o Hyperplasia of bone marrow follows lYiJul?y to the hematopoietic tissues. 377. McCLOSKY^ Wo T., PR.ICE^ C. W., VAN WlNDLE, Wo, For the guinea pig LD50 dosage is from 100 to 200 micrograms per kg., and that for the aog appears to be of the same magnitude. The normal mouse tolerates 100 micro- grams per animal, but tolerance is greatly reduced (to I5 micro- grams per mouse) with subcutaneous tumors. The polysaccharide acts through the central nervous system and not the peripheral areas in the animal; this^ is shown by the minute amounts which will produce fever, .-counteraction of fever by antipyretics and extreme vasoconstriction noted after administration. The febrile reaction may be influenced by the environmental temperature. When the spinal cord is cut, the drop in temperature advanees at a rate of over 2° C. per hour, 441. BEESON, P. B. Development of tolerance to typhoid bacterial pyrogen and its abolition by reticuloendothelial blockade Proc, Soc, Exper. Biol, & Med, 61:248-250, 1946 Tolerance develops when daily injection of typhoid pyrogen is continued for a considerable period of time. It is believed that an accelerated rate of disposal of the foreign substance may underlie the phenomenon. The reticuloendothelial system is presumed to be closely connected with this mechanism, since tolerance development is prevented by reticuloendothelial blockade. 442. BHINDLE, H. and RIGBY, G„ The preparation of non-p3rrogenic water and infusion fluids, using activated charcoal 15^ . ^ . -19^6- Qtly. J. Pharm. Pharmacol. 19:302-339* 19^6. See also: Pharm. J. 157:85, 19^6 Untreated waters from Manchester water mains or from a Cheshire stream were agitated at intervals for 13 minutes with charcoal (0.1 per cent) and filtered through sintered glass. Pyrogenic activity, as shown by production of fever in the rabbit, was much reduced. The average rise in temperature was at least 1.50 C. before treatment, and 0.3° C. after. Strongly pol- luted water could not be rendered pyrogen-free if storage preceded treatment. Heavily contaminated pharmaceutical solutions required more than 0.1 per cent charcoal. There was little adsorption of medicaments on charcoal; procaine HCl solution was an exception with adsorption of 27 to 35 per cent. 443. DILLER, I. C. and SHEAR, M. J. Cytological effects of s. marcescens polysaccharide du tumors Cancer Res. 6:488, 1946 (Abstract) A single injection of the polysaccharide isolated from S. mar - cescens caused striking degenerative changes and damage to cell nuclei in mouse sarcoma 37. Alterations were evident within 2 hours aft^r the injection; cells appear to be most st:g?ongly affected during the division stages. The impact of the polysaccharide was most clearly seen In the period of mitotic activity, and at four hours after administration of the agent no division could be detected. When undamaged cells were seen after 6 hrs., they were in the resting phase. Normal tissues which divide at a rapid rate (intestinal epithelium) were damaged by the polysaccharide. Spontaneous tumors of the rat and mouse and neoplastic tissue from the human patient were examined after polysaccharide therapy. The nuclear changes were similar in all material studied, but the degree and extent varied . 444. DUNN, T. B. and LEHMANN, S. 155 - 1 9 4 6 - Cancer Res, 6:488, 19^6 (Abstract) Transplanted epithelial tamors of the mouse appeared to be un- changed on gross examination 24 hours after a single injection (0.1 mg,) of So marcescens polysaccharide. Microscopic examina- tion revealed extensive necrosis in the five types of epithelial neoplasms observed: adenocarcinoma of the small intestine; myo- epithelioma of the salivary gland; pulmonary tumors and two squa- mous cell carcinomas. The effect of bacterial polysaccharides on carcinomas may be overlooked unless microscopic studies are made. ^^5o GLUCK, R. and WILSO]^, J. L. Fever produced by the oral administration of amino acids Am, Jo Dis, Child. 71s601-6lO, 1946 Fever from an undetermined cause appeared in infants ill from ex- cessive dietary Intakes of monosaccharides and casein hydrolysates in sterile solutions. Six well infants had sudden elevations of temperature on the second day of feeding; normal levels were re- sumed within 24 hours. The fever was not associated with dehy- dration nor was it influenced by an antibiotic (sulfadiazine). The work of Reitschel and of Holt is recalled. A specific dynamic action of amino acids and not a pyrogenic effect may be responsi- ble for "oral" fevers, 446 » FAVORITE, G, 0, and MORGAN, Ho R, Therapeutic induction of fever and leucocytosis, using a purified typhoid pyrogen J. Lab. Clin. Med, 31:672-676, 1946 When a purified pyrogenic antigen Isolated from E„ t yphosa is injected intravenously fever, profound leukocytosis, localized pain in the head, back and legs, and occasionally, nausea and vomiting follow. Symptoms disappear, leaving a sense of fatigue and exhaustion. The leukocytosis produced is characterized by the appearance of many granulocytes of the non-filamentous type; glucose, chloride and C02-comblnlng power of the blood vary little from the norm. The leukocytosis was considered the most valuable aspect of pyrogen therapy as shown in the treatment of neurosy- philis. 447. KOCH, P. K. and OLITZKI, L. The action of dysentery toxins on different laboratory animals Exper. Med. & Surg. 4:54-68, 1946 156 - 1 9 ^ 6 -i Two variants of S. dysenterlae were examined, and both a neuro- toxin and thermostable lethal factor were Isolated. In the S- varlant a thermostable factor, lethal for mice and small animals, is responsible for hemorrhage of the cecum (rabbit) when injected with the neurotoxic principle present in both S- and R-variants, Other thermostable, toxic materials may be involved in the changes seen after administration of S. dysenteriae ; these changes include hypothermia, decreased liver glycogen output, leucopenia and decreases in ascorbic acid in the adrenals. 448. KUNA, S., EDISON, A. D. and BUTZ, G. A method for large scale testing for pyrogen J. Am. Pharm. A. (Sci, Ed.) 35:59-63, 1946 Temperature elevations may be observed in the rabbit after handling. A thermocouple box method has been devised which eli- minates the possibility of error from such factors. Other pro- cedures are outlined which may increase sensitivity in the rabbit. Thermogenic response is intensified when low initial temperatures exist. 449. LEWIS, L. A. and PAGE, I. H. Method of assaying steroids and adrenal extracts for protective action against toxic material (typhoid vaccine). J. Lab, Clin. Med. 31:1325-1329, 1946 Since some protective ability had been previously demonstrated for adrenal extracts against the toxic effects of typhoid vaccine, an assay method was devised to determine the factor or factors re- sponsible for such protection. Adrenalectomized rats were given a test dose of typhoid vaccine which was predetermined to be the MLD for the species. Various adrenal extracts and other steroid compounds were administered once or twice daily for three days before the vaccine injection. Survivors were sacrificed after 21 days. The efficacy of 5^ glucose in maintaining blood sugar levels and the protection afforded aginst the toxicity of ty- phoid vaccine were additional features of the study. Of eleven steroids tested, ll-dehydro-17-hydroxycorticosterone was the most powerful protective agent, but some capacity for protection was shown by all compounds with an linkage in the 11-position. No differences in potency could be demonstrated between natural and synthetic Compound A acetates. Maintenance of blood glucose alone proved to be ineffective as a protective measure. 157 -19^6- 450, MACPHERSON^ Cc F„ C«. HEIDELBERGER, M^ ALEXANDER, H. E„ and LEIDY, Go The specific polysaccharides of types A, Bj, C^, D and F, Hemo - philus Influenzae Jo Immunol. 52s 207-219^ 19^6 The chemical, phys-lcal and immunological properties of prepara- tions of specific carbohydrates of H, influenza e are described o ^51* MILLER, Co F, and BOOR^ A„ Ko Protection of mice against the lethal action of gonococcal endo- toxin by penicillin Proc. Soc. Exp. Biolo & Med, 6li 18-20, 1946 Crude gonococcal endotoxin was injected in graded doses into the peritoneum of the mouse , Subcutaneous doses of 15OO units each of penicillin were given at intervals ranging from 90 minutes before to 24 hours after administration of the endotoxin o Seventy- six per cent of all control mice died in comparison to 360 5^ when penicillin wras employed o ^52» NAUTS, H. Co, SWIFT^, W, Eo and COLEy, B. L, The treatment of malignant tumors by bacterial toxins as developed by the late William B.. Coley, Mo Do, reviewed In the light of modern research Cancer Res„ 6s205-2l6, 1946 The authors review the use of bacterial toxins in the treatment of malignancies 5 as reported in the literature of the past 50 years. The basic principles underlying the choice of these agents and their place in the modern therapeutic armem.entarlum against neo- plastic disease are given In detail, A careful appraisal is made of 'ColeyrtQxins' and similar agents used in tumor therapy, and errors In the earlier application of these substances are judged in the light of recent developments. More scientific study is indicated, ",„, toxin therapy has clinical value and ,, .further extensive research is warranted to produce better preparations and further refinements In the technic of administration,,," A bibliography containing 80 references is appended. 158 -19^6- 453i OLITZKI, Lo, CZACZKES, J. W. and KUZENEK, A. Endotoxlc factors of Rickettsia Frowazekl and their Immunological relationship to the endotoxins of other gram-negative micro- organisms J. Immunol. 53:365-370, 19^6 Hypothermia and decreased liver glycogen follows the Intrab- domlnal Injection of heat-killed Rickettsial organisms. To determine whether or not Immunologic relationships exist between these factors In R„ Frowazekl and In certain other gram-negative bacteria ( Prote^a , S. dysenterlae ) and two gram-tjosltlve bacteria, Corynebacterlum erose and Mycobacterium butyrlcum . Any of the three gram-negative organisms elicited Immunization against hypo- thermia and decreased liver glycogen produced by either of the other two. This Is conceded to be "a specific Immune reaction directed against a toxic product which Is a common constituent of a large group of microorganisms." The gram-posltlve organisms used did not elicit hypothermia or Immunity against temperature reduction. 454. OLITZKI, L., SHELUBSKY, M. and HESTRIN, S. Pathogenlzlng effect of different carbohydrates on Eberthella typhosa Proc. Soc. Exper. Biol, Med, 63:491-496, 1946 In determining the chemical basis for the pathogenlzlng activity of certain carbohydrates, mice were Injected with the test organism (E_^ typhosa ) Intraperltoneally and with a sterile aqueous solution of the tested pathogenlzlng substance In varying concen- trations. By this method 15 polysaccharides and 11 simple sugars and oligosaccharides were examined. Three classes of carbohy- drates were distinguished: (1) powerful pathogenlzlng sugars, levan, dextran, mucin and agar;; (2) moderate pathogenlzlng In two cellulose oreparatlons. In gum acacia, glycogen, mannan, and Inulln; (3) non-pathogenizlng crystalline sugars and the starch and galac to -mannan of the polysaccharides. Pathogenlzlng ability was enhanced by addition of kaolin to the solution injected. The pathogenicity of levan, produced in vitro , may be an intrinsic property. It is suggested that specific colloidal patterns, rather than polar groupings or individual unit structure, may underlie pathogenlzlng activity. 455. PAINE, T. P. Illness in man following inhalation of Serratia marcescens 159 -19^6- J. Infect. Dis. 79:226-232, 1946 Pour adult males, two of whom had histories of previous exposure, were subjected to an aerosol concentration of S. marcescens of approximately 2 million per cubic foot of air for two and one- half hours. Blood, nasal secretion and sputum cultures were made, serum agglutinins determined and blood changes recorded. Two and one-half to four hours after the exposure all subjects became acutely ill. Ocular and respiratory symptoms appeared. Chills and fever, tachycardia and generalized myalgias were present. Subjective improvement appeared after diaphoresis and defervescence. No significant changes in blood or urine components were noted, but sputum and nasal secretions produced positive cultures. Marked neutrophilia appeared at the onset of the reaction. Specific serum agglutinins were present in high titer. Previous exposure appears to be immunologically significant 456. REIMANN, S. P., HOLLOMAN, A. L., OAKEY, R., KcCONNELL, J. R. and SHEAR, M. J. Gross and microscopic pathology of human tumors following adminis- tration of S. marcescens polysaccharide Cancer Res. 6:489, 1946 (Abstract) Without previous sensitization^ the injection of a polysaccharide prepared from B. prodlgiosus produces necrosis and hemorrhage in both animal anB" human tumors. Intravenous injection of the poly- saccharide in a single dose or in divided doses, was followed in a few hours by swelling in the tumor area. For several patients, a constant Intravenous drip of the polysaccharide in solution was used and, for others, intraperitoneal Injections. Diffuse ecchsrmosis appeared within 48 hours in tumors near the surface. The size of the tumor is believed to be a determining factor in Judging the amount of necrosis and hemorrhage produced by a given dosage. Small neoplasms showed more extensive necrotic changes. Microscopically, the hemorrhages were seen to be focal in most cases, and the necrosis was of the liquefaction type. The distinction between hemorrhage from polysaccharide and that occurring spontaneously in softer sarcomas is often a finely drawn one. Fibrosarcomas show little or no hemorrhage, hence presence of these changes after polysaccharide injection may be considered a positive confirmation of polysaccharide activity. ^57. TODD, J. P., MILNE, G. R. and LAURIE, J. P. Non-pyrogenic saline infusion fluids Chem. and Druggist 145:536, 1946 160 -19^6- The definitions of "pyrogen-free" as a terra for solutions are reviewed and standards are discussed. Pyrogen-free water is easier to prepare than pyrogen-free saline solution, and the authors conclude from such findings that NaCl per se is pyrogenlc. 458. TODD, J. P. and MILNE, G. R. Tests on nonpyrogenic fluids Fharm. J. 156:157-158, 19^6 The skill of the operator is considered to he higMy important in the production of pyrogen-free intravenous solutions. Pyrogen tests on tap water, distilled water, normal saline and dextrose saline solutions are reviewed, 459. TODD, J. P., MEARNS, J. T. and MILNE, G. R. Preparation of nonpyrogenic saline infusion fluids Pharm. J. 156:158-159, 19^6 The pH of dextrose-^saline solutions bears an important relation- ship to certain changes which lower standards set for such fluids, 460. TONNESEN, M. and VESTERDAL, J. The pyrogenic effect of Danish penicillin (in English) Acta Pharm. Toxicol. 2:47-68, 1946 These experiments were performed to determine whether the pyro- genic effects of Danish penicillin could be tested in a manner similar to that adopted in the U.S. P. XII. In rabbits, rectal temperature increased after injection were used as a measure of pyrogenicity; the same preparations were tested simultaneously in therapeutic doses on both normal humans and those with gono- coccal infections. Removal of pyrogen from the preparations was attempted. With the test used in the United States, it was noted that penicillins meeting the requirements did not usually cause febrile reactions in humans, A marked reduction in pyrogen concentrations could be obtained by filtration through the Seitz equipment. Guinea pigs had no febrile responses to penicillin. A large number died within 4 days from toxic conditions which could not be correlated to the presence or absence of pyrogens. l6l -19^6- TUCKER, J. Typhoid shock therapy- Cleveland Clin. Quart. 13:67-72^ 19^6 Experiences with fever elicited by typhoid vaccine in several thousand patients during the past 15 years have been useful for deterrainlng correct applications and contraindications for typhoid shock therapy. Most successful results have been rea- lized in the following conditions: central nervous system virus Infections, chronic rheumatoid arthritis, chorea, and eye and skin diseases. WARREN, M. R. and WERNER, H, W, The evaluation of antipyretics against pyrogen-induced fever J. Am. Pharm. A. 35:257-259^ 19^6 A purified pyrogen was prepared from Proteus vulgaris by cellular lysis, repeated phenol extraction, dialysis and acetone precipi- tation. The minimal pyrogenic dose was 0.5 cc • per kg. body weight in the rabbit when the pyrogen was injected subcutaneously . Temperature was reduced to normal levels by the oral administra- tion of amlnopyrene, acetanilid or acetylsalicylic acid; aceto- phenetidln arrested temperature Increase but did not reduce fever. WEENS, H. S. and HEYMAN, A, Cardiac enlargement in fever therapy Induced by intravenous in- jection of typhoid vaccine Arch. Int. Med, 77:307-316, 19^^6 Enlargement of the heart during typhoid vaccine therapy was noted In 8 of 15 patients with neurosyphilis. In four other patients, cardiac changes persisted for six months following hyperpyrexia. No sigrllflcant differences could be found between patients with normal cardiac size and those with enlarged structures. Blood volume, cardiac output, and protein and hemoglobin levels did not differ widely from the norm. WESTPALL, B. B. and DUNN, T. E, Blood uric acid and proteose, body temperature and glomerular clearance of rabbits Implanted with the Brown-Pearce carcinoma and treated with the polysaccharide from Serratia marcescens J. Nat. Cancer Inst. 7:115-121, 19^6 162 - 1 9 4 6 - Blood proteose and uric acid, creatinine and creatinine clearance were determined in adult male rabbits after injection 6f a single dose of S. marcescens polysaccharide. All animals bore Brown- Pearce carcinomas at least three weeks old. The range of dosage extended from 5.0 to 300 micrograms per kg. body weight and all animals tolerated 5-D micrograms per kg. At this level, no sig- nificant rise in blood proteose occurred. There was a slight in- crease in blood uric acid with accompanying decrease in glomerular filtration. Hemorrhagic changes in tumor tissue were similar to those which occur spontaneously and were therapeutically unimportant. Larger dosages, in the presence of proliferating tumors, brought peripheral vascular collapse; at the 50 micro- gram per kg. level, tumor hemorrhage, ascites, decrease in renal clearance, collapse and death followed in sequence. i^65. WRETLIND, K. A. J. About the pyrogen activity of dialyzed casein digest Acta Physiol. Scand . 12:385-388, 19^6 (in English) Temperatures of rabbits given aminosol (3.3^ solution) by the intravenous route rose an average of 0.41° C. within one hour. The solution was used alone and with glucose additions. In the third hour, the increased temperature still existed to a lesser degree (0.28° C). 466* ZINOV'EVA, M. T. Mineral metabolism. Calcium level in arterial and venous blood in all kinds of fever (Translated Title) Byull, Ekspt. Biol. Med. (Leningrad) 21:70-72, 19^6 Fevers prolonged two days are accompanied by a drop in both the arterial and venous blood calcium content. In fever induced through the injection of metabolism-heightening chemicals (as d initro phenol ) , calcium rises early and falls to normal with the temperature. In pyrexia produced by amine toxins (from putrified meat) the calcium of blood rises only after the reduction of temperature from fever levels. 163 - 1 9 4 7 - ALGIRE, G. H., LEGALLAIS, P. Y, and PARK, H. D„ Vascular reactions of norffial and malignant tissues in vivo . II. The vascular reactions of normal and neoplastic tissues of mice to a bacterial polysaccharide from Serratia marcescens (Bacillus prodigiosus ) culture J. Nat. Cancer Inst. 3:53-62, 19^7 The polysaccharide fraction P-3 was injected intraperitoneally (0.2 mg. and 0.02 mg.) into mice bearing transparent chambers in dorsal skin flaps. Daily quantitative measurements were made of the vascular bed in normal striated muscle and neoplastic tissues prior to and follov/ing tumor transplantation. The capillary blood supply v^as traced by photographs, as were the changes preceding hemorrhage and necrosis and the pattern of regrov.'th v,'hen it occurred. In both normal and neoplastic tissue, a period of vascular stasis preceded hemorrhage. Occlusion of capillaries was observed in both tumor and normal striated muscle tissue; edema was present. Where the tumor host survived, the surviving tumor cells began new growth with capillary proliferation. The mechanism through which hemorrhage and necrosis takes place is closely related to tissue anoxia and capillary damage. BARSI, I. A new treatment of rheumatoid arthritis Brit. M. J. 2:252-253^ 19 '47 A febrile reaction vjas seen after the first infusion of 300 ml. of blood (from pregnant women) into male and female patients. Improvement of rheumatoid arthritis followed in 6K% of the group; relief from symptoms was spectacular. The possibility that a mild "protein" shock Initiates benefits in this therapy is dis- cussed . BECK, L. v., DILLER, I. C, BLAUCH, B. and FISHER, M. Reduction in toxicity of Serratia marcescen s polysaccharide to tumor-bearing mice produced by beef adrenal extract (Upjohn) Cancer Res. 7:725, 19^7 (Abstract) When large doses of Shear's polysaccharide (S. marcescens ) are required to produce hemorrhage and necrosis in extensive or re- sistant tumor transplants in mice, toxicity is the limiting factor, The preparation P-S (National Cancer Institute) was lethal in 164 - 1 9 4 7 - 500 gamma doses for 64 of 75 mice within 48 hours. All mice bore 7-day transplants of sarcoma 37. A second group, bearing neoplasms of the same age, were given beef adrenal extract prior to administration of P-8 polysaccharide and the same amount (0.25 cc.) at the end of the working day. Of these, 22 In a group of 45 survived 48 hours or longer. The possibility of this difference being the result of chance was estimated to be about 1 in 10,000. A concentrated hog adrenal extract in oil was ineffective in counteracting the lethal effects of P-8 poly- saccharide. 470. BEESON, P. B. Tolerance to bacterial pyrogens. I. Factors influencing its development J, Exper. Med. 86:29-38, 1947 Repeated dally Intravenous injections (7 to 10 days) of pyrogens from E. typhosa , B. prodlglosus and Ps. aeruginosa produces a gradual diminution of febrile response. Tolerance develops and the Increase in body temperature produced is slight and it re- mains constant. Tolerance is lost after a period of rest and pyrogens again produce higher febrile levels, on resumption of injections. No passive transfer of tolerance could be confirmed. Cross tolerance was noted. Antipyretics did not alter the course of development of tolerance. Amldopyrlne, administered through a stomach tube 1 hr. before injection of typhoid vaccine, prevented febrile response. Cab- inet fever therapy did not reduce responsiveness to pyrogens. 471. BEESON, P. B. Tolerance to bacterial pyrogens. II. Role of the reticuloendo- thelial system J. Exper. Med. 86:39-44, I947 Tolerance to pyrogens in rabbits may be the result of stimula- tion of the reticuloendothelial system. After tolerance was established, febrile response could be heightened through blockade of the reticuloendothelial system. Tolerance develops, according to the hypothesis presented, when, ability to remove pyrogens (or other bacterial toxins) from the blood is enhanced through awakening of the defense mechanism. Protection Is thus given against tissue injury. 472. BEESON, P. B. l65 -19^7- Effect of reticuloendothelial blockade on immunity to the Shwartzman phenomenon Proc. Soc. Exper, Biol, Med. 64:145-149, 194? When Thorotrast injections followed typhoid vaccine, rabbits naturally immune (or rendered immune through previously invoked Shwartzman reactions) developed areas of hemorrhagic necrosis, and the toxic effects of the vaccine were enhanced, iiT? BERNSTEIN, C, and KLOTZ, S, D. Fever therapy in herpes zoster J. Labo & Clin, Med. 32:1544, 194? Mixed typhoid vaccine injected intravenously brought prompt relief from true herpes zoster. There was an early disappear- ance of pain, n--!i. BERTRAND, I. and QUIVY, Do Le probleme des pyrogenes . Son etat actuel (Problem of the pyrogens. Actual state) Rev, d'Heat. 2:234-240, 194? The chemical structure of the pyrogens has not yet been fully explained. Carbohydrates are present in relatively large amounts but the nitrogen content is negligible. Polysaccharides are pre- sent. The pattern of molecular form should be studied further. Methods of testing for pyrogenic contaminants and the role of equipment (glass and tubing) in harboring pyrogen-producing bacteria are discussed. In transfusion of blood or infusion of fluids, the rate of infusion may, if accelerated, produce dan- gerous pyrogenic reactions when contaminants are present in stored blood or solutions. U-] I BLACK-SCHAPPER, B,, HEIBERT, T, G, and KERBY, G. P. Experimental study of purpuric meningococcemla in relation to the Shwartzman phenomenon Arch. Path, 43:28-54, 194? Twice-washed meningococci, living or dead, possess preparatory and provocatory substances with ability to induce the Shwartzman phenomenon. The toxic materials were present in small amounts only in the washings. Potency was highest in strains producing 166 -19^7- purpuric meningococcemla. Bilateral renal necrosis, found after Injection of living organisms, was believed to be the product of vasospasm and the thrombosis it engendered. 476. BOQUET, P., DELAUNEY, A., LEHOULT, Y, and LEBRUN, J. Action d'un extrait du bacille typhlque sur la pression arterielle du lapin (Action of an extract of Bacillus typhosa on the arterial pressure of the rabbit) Compt. rend, Soc . biol, 141:269-271, 19^7 Marked, rapid and sustained peripheral vasoconstriction followed injection of B. typhosa endotoxin in the rabbit. Two to I6 mg. of the toxic substance were injected by subcutaneous, intra- peritoneal or intravenous routes. The carotid pressure remained constant during the toxic period; in extremes, a reduction occurs, as would be expected. 477. BOQUET, P., DELAUNAY, A,, LEHOULT, Y. and LEBRUN, J. Observation direc^e des reactions vasculalres cutanees chez le lapin soumis a I'epreuve d ' une endotoxine typhique (Direct observations of the cutaneous vascular reactions in the rabbit subjected to typhus endotoxin) Compt. rend, Acad. Sci, 225:1193-1194, 1947 The reactions of cutaneous vessels in the ears of rabbits were studied by means of window-flaps and microscopic examinations. Contraction of a severe degree occurs 5 to 15 minutes after intravenous or intraperitoneal injection of 6 to 8 mg. of a B. typhosa polysaccharide-lipid-polypeptide antigen; the cycle of alternating dilatation and contraction which follows is con- fined to arterioles alone o Removal of the upper cervical ganglion did not alter the response. The initial response to purified B. typhosa antigen is believed to be independent of local sympathetic innervation and to resemble similar reactions observable in anaphylactic and traumatic shock. Leucopenia and inhibition of diapedesls accompany this manifestation of Intoxication, 47a BRADLEY, S. E. and CONAN, No J. Estimated hepatic blood flow and bromsulfalein extraction in normal man during the pyrogenic reaction. J. Clin, Invest. 26:1175, 1947 (Abstract) The cardiac output and renal blood flow are increased after 16? 19^7- pyrogen administration even v;hen fever is prevented by anti- pyretic drugs. Hepatic circulation in normal human subjects before, and after, intravenous injections of typhoid vaccine was traced through bromsulfalein clearance and hepatic venous cateterization. The blood flow in the liver increased in all subjects; to 300 per cent increase was noted in one indi\/idual. Despite hyperemia and increased bromosulfalein loading, the latter was removed from blood at a rate 50^ below normal levels. Hepatic venous pressure rose occasionally as hyperemia developed in the liver. ^-'.7 1, BRAGDON, J, H, The hepatitis of hyperthermia New England J. Med, 237:765-769, 1947 Liver damage may be seen after fever is induced by physical or biological methods. Hepatitis, believed to be of virus origin may be activated through increased body temperatures. The critical temperatures above which liver cells are irreversibly changed are probably varied, but are believed to be not far above those encountered frequently. Anoxia, or the destruction of functioning enzyme systems, may underlie liver cell necrosis; the same factors are destructive to certain central nervous system cellular components. nSi:'. BUENO, P. Reticuloendothelial cells reacting to toxic antigens and to infection Archo Path. ^4:635-638, igii-J Nuclear tumefactiou and disintegration in the undifferentiated mesenchymal cells, in germinal elements of lymphatic tissues and lymph nodes, and the Kupffer cells of the liver of the guinea pig followed subcutaneous or intracardiac injection of the anti- gens of p aratynhoid A., brucellosis, anthrax, tetanus and diphtheria, organisms, ...--. ... Close relationships exist between sites of antigen activity and those concerned with antibody formation, v.e. . CHAMBKRS, W, W. and WINDLE, W. F, Site of action of a bacterial pyrogen in cats with central nervous system lesions 168 -1-9 4 7- Pederatlon Proc. 6:89, 19^7 (Abstract) In the normal cat Injection of a purified pyrogenic extract obtained from Fseudomonas aeruginosa (PYROMEN) produced pilo- erection, chills and fever"! Only fever occurred when the pyro- gen was administered to cats with chronic hypothalamic lesions and no response was registered in the chronic spinal animal. The last-named show poor adjustment to environmental temperature changes. 4.82<. COLLIER, H. 0, J, and PARIS, S. K. _, The decline of pyrogenic activity of intravenous solutions during storage Quart. J. Pharm. Pharmacol. 20:376-380, 19^7 It has been reported that strongly pyrogenic solutions may lose their activity during storage. To test the validity of this theory, solutions of ten compounds commonly used for intravenous therapy were stored at reduced pressures (508-635 mm. Hg.) and tested for pyrogen content at intervals. Solutions included saline, dextrose M/6 sodium lactate. Darrow's solution, Hart- mann's and sodium sulphate solutions. The average span of pyrogenic activity was 92 days or less; in one instance^ pyrogens were present after 110 days storage. Temperature and light were relatively unimportant factors in the storage life of pyrogens; initial concentration of pyrogens in solution was less significant than the chemical nature of the pyrogen under consideration and the presence of stabilizing substances. Two solutions of the same type may contain pyrogens widely dissimilar. The rate of loss of pyrogenicity varied widely. In general, dilute solutions were less stable for pyrogen retention, but it was noted that such substances can exist in solid materials, eg. dextrose. It was also noted that the febrile activity of pyrogens wanes after long storage. 'i^BS* CONDINI, P. Amora sulla bactererterapia dei tumori (Bacterlotherapy of tumors) Terapia (Milan^ 32:69-70, 19^7 '4tS4. CREECH, H. J., HAMILTON, M, A., DILLER, I. 6,, NISHIMURA, E. T. and SHEAR, H. J. Comparative studies of the immunological, toxic and tumor-necro- tizing properties of S. marcescens polysaccharides l69 - 1 9 4 7 - Fractionation of the polysaccharide from one strain of S. mar - c esc ens has yielded a product which appears to be less ^oxTc" and antigenic In the mouse. No significant alteration of the tumor-necrotlzlng property occurred. Studies have been made of the protection afforded by passive Immunization of mice against the toxic fraction of the polysaccharide from the "GW" strain. The gamma globulin fraction of rabbit antlsera, bearing anti- bodies, protected a large percentage of the animals when In- jected a few hours before the Injection of a lethal dose of polysaccharide. Previous Injection of the fraction Into mice bearing sarcoma 37 prevented toxic effects of a large dose of S, marcescens polysaccharide but did not Interfere with tumor necrosis, A~straln of S. marcescens (724) has been found to be capable of producing less toxic polysaccharides. 485. DILLER, I. C. Degenerative changes Induced In tumor cells by Serratl a mar - cescens polysaccharide Cancer Res. 7:605-626, 1947 A detailed account of the cellular changes Induced In tumors by the polysaccharide of S. marcescens Is presented. Studies were carried out on mouse sarcoma 37, on spontaneously appearing rat and mouse carcinoma and on human biopsy material taken from 16 carcinoma patients. The combined effects of polysaccharides and roentgen therapy on neoplastic destruction were observed. Two effects of polysaccharide activity were noted; one, a vas- cular change, the other, one of nuclear destruction. Maximal damage was seen within six hours. There was marked Inhibition of resting cell division for three days after treatment. In some animals no viable cells were detected three days after treatment with a dose lethal for one-fifth to one-third of the mice. Roentgen therapy Increased three-fold the number of tumors which showed regression. Injection dlr»ectly Into the tumor did not Inhibit growth. Resistance to the necrotizing effects of polysaccharide developed In the tumor host after repeated Injections, Human tumors underwent similar but less pronounced destructive changes, 486. DILLER, I. C. The effect of simultaneous administration of bacterial poly- saccharide and adrenal cortex extract on cells of mouse tumors and on the adrenal glands of the host Cancer Res. 7:715, 1947 (Abstract) The action of the polysaccharide of S. marcescens on sarcoma 37 170 -19^7- In mice was not Inhibited by simultaneous administration of adrenal cortical extract. The necrotizing effect was delayed with maximal effects appearing in 24 hours. Chemical as well as structural changes are suggested by the appearance of the cytoplasm of cells and their staining characteristics. Cellular changes in adrenals of the host follow administration of either substance alone; damage appears to be prevented by simultaneous injection. 48?. EDSALL, G. and WETTERLOW, L. H, Missed contaminations in biologic products: The role of cryophlle bacteria J. Bact, 54:31-32, 1947 Bacterial species which thrive below the incubation temperature ranges produce pyrogens; refrigerated serums^when once contami- nated, are fertile sources of such pyrogenlc substances. Gram- negative organisms which grow only at lower temperature ranges have been isolated; they resemble Pseudomonas and grow most actively at 20 to 25 degrees C. but will multiply at degrees. Tests for pyrogens should be made at room temperature as well as at 35 to 37°C. 488. PELTON, L. D., PRESCOTT, B., KAUFMAN, G, and OHINGER, B. Studies on immunizing substances in pneumococci. XIV. The dis- tribution of specific polysaccharide in mouse tissues after injection of a "paralyzing" dose Federation Proc. 6 (Pt. 2) 427, 1947 (Abstract) In the mouse a large dose of the antigenic polysaccharide of pneumococci "paralyzes" the immunologic mechanism for about 15 months; the phenomenon is type-specific. The concentration of the antigen in the tissues was traced and comparisons made of hlstochemical preparations from normal animals. In order of decreasing precipitin titer the polysaccharide was found in these tissues: liver, spleen, kidney, skin, bone marrow. In some instances, it could be demonstrated in muscle and lung tissues and in urine and the intestines. It was present after 15 months in the liver but had decreased or was absent in other tissues. Mice Injected with a paralyzing dose of whole cell vaccine showed similar distributions of polysaccharide. 171 -19^7- 489- FRANCE, 0. and LOSDAN, M. Piretoterapia biologica en reumatismo Inflamatorlos (Biolo- gical pyretotherapy in inflammatory rheumatism) Ref. argent, reum. 12:72-75, 19^7 As adjuvant therapy with antibiotics (sulfonamides or sulfona- mlde-penicillin injections) typhoid vaccine containing both antigenic and metabolic products of the bacteria was adminis- tered. Dosage ranged from 100 to 500 million organisms per ml. on an average, but injection of 2000 million bacterial cells daily proved to be innocuous. In a series of patients with rheumatism of septic origin, 92^ received benefit; there was some response in cases of inflammatory rheumatism. Rheumatoid arthritis was not Improved. /iO.-). GEORGI^ C. E. Pyrogen testing with "Polish"rabbits J. Am. Pharm, A. 36:95, 19^7 The small size of the "Polish" rabbit makes it an economical and useful animal for the testing of pyrogens, 491. GIPPORD, S. R. Ocular Therapeutics (A Handbood of) Philadelphia, Lea and Pebiger, Inc. 4th Edition, revised by D. Vail, 1947, P. 119. A nonspecific action in ocular infections is credited to a "mixed toxin" derived from killed cultures of streptococcus erysipelatis , and B. prodigiosus , grown separately, mixed to- gether and diluted to strengths designated by the percentage of protein contained therein. The adult dose is 3 minims intra- muscularly. Within four or five hours slight chills are followed by mild temperature increases (100° -102°) and a slight inflammation at the site of injection. Results have been re- warding in uveal Infections, corneal ulcer and postoperative iridocyclitis e 492- GINSBERG, H. S., GOEBEL, W. P., and HORSPALL, F, L.^JR. Inhibition of mumps virus multiplication by a polysaccharide Proc. Soc, Exper, Biol, Med. 66:99, 19^7 172 -19^7- Multlplication of the mumps virus in the chick embryo can be inhibited by the capsular polysaccharide of Friedlander 's bacillus , type B. After adsorption of the polysaccharide chick erythrocytes do not adsorb the virus. 493. HARTLEY, P. The decline of pyrogenic activity in intravenous solutions during storage Quart. J. Pharm. Pharmacol. 20:444, 194? Wide variations in stability between different types of solu- tions must be considered in reckoning the rate of disappearance of pyrogens in stored solutions. Rapid disappearance of pyro- gens may be seen in one and long continuation of pyretic acti- vity in another. The presence of pyrogenic activity can be demonstrated after three years' storage. 494' HOLLOMAN, A. L. Reactions of patients and of tumors to injections. of Serratia marcescens polysaccharide in eight cases of malignant disease Approaches to Tumor Therapy , Araer, Assn. for the Advancement of Science, Washington, D. C. XI. pp. 273-276 Four patients with fibrosarcoma, two with Hodgkin's disease, one with malignant melanoma and some with chondrosarcoma were treated with the polysaccharide of S^ marcescens . The initial dose was O.OO5 mg.; this was increased later to 0.04 mg. in a single dose. Reactions were severe and resembled those of shock, although anti-shock therapy was Ineffective in treatment. Elevation of the lower half of the body, and continuous intra- venous drip of a solution of 5^ glucose in saline, containing 1 mg. of thiamine and a low concentration of epinephrine were employed. The highest temperature elevation recorded was 10S.4°F, A short intense rise in blood pressure was succeeded by hypoten-.". sion. 495* HORSFALL, P. L,, JR. The modifying effects of certain substances of bacterial origin on the course of Infection with pneumonia virus of mice (PVM) V. J. Exper. Med. 85:623-646, I947 Since it has been demonstrated that Infection subsequent to Inoculation with pneumonia virus could be modified in mice by injections of streptococcus MG , the effect of other bacterial species was determined after Intranasal inoculations with PVM. Both living and dead bacteria in various concentrations and 173 19^7- bacterlal polysaccharides were employed. In addition, non- bacterial polysaccharides were injected. Varied time intervals between inoculations were observed. Streptococcus MG , S. sali - varius , type II and Group A hemolytic strentococcus were in- jected during the test periods. A second pneumococcus organism, E. coll and H. influenzae , type B., were included in the group. Virus titration end points and hemagglutination titers were determined in the infected lungs as well as the frequency and degree of pulmonary consolidation o Both bacterial and non-bacterial substances modified the course of PVM Infection, but were inactive when administered by other than the nasal route. They appeared to inhibit virus multiplication. Competition may exist between these active substances and PVM for some intracellular system required for multiplication of the virus. Chemical blockade of virus re- ceptors in the cells of the respiratory tract did not appear to be involved in the mechanism of inhibltiono The evidence, still unconfirmed, would indicate that the active component may be a purified polysaccharide, 496. JAGER, B. V. and NICKERSON, M. The altered response of human beings to the intramuscular ad- ministration of typhoid vaccine during massive salicylate therapy. Am, J, Med, 3:^08-422, 19^7 The effects of injection of typhoid vaccine in a control group of healthy adults and in patients suffering from arteriosclerotic heart disease, acute rheumatic fever and from multiple sclerosis were contrasted vilth those observed in 14 patients receiving massive salicylate therapy, A number of Individuals in both groups had been previously immunized against typhoid. Salicy- lates as medication had been administered for periods ranging from 7 to 132 days before typhoid injections, and were continued for 16 to 70 days after. While the control group exhibited typical reactions to typhoid vaccine - development of H and antibodies, transient leuko- cytosis, lymphopenia, a rise in the red cell sedimentation rate and plasma fibrinogen levels and Increases in gamma globulin - the patients treated with salicylates had only slight changes or none. The systemic and local reactions noted in individuals previously Immune to typhoid were absent during massive sali- cylate therapy. Antibody production may be prevented through the action of salicylates by a reduction in toxicity of antigenic proteins or through selective liver damage which Inhibited pro- duction of precursors c A direct action on lymphocytic antibody production may be the result of adrenal and pituitary stimula- tion or there may be rapid destruction of typhoid toxins in the circulation. - 1 9 4 7 - 4^97. KTJN, E. Effect of meningococcal endotoxin on histamine content of blood and tissues of rabbits Proc. Soc, Exp o Biol. Med, 66:197-201, 1947 Intravenous injection of meningococcal endotoxin reduces blood histamine and Increases that of liver and muscle. Hista- mine levels in the blood could not be sustained by simultaneous administration of endotoxin and histamine; the latter procedure appeared to shorten the survival time of test animals. :498. McCONNELL, J. R.^ HALLETT, S. P. and SHEAR, M. J. Effect on sarcoma 37 in tissue culture of two tumor-necrotizlng agents Cancer ReSc 7s7l6^ I947 (Abstract) Hanging drop cultures of sarcoma 37 grown for I8 hours were treated directly with concentrations of emetine hydrochloride ranging from 10 mg. per cc„ to 0=00001 rag. The cells rapidly disintegrated, nuclei shriveled and became pyknotic. The rate of destruction was proportional to emetine concentration and toxicity appears to reside in a rapid surface reducing effect. Similar concentrations of S. marcescens polysaccharide produced no necrotlaslng effect in vTFro. The method is informative but does not appear to be as reliable as a screening procedure as in vivo tests, 499. MONDOLPOp Ho and HOUNIE, E, Sobre el orlgen del plrogeno bacterlano (On the origin of bacterial pyrogens) Dla Med, 10:1724-1725, I947 In a review of the factors concerned with pyrogen production, the role of culture medium in increasing pyrogenlclty of super- natant fluids is described. Blood serum Increases the pyrogenl- clty of E. coll cultures. 500. MORGAN, H. R. and, BENNETT, G, A. Intra -articular changes Induced in rabbits by Injection of typhoid somatic antigen Arch, Path. 44s609-620, 1947 The toxic somatic antigen of S. typhosa was injected directly into the sub-patellar Joint of the rabbit in dosages ranging from 0,25 mgo to 0,5 rag. and the injections were continued at inter- vals of 3 to 7 days for varying periods of time. Concomitant in- jections Intradermally were employed as conditioning procedures preparatory for the Shwartzman reaction and were followed by lib - 1 9 ^t 7 - provocative injections l8 to 24 hours later. Tissues were ex- amined both iiiacroscopically and microscopically, Repeated intra -articular injection of the antigen produced acute arthritis v^hich progressed to a chronic state. Synovial tissue hypertrophy, surface "lipping" and subsynovial lymphoid accumu- lations were seen. The dermal reaction passed through a self- limiting course. Vascular thrombi were extensive throughout heart, lungs and liver. NASr^TB, P. A, The decline of pyrogenic activity in Intravenous solutions during storage Quart. J. Pharm. Pharmacol, 20:'i-45, 19^7 In the discussion during the symposium, Nasmyth noted that the work of Collier and Paris^ just reported, had shown that a vjide range of temperatures might be seen in the normal rabbit. In the seven employed by these investigators, the differences ex- tended to 500^ and the lower of the temperatures recorded in these rabbits was TA'ell within normal limits for the species. OAKEY, R, Reactions of patients to injection of Serratia marcescens poly- saccharide in nine further cases of malignant disease Approaches to tumor therapy , American Association for the Advancement of Science, 1947* pp. 277-27-3 Serrati a marcescens polysaccharide may be given to patients re- peatedly with the necessary safeguards against extreme toxic and shock states. No tumor vjas completely destroyed when 0.03 to 2.0 mg, of polysaccharide was given in 1 to 14 injections to members of a group of 9 patients bearing tumors of varied types; changes in the f^ize and consistency of most of them could be seen. The systemic reactions were similar to those noted with other pyro- genic substances; the most alarming feature was the fall in blood pressure with its threat of complete peripheral circula- tory collapse, OGHOA, A, G. and PIGUEROA, E, S, Los Polisacaridos de Sporotrichum schenckii (Polysaccharides of Sporotrichum schenckii) -19^7- Rev. d. Inst, salub, y enferra. trop. (Mexico) 8:143-153, 19^7 The method of Palmer and Gerlough (C. A. 3^:7328^) was applied to 2.25 Ova. of the dried fungus, Sp . schenckil . A small quantity (0,03 Gm.) of a compound extractealDy this method gave a posi- tive Molisch reaction and reduced Benedict's solution after hydrolysis. A carbohydrate was obtained by alcohol precipitation of the culture medium (O.IO Gm. in 230 cc. of medium) which was negative for Millon, biuret and xanthoproteic tests, Netther the compound or its carboh^/^drate component were antigenic or toxic; both were precipitable by homologous and heterologous immune rabbit serum and by serum from a patient with sporo- trichosis. 504* PERRAULT, A. and SHEAR, M. J. Large scale preparation of the tumor-necrotizing polysaccharide from S. marcescens Cancer Res. 7:714, 19^7 (Abstract) Culture of S. marcescens in synthetic media may be adapted to large scale operations (up to 350 liters). No differences in potency between preparations so secured and those obtained in small scale can be seen. Active fractions from the organisms themselves may be subjected to purification. 505' RADEMAKER, L, Reactions to intravenous administration to solution J. A.M. A. 135:1140-1141, 1947 The majority of pyrogenic substances can be eliminated from so- lutions during manufacture by use of triple distilled water, immediate sterilization of water, solutions and glassware. Rigid cleansing of distilling apparatus must be done periodically. Pyrogenic materials retained in moisture films on glassware, in tubing and needles, can be eliminated by washing and sterili- zation. Adsorption filtration of solutions is possible and is an additional safeguard. 506. REUBI, P. Le traitement de la sclerose en plaques (Treatment of multiple schlerosis) Schweiz, Med, Wchnschr. 77:1177-1179, 1947 17^ -19^7- Por multiple sclerosis^ pyretotherapy, vaccines, antlmyelotic substances, coagulation inhibitors, vasodilators and radio- active materials were ineffective. Some results were seen in a few patients after antihistamine administration , The brain tissue extract of V, Muralt is said to activate nerve regenera- tion; a tentative trial of this substance is suggested by the author. ROTENHEIM, C. A., SATKE^ H. A. and LIMAYE, M. V. Uber Pyrogene (On pyrogens) Pharm, Acta Helveto 22:673-678, 19^7 A review of pyrogens, from the standpoint of the interest of pharmacist and manufacturer, with methods for eliminating such substances from solutions. SACK, T. and SELIGMN, A. M. Some effects of iodinated bacterial polysaccharide on patients with malignant tumors Cancer Res o 7:715* 19^7 (Abst.) When iodinated polysaccharide from So marcescens was administered intravenously to seven patients with metastatic carcinoma, the effects of massive dosage could be observed, since from 2 to 3000 gammas were administered as individual doses. Post-injection reactions followed a common pattern, namely, chill, a temperature increase sustained for one or more hours and a gradual fall to normal levels within 12 to 30 hours after injection. The blood pressure rose during the chill, fell when temperature reached maximal levels, with a hypotensive period occurring 8 to 15 hours after injection. In four Instances antishock therapy was re- quired. Asthmatic symptoms, albuminuria and mild congestive heart failure appeared » However, the reactions did not differ markedly from those which occur after administration of the un- treated polysaccharide. Post-injection exhaustion appeared to be prevented or greatly reduced by adrenal cortical extract, given in combination with the iodinated polysaccharide » SMITH, W„ E. and PENNELL, R. Be Reducing the pyrogeniclty of concentrated protein solutions J, Bact. 5^:715-718, 19^7 A method is described for elimination of pyrogens from concen- trated protein solutions, such as serum, plasma and hemoglobin. 178 -19^7- This is accomplished through the use .of a new type of Setlz pad, special filters and an ion exchange agent "decalso". "Pyrogen removal is a function of the degree of pyrogeniclty and the concentration of the protein solution and the proper relationship of the amount of 'decalso' and filter pad area to these variables." 510. STUTTGEN, G. Die Beeinflussung des cholinesterase im Serum des menschlichen Blutes durch pyrifer und Uo V. Bestrahlung, besonders im hin- blick auf die Therapie einzelner Dermat^sen (Regulation of cholinesterase in human blood serum by means of pyrifer and U. V. light rays, particularly in view of therapy of certain dermatoses) Klin. Wchnschr, 24:758-759> 19^7 It has been postulated that the bacterial product, pyrifer, regulates the Equilibrium maintained between the vagotonic and syrapathotonic systems. In testing this theory, its effect on cholinesterase was ascertained. It was noted that, with increased cholinesterase activity, ultra violet light rays produced erythemic skin changes, 511. WEGER, P. tJber rein dargestellte hochwirksame Pieberstoffe (Highly potent pure pyrogens ) Naturwissenschaften 34:59-60, 19^7 The effects of pyrogens from Eo typhus , E. coll., proteus , pyocyanus and abortus equi organisms were observed in the rabbit, mouse, horse and in man, A response could be elicited in the rabbit through the administration of 0.25 micrograms, but higher doses gave a higher temperature level. During this period animals appear quite normal and maintain their weights. Tolerance does not appear on repeated daily injections, while, in human beings* increased doses must be administered in order to achieve the same responses o Chemical analyses of the pyrogens used are reported. 179 -19^3- 512. ALBSRTY, R. A. and HEIDELBERGER , M. Fractionation and physical-chemical studies of a comtnercial preparation of the specific polysaccharide of Type I pneumococ- ous' J. Am. Chem, Soc , 70:211-213, 1943 A colloidal electrolyte was separated from Type I pneumococcus. Electrochemical and solubility characteristics resembled those of the proteins." The crude preparation showed an isoelectric point at pH 2.3, After fractionation with isopropyl alcohol, electrophoresis gave an isoelectric point for one component, that of nucleic acid, slightly below this figure (2,0). 513- ALEXANDER, L., LOMAN, J., LESSES, M, F. and GREEN, I. Blood and plasma transfusions in multiple sclerosis Multiple Sclerosis and the Demyelinating Diseases . Baltimore, The Williams arJ WlTkIns~Co., l9$0. Chapter 13. The high incidence of pyrogenic reactions in patients with multi- ple sclerosis is in contrast with those reported in the litera- ture on transfusion reactions. Fifty patients in a group of 111 with multiple sclerosis were selected for study. Whole blood and plasma transfusions were given on the theory that, if it be a virus disease, passive Immunity m.ight be conferred through active immunity existing in healthy donors. Saline infusions and immune globulin injections were utilized in an effort to obtain information on fractions of blood which might be therapeutically useful. Reactions oc- curred in 27:^ of the 293 transfusions given or in 50^ of the pat- ients. There were no hemolytic reactions. There were 30 pyro- genic reactions involving iBfo of the patients. Allergic symptoms appeared after transfusion in lk%. lOfo of these were seen during the first transfusion. Both allergic and neural symptoms were often present in combination , Fever > temporary paralysis or spasticity, diplopia and "blindness" were seen. In the group of 23 patients who were benefited by transfusion, 60fo had reac- tions. Of these, 26fo were allergic reactions. Among the patients who did not improve after transfusion, 30^ had allergic reactions. Clinically significant improvement was seen in 3V of all patients treated; 6^ had incomplete remissions, three complete remission. Improvement vjas seen in but one patient after injection of immune globulin. 514. BAYER, 0. and HORSTER, J. A. Morphologische Veranderung an Plasmocytomzellen unter Pyrifer- wirkung (Morphologic alteration in plasma cells mider pyrifer 180 -19 4 8- Klln. Vchnschr. 26:623-625, 1948 i^K^SfJ®!^^ °^ plasmacytoma was made for a patient whose blood 5i«iJJ« "Sr'^2'^f ^"ssell body cells with Increased globulin nir^i^?- ^The total protein In the blood serum was 8:9 Gm. ErtL !?!' 5.8 Qm. per cent was globulin. Autoagglutlnatlon 35S w?rrse^«^n?!3 *^S °fllf «nd serum. Of the leukoc^JaC 6400) wfJ»n?!«!!^ ??*''• Forty-three per cent of the lymphocytea VeaLd d.;ni,?i^*- K??/**^^^^ puncture, marrow sp^lmens re- vlSuolea ^^ basophilic cells with extruded nuclei and many vf^Mrtii^^^jJi?'^ ®^,?5E pyrlfer, the temperature rose to 39.5O c. tSe norL? ^Joi.°*^\%^''^"'^"^''^?^ ^'^^ staining qualities approachi SlevatloS ;Sr?es2mJJed?°'''"'' «PP^«^«n°«^ the temperature 515. BECK, L. v., BERKOWITZ, D. and SELTZER, B, Jf aJpa?fn?^svsto?l^h?LJ""°'*"^^^^^^^^"^ «8*^^^«- ^^I- ^^•^^^ Mt»fliS«r«. 4. '^ ^^° ^■'•°°^ pressure In mice of the Serratli . marceaoens tumor-neorotlsslng polysaccharide of Shea r! * Cancer Res. 8:162-168, 1948 peJltoneJnf ir?S/mon«!'^ S^ ^* ""^''°^°«!"° ^" Injected Intrt- per mouse wis „?* "'?"*'*; Dosages ranged from 5.0 to 100 gammti a deflnit; JS r>^iS® ^!*!;^'^ transplanted tumors (Sarcoma 37) Ju?l"SiiowSS TJan'in'Jhr'" i^aPP«r«^^t aystillc blSod irea- phenomenon Th«\v?ii4.^^*t* '^^^^^^ temperature accompanied this to the redictloSs?n«vs?ni ?"'"'''' *''** ^°^* ^^'^^'^^ relationship mice Showed smai?*;.^?^^® pressure and temperature. Normal saccharide we^eiS^iSf!?^''^*''*:^.'*^*'" ^«^S«r doses of poly- response to ?oxi???v«?f!^*?% ^?f '^^S^*'*' °^ prostration and creased in the mSiae ?n Sr.i?i*°*^°'' 2f polysaccharide waa In- t issue present, ^^""^^^ proportion to the amount of tumor 516. BELLAOH, H. Connecticut State M. J. 12:843, 1943 trauSn'of%ySgoJ?'?ac'c?nr ""Id^JL^? ^«\?^^^^ved after admlnls- a prompt reoo?erv The do^po-f h^*"®** antl-shoek therapy brought faStor in detemnin^ ?h2 ?nfldfn«. «S* ^PP^a^ to be a major ^v^*ro*ning Tine incidence of untoward reactions. Carefu: - 1 9 4 8 - study of patients before Institution of therapy and hospitali- zation during treatment is advisable. 517. BENACCHIO, Lo Contributo clinoco alia terapia vaccinicia endovenosa nelle infezlone tifo -part if lone (Clinical contribution on intra- venous vaccine therapy in typhoid -anti -typhoid infection) Gior, batteriol. e Immunol. 39:337-353, 19^8 Forty-eight of 50 patients serologically positive for E. typhosa received anti-typhoid vaccine intravenously, with recovery following therapy considerably accelerated. The roseola herpes disappeared soon after injection, the spleen diminished In size. Leukocytosis and eosinophilia were observed during the treatment. 518. BOQUET, P., DELAITNAY, A., LEHOULT, Y, and LEBRUN, J. Observation direct des reactions cutanees chez le lapin soumis a I'epreuve d'une endotoxine typhique (Direct observations of vascular reactions of the skin in the rabbit injected with ty- phoid endotoxin) Compt. rend. Acad. Sci, 225:1193-119^, 19^8 Injection of 6 to 8 mg, of purified typhoid glucido-lipido- polypeptide antigen produces i^ithin 5 to 15 minutes constriction and dilatation of the arterioles. This is the first symptom of typhoid intoxication. Sympathetic innervation of blood vessels does not prevent vascular reactions, 519. CREECH, H, J., HAMILTON, M. A„ and DILLER, I. C. Comparative studies of the immunological and tumor-necrotizing properties of polysaccharides from Serratia marcescens ( Bacillus prodigiosu s) Cancer Res, 8:318-329, 19^8 Comparative studies of the immunological, toxic and tumor-necro- tizing properties of purified polysacchsrides obtained from cul- ture filtrates of S. marcescens (P3, P5 and Pio) and those of fractionation products from one straln'of the same organism are prjc^ented. jminunisatic^n of rabbits folloKi^^ tiie inje-ction of 2 Big o of polysaccharide in divided cJoses over e period of two weeksj the antisera was fractionated and studied serologically. The lethal dosage was determined oj the mortality which resulted from intraperitoneal injection of 100 to 2000 gammas of the materials into normal mice. Tumor-necrotizing potency was 182 -19^8- evaluated by histologic examination of tumor tissue following administration of 10 or 20 gammas of the preparations into Swiss mice bearing transplanted Sarcoma 37 • Toxicity and antigenicity were more pronounced in P3 type poly- saccharides, while less variation between the three types was evident in their effect on hemorrhage and necrosis production in tumors. Serologically the polysaccharides from two strains of S. marcescens differed. Some fractionation products were but weakly antigenic and relatively nontoxic but retained tumor- necrotizing properties. Storage for a period of years reduced anti-neoplastic qualities but altered toxicity and antigenicity very little. Freezing appeared to enhance the tumor-necro- tizing acitivity. 520. CREECH, H, J,, HAMILTON, M. A,, NISHIMURA, E, T. and HANKWITZ, R , F. , JR « The influence of antibody containing fractions on the lethal and tumor-necrotizing actions of polysaccharide from Serratia marcescens ( Bacillus prodigiosus ) Cancer Res. 8:330-336, 19^3 Normal mice and those bearing dorsal transplants of Sarcoma 37 were passively immunized with gamma globulin fractions isolated from rabbit serum after injection of polysaccharides produced by two strains of S. marcescens . Both antisera and gamma glob- ulin fractions projected mice against lethal doses of poly- saccharide from the same strain of S, marcescens but not against that of a heterologous strain. One type of antisera and gamma globulin gave no protection against homologous polysaccharide. Lethal acitivity of one polysaccharide was decreased by use of the specific gamma globulin fraction. The reduction of lethality did not affect tumor hemorrhage production in the mouse, 521. DELAUNAY, A,, BOQUET, P., LEBRUN, J., LEHOULT, Y. and DELAUNAY, M. The mode of action of bacterial endotoxins, IV. The vasomotor disturbances and their consequences in the intoxicated animals, J. Physiol. 40 J 89, 19^8 The mesenteric vessels of guinea pigs and mice and the cutaneous vessels of the rabbit ear were examined microscopically after a lethal dose of S, typhi antigen. A few minutes after injection of the antigen, irregular contractions of arterioles and medium- sized arteries were seen, with weaker contractions affecting the venous side. Dilatation of the vessels occurred in the terminal stages. Throughout intoxication, diapedesis of leukocytes was inhibited. 183 -19^3- 522. DILLER, I. C., BLAUCH, B. and BECK, L, V. Histological changes In adrenal glands of turaor-bearing mice injected with Serratla rnarcescens polysaccharide alone and in combination with adrenal cortical extract Cancer Res. 8:591-605, 19^8 Young albino mice bearing 7 "day-old implants of sarcoma 37 were injected with either 0«02 mg. P-3 polysaccharide intra- peritoneally ot O.5 cc , of adrenal cortical extract (Upjohn) by the same route but in divided doses or the tv;o substances in combination. Similar experiments were carried out with mice bearing methylcolanthrene induced tumors and also with litter mates. Both survival studies, tumor growth measurements and histologic examinations of tumor and adrenal tissues followed. Either the polysaccharide or the adrenal cortical extract caused tumor hemorrhage and necrosis, and similar effects on the adrenal glands were noted. The adrenal medulla showed more extensive necrotic changes than did the cortex. In combination, poly- sacchaEide and adrenal cortical extract delayed tumor necrosis and produced minimal glandular changes. In healthy mice or tumor bearing mice where the growth Is still in the primary stages, no tumor necrosis and little adrenal damage followed the adminis- tration of these agents ^ O c 523. FARR, R. S., LEQUIRE, V. S„, SCHORK, P. K. and GAYHART, C. H. The augmentation of the pyrogenic and leukocytic effects of typhoid vaccine by homologous plasma in the rabbit Project NMOO7039. Report No. 17, Kaval Medical Res. Inst. 19^8 This article is reviewred in detail in: Proc. Soc . Expero Biol. & Med. 75:661-666, 1950 524. FRONTALI, N. and TOOCHI, G. Gil inhibitori enzlmaticl nel process© febbrlle; (Enzymatic inhibitors and the febrile process) Boll. Soc. ital. biol. sper. 24:245-2^7, 1948 "Piretamlna" was administered by various routes and the effect of chemical inhibitors assessed, 525. GINSBERG, H. S., GOEBEL, W, F. and HORSFALL, P. L., JR. 184 - 1 9 4 8 - The inhibitory effect of polysaccharide on mumps virus multi- plication J. Exper. Med, 87:385-410, 1948 The viruses of mumps, influenza A and B and Newcastle disease were cultivated in allantoic fluid and Inoculated into fertile seven-to-eleven-day-old eggs. The inhibitory properties of the capsular polysaccharides of Fried lander's bacillus , types A, Bp and C, and streptococcus MG polysaccharide were tested, as were those of levari and dextran, blood group substance A, apple pectin and commercial corn starch. Hemagglutination was used as a measure of mumps virus concentration. It was found that the polysaccharides from type specific Friedlander bacilli inhibit the multiplication of mumps virus in the allantoic sac of the chick embryo c Concentrations as low as five gammas were effective. This polysaccharide had no effect on other viruses used. in the studies, and no other polysaccharide inhibi- ted mumps virus. The mechanism involved may be one of blockade of the metabolism of host cells and not one Influencing the virus or its infectivity 526. GINSBERG, H. S., GOEBEL, W. P, and HORSFALL, P. L,, JR. The effect of polysaccharides on the reaction between erythrocytes and viruses, with particular reference to mumps virus J. Exper. Med. 87:411-424, 1948 In an effort to determine whether or not a single mechanism is involved in the inhibition of hemagglutination and multiplication ° /I'^J^"^®^ ^ ^^^ polysaccharides of Friedlander bacilli A, B, and C, or of other non-bacterial polysaccharides, the viruses oi mumps. Influenza A, B, and Newcastle disease or PVM were ti- trated against chicken, human group and mouse erythrocytes. Polysaccharides active as inhibitors do not block adsorption Of the virus by erythrocytes nor by cells of the living allantoic memDrane in all instances o There is no correlation between effects of polysaccharides on hemagglutination by viruses and tneir inhibition of virus multiplication. Wide variation is shown between in vitro and in vivo inhibiting activity of polysaccharides. 527. HALL, V. E., FIELD, J. and GRANT, R. The metabolic activity of the central nervous system as it affects the thermostatic behavior of the body. Memorandum Report, MCREXD-686-113D, UoS, Air Force Materiel command, 194o 185 -19^8- 528. HALL, V. E., GRANT, R. and FIELD, J. The Influence of substances affecting body temperature on thermal polypnea Federation Proc. 7:^8, 1948 The effect of substances which alter body temperature was deter- mined on oxidative and glycolytic activity of cerebral cortex. In the same studies, the respiratory response to heat (thermal polypnea) was carefully measured. Thermal polypnea appears when the rectal temperature of the rabbit has been increased about 2°C. by administration of typhoid -paratyphoid vaccine. When panting is present before injection, it ceases within fifteen minutes, and inhalation of 95^ oxygen (and % CO2) is not de- pressed by vaccine. Normal respiration is observed in the vagotomized rabbit. Polypnea may be provoked in the rabbit by 3 niM per Kg, magnesium chloride at environmental temperature of 20° Co or higher. 529. HALL, V. E,, FIELD, J, and GRANT, R. The metabolic activity of the central nervous system as it affects the thermostatic behavior of the body Memorandum Rpt , U, S. Air Force Air Materiel Command MCREXD- b9b-113D, 19^, 99 PPc The effects of intravenous injections of typhoid -paratyphoid vaccine in the rabbit and the cat were carefully studied by collaborating investigators, and comparisons were made with those noted after injection of a number of chemical thermogenic and thermostatic substances. The site of action of pyrogenic substances in the central nervous system, reactions after "shock" doses and effects of T.P.T, vaccine on heat production, heat loss and cold defense were ascertained and evaluated. While results were inconclusive and no proof of a thermal "trigger" reaction in the central nervous system was forthcoming, the report enumerates many interesting facts on calorogenesis after' pyrogen administration and presents a series of methods well adapted for use in such studies. 530. HANSEN, J, L, Hyperthermia in association with shock Acta chir, Scand, 96:530-5^6, 1948 Although the body temperature during traumatic shock is usually - 1 9 4 8 - below normal levels ^ postoperative hyperthermia has been re- ported. Rectal temperatures may reach maximal limits within 24 hours after operation while shock is pronounced and no infection appears to be present; decreases are rapid following treatment for shock » The phenomenon has been noted after gastric operations, particularly when cancer or ulcer have been found. The clinical picture is one of coldness of the extremities, marked blood pressure reductions, oliguria; the pathology represented included oedema of cerebrum, vasodilatation, stasis and intra- vascular space alterations. Serous exudate of the nervous tissue was noted in the brain stem. It is suggested that hyper- adrenalemia would produce similar symptoms (arteriolar contractions paleness^ piloerection and perspiration). It has been shown that adrenalin itself may be pyrogenic. Impedance of blood flow at the portion near the vena cava may be a factor. 531. HATTA^ S., AOYAMA, K„, and TANJI, S. Studies on the bacteria (and harmful substances) Japanese J. Pubo Health, 5^24, 1948 532. HICKS, M., HOLT, H., GUHIRAND^ S. and LEAVELL, B. S. function^* °^ spontaneous and artificially induced fever on liver J. Clino Invest o 27^580-587, 1948 Diminished bromsulfalein clearance is seen in induced fever and may be the result of impaired function in hepatic tissues. Ab- T/Zi ^f?^^*i°^ ^/ bromsulfalein is seen du?ing feb^flf^erlods S i^;!?5 5%^""^ ^?^y temperature at the time of testing must be considered in evaluation. 533. KIRCHMAIER, H. and SCHOLTZ, W. f^5?li^?^^!l?^''^i"''f f®^ '^P^"^ ""^ Paratyphus im Kindesalter (Pyrifer treatment of typhus and paratyphus in childhood) Artzl. Wchnschr. 3s 426-428, 1948 S?lf onP^?^^f"n^«^?'"f "ff^ ^^^^ ^" °^^^^^' ^^^ diarrhea ceased dren iS wl?h ?vnhJ?i^o«^°''^ "/ E^^^^^ ^^^^ administered to chil- «?oSd th^ npr.?^S nJ*^.?? Paratyphoid fever. For the entire that^orJnSJ^^ ,^^ illness was not appreciably shortened over that occurring under conservative treatment. 1S7 - 1 9 4 8 - KUN, E. Effect of bacterial endotoxins on glycogen synthesis Procc Soc. Exper. Biol. & Med. 68:496-498, 1948 The influence of endotoxins from Salmonella and meningococcal organisms upon the synthesis, in vitro and in vivo , or glycogen was studied. In the rat diaphragm and rabbit liver slices there was inhibition of glycogenesis from pyruvate and glucose; insulin diminished this inhibition in vitro in the rat diaphragm, In vivo toxins completely prevented glycogenesis in the liver oT the rat. 535. KUN, E. Inhibition of the phosphorylation of glucose by meningococcal endotoxin J. Biol. Chem. 174:761-762, 1948 Since the addition of Zn-free insulin to meningococcal endotoxin prevents the inhibition of glucose utilizarion^'in rat muscle extracts in vitro , it is believed that meningococcal endotoxin prevents phosphorylation of glucose through a reduction of hexokinase activity. " , . oThe disturbances of the carbohydrate metabolism in meningococcal toxemic rabbits and meningococcic meningotis in humans,., may be explained by a direct effect of meningococcal endotoxin on ensyraatic reactions in the host.,," 536. KUN, E., and MILLER, C. P, Effect of bacterial endotoxins on carbohydrate metabolism of rabbits Proc. Soc. Exper o Biol. & Med, 67:221, 1948 The injection of lethal doses of sterile, unpurified meningo- coccal and Salmonella endotoxins in the rabbit, increased blood glucose, lactic acid and inorganic phosphorus.. Liver glycogen decreased while lactic acid content of tissues increased; pyruvic acid in blood and tissues was much reduced. Succinic -dehydro- genase activity in both muscle and liver was inhibited; cyto- chrome oxidase activity v/as not affected. A state of tissue anoxia may exist vjith corresponding interference with carbo- hydrate metabolism. 188 - 1 9 4 8 - 537. LEWIS, L. A. and PAGE, I. H. Changes In blood leukocyte level of adrenalectotnlzed and normal rats following administration of typhoid vaccine Am. J. Physiol. 153:148-152, 19^8 Adrenalectomized rats were maintained on either adrenal extract, dehydrocorticosterone acetate or physiologic saline solution for three days, at which time 1.33 MLD of typhoid vaccine was administered intraperitoneally. Determination of blood leuko- cyte and differential levels and of hemoglobin followed. Results were compared with values found in normal animals and humans after immunizing doses of typhoid vaccine. Blood leukocyte values changed little after injection of adrenal extract, compound A acetate or saline, but marked lymphopenia and neutrophilia were noted after typhoid vaccine injections. These were enhanced by previous treatment with the steroids. Within 24 hours, all animals receiving saline alone succumbed; pre-treatment with hormones prevented lethal effects of typhoid vaccine. The lymphopenia does not appear to be altered by adrenal cortical hormones, but the increase in neutrophils is markedly augmented. 538. MILLER, C. P., HAWK, W. D. and BOOR, A. K. Protection against bacterial endotoxins by penicillin and its impurities Science 107:118-119, 1948 The protective effects of penicillin against a series of endo- toxins injected into the mouse was confirmed through observa- tions of animals receiving both purified and impure penicillin before intraperitoneal administration of endotoxin. Preparations were derived from gram-negative organisms. Such protection was demonstrated against the endotoxins of S. paratyphi A., S. para.^ "t^yphi B., Shigella paradysenteriae , S. enterltides , S, aertrycke and Aerobacter . The LD50 for mice pre-treated with penicillin was three times greater when the cyrstalline product was employed and nine times greater when mice were given the impure product. The impure penicillin preparation lost its protective activity when treated with penicillinase or heat sufficient to inactivate penicillin; addition of the original amount of crystalline peni- cillin restored its capacity for protection. 539. MORGAN, H, R, Resistance to the endotoxins of enteric bacilli in man 189 -19 4^ u — J. Clin. Invest. 27:706-709, 1948 Seven patients, two with gonorrhea, two with asymptomatic sero- logic syphilis and three without Infections, received either the somatic antigen of S. typhosa , that of S. schottmullerl or Sh. d ysenterlae . Tolerance to the toxic effects of the antigens Be"vel8ped after repeated Injections. Subsequent Injections did not produce hyperpyrexia and other symptoms, and cross-tolerance developed between the heterologous antigens. However, specific "0" agglutinins were demonstrable only for Immunologically re- lated antigens. 540. MORGAN, H. R. Tolerance to the toxic action of somatic antigens of enteric bacteria J. Immunol. 59:129-134, 1948 Rabbits developed tolerance to the pyrogenlc effect of the so- matic antigens of S. typhosa , S. schottmullerl and Sh. dysen - terlae within three to four days following initial intravenous injections. Such tolerance was not specific for antigenic structure and appears to bear little relationship to the pre- sence of specific circulating antibody. After a rest period, the teslstant state disappears at a time when the level of cir- culating antibody still remains specifically elevated. Animals develop specific antibodies without comparable decreased in febrile response to pyrogenlc antigen, and the preparation from Sh. dysenterlae which is but feebly antigenic induces an active state of tolerance. 541. PINGERT, P. P, and PERRY, C. W. U, S. Patent 2,432,970, 1948 A method for reducing the pyrogen contents of parenteral solutions sensitive to temperature changes and to usual acid and alkaline treatments is described, 542. RABINER, A. M., ROSENBERG, M. and FRIEDMAN, H. Neuronitis and neuronapathy Ann. Int. Med. 29:432-444, 1948 For 6 of a group of 7 patients presenting the classic symptoms of acute infectious neuronitis or neuronapathy, benefit was - 1 9 4 8 - seen after typhoid vaccine therapy. Relief of pain was the most dramatic feature of this treatment. Acute inflammation of the peripheral nerves, nerve roots, brain stem and cord sub- sided more slowly, and the recovery of motor power lagged behind other improvements. In two patients there was an immediate return of sensation after the first injection of vaccine; in others, a considerable delay was observed. In the areas in- volved, regional hyperesthesia and hyperalgesia were noted. The excellent responses to vaccine therapy which occurred with- out noteworthy temperature elevations would appear to challenge the current belief that the beneficial effects of vaccino- therapy depend on the creation of lethal environmental condi- tions for infecting organisms. 543. RAUSS, K. A dysenterla vedoltas kerdese (The problem of immunization against dysentery) Nepegeszsegugy, 29:449-454, 1948 Trichloracetic acid extracts of S. dysenterlae protect mice against infection while type-specific activity is found in vaccines prepared from the same organism. It is believed that the toxic substance and the protective factor are identical. 544* SACK, T. and SELIGMAN, A. M, Chemical alteration of polysaccharide from Serratla marcescens . II. Effects of lodopolysaccharide in patients with malignant tumors J. Nat. Cancer Inst. 9:19-34, 1948 Intravenous injections of lodopolysaccharide, in dosages ranging from 2 to 3*000 gammas, were administered to seven patients with inoperable or recurrent Roentgen-resistant malignant tumors. The polysaccharide was given over varying periods ranging from 1 to d4 days, or 1 to 9 injections. The toxic reactions which fol- lowed resembled those observed after the administration of un- modified polysaccharide and consisted of a prodromal period, a chill 15 to 45 minutes after injection, a period df flush and maximal temperature and progressive hypotension and defervescence. Tolerance to lodopolysaccharide developed rapidly. Cross resis- tance to the effects of unmodified polysaccharide appeared. No -olinidai ev-ldenee of tumor destruction could be found. 191 -19^8- 545. SELIGMAN, A. M., SHEAR, M, J„, LEITER, J. and SWEET, B. Chemical alteration of polysacchc?.ride from Serratla maroescens . I. Tumor-necrotizing polysaccharide tagged with radioactive iodine J. Nat. Cancer Inst. 9:13-13, 1948 Radioactive iodine was incorporated in the molecule of the Shear polysaccharide and its effects oa normal and tumor- bearing animals and humans were observed. Saturation of the mole- cule occurred over a broad range of I concentrations; a stable io- dine linkage could be demonstrated. When injected intravenously in dosages ranging from 12 »5 to 300 gammas, radioactivity disappeared rapidly from the blood stream, but there was a prolonged maintenance of a residum (about 20^), Greatest radioactivity was present in the liver, lung and kidney, decreasing in this order, Ti-nior -necrotizing properties were not affected, and little radioactivity existed in tumor tissue, 546. TAL, C, and OLITZKI, L, The toxic and antigenic properties of fractions prepared from the complete antigen of Shigella dysenteriae Jo Immunol. 58:337-348, 1948 A series of fractions were prepare.i from the complete antigen of the S strain of Shigella dysenteriaeo A phospholipid, a con- jugated protein and a simple protein, undegraded and degraded polysaccharides were found on fractionation , The conjugated complexes contained varying amounts cf phosphorus while the degraded substances were free of this elements These fractions were tested for their ability to produce the following alterations in animals: lethal effects (mice); hypo- thermia ( in mice, rats and guinea pigs); leukopenia (guinea pig and rabbit); reduction of liver glycogen and adrenal ascorbic acid (in rats); the Shwartzman phenomenon (rabbits) and hemor- rhage production in adrenals (guinea-pig) or placentas of preg- nant mice. Antigenicity of the fractions for the rabbit was determined , The simple protein, phosphorus-froe., did not elicit the endotoxic reactions produced by the conjugated complexes. The conjugates reduced glycogen and ascorbic acid, and produced leukopenia and hypothermia. Production of a type specific antigen followed administration of the protein. The undegraded polysaccharide produced the Shwartzman reaction, leukopenia and hypothermia and. 192 -19^8- combined with small quantities of S. dysenterlae or E. typhosa (0 form), was capable of definite pathogenlzing action-, Antl- genicity depended on the linkage of carbohydrate and protein. 547. TARDIEU, Go, GUILLAUMONT, Bo and SUTTER, J. Encephallte choreique ou choree prolongee. Evolution tardive vers le parkinsonisme« Success de la pyretotherapie par le TAB puis de la radiothrapie des noyaux gris centra ux. (Choreic or prolonged encephalitis. Late evolution toward parkinsonism. Success of pyretotherapy by TAB and then radiotherapy of the central gray matter) Bull, Soco medo Hop. 64? 334-335, 1948 ^JiuJ®^^"'' °^^^®^ stemming from rheumatism responded to TAB therapy within a short period, but relapse followed one year later. TAB therapy was unavailing at this time, but some remission followed roentgenotherapy of basal ganglia, 548. TAUB, A. and HART, P, Detoxification of pyrogens by hydrogen peroxide in some U.S. P. injections J. Am, Pharm, A, 37? 246-250, 1948 Effective destruction of pyrogens in water, saline solution, or dextrose-saline solution intended for injection, may be carried i-^l zl 5f "f®^°^ hydrogen peroxide and prolonged boiling (1 hr.) for the first two fluids and by treatment with 100 to 200 mg. acld-waahed activated charcoal (per 100 ml,) and filtration througl a Selaa candle, for dextrose saline solution. 549. TAYLOR, R. D., CORCORAN, A, C,, PERTIG, H. H« and PAGE, I. H. persons^°*^ °^ l^acterial pyrogens on malignant hyper»tensive J. Labo Clin, Med, 33:1469-1470, 1948 A group of 35 patients, each with clearly-defined symptoms of !^fii®"®"* hypertension, received repeated injections of bacterial pyrogens which produced both fever and leukocytosis. The re- ^«o«. ''^''^ evaluated from the standpoints of changes in arterial pressure, cardiac, cerebral and renal functions and fundoscopic Signs, ^ Diastolic pressure was reduced in I6 of 35 patients. Fourteen 193 -19^8- patients became free of retinal hemorrhages and, of l6 patients with congestive heart failure, five were relieved during therapy; electrocardiograms became normal in seven, and heart size de- creased, for the entire group, from plus 1% to plus 5^ during treatment. Tolerance to pyrogens appeared in five to nineteen weeks when arterial pressures rose. However, the malignant syndrome did not, in the majority of patients, reappear. Remissions for periods of 24 to 30 months, on an average, were obtained by consistent treatment. Bacterial pyrogens are effec- tive in the absence of severe renal damage. 550. WAKIM, K. G., KRUSEN, P, H. and ELKINS, E, C, Effect of artificially induced fever on circulation in arthritic patients Arch. Phys. Med. 29:274-284, 1948 In a discussion of fever production through the use of passive (physical) agents and active substances (colloids, bacterial proteins, living parasites), it is noted that prodromal and chill phases are absent in the former. Both increase leukocyte formation and accelerate cardiac output, blood flow and the size of capillaries. There is an increase in metabolic catabolisra. 51. WELL9 J. A. and RALL, D, Po Mechanism of pyrogen-lnduced fever Proc. Soc. Exper. Biol, & Med. 68:421-424, 19^8 pyrogen (PYROMEN) will induce fever under conditions where increased heat production from muscular activity is impossible. Under such conditions, the mechanism of the pyrogenic reaction is one of rapid reduction of heat losses. 194 -19 4 9 552. ANDERSON, W. H. and BRODERSON, R. Hypothermia In the mouse as a bloassay of endotoxin protection factor In Impure penicillin Proc. Soc. Exper. Biol. & Med. 70:322-325, 19^9 Young adult mice conditioned In a constant temperature for two days before and during experiments received either (1) 0.5 nil. Impure penicillin containing 10,000 micrograms crystalline penicillin per ml. Intraperltoneally 20, l8 and 2 hours before Injection of 0.05 ml. of endotoxin (2) Impure penicillin alone or (3) no treatment. In further experiments hydrogen peroxide oxidation was used to destroy protective activity, and comparisons were made with controls protected by unoxldlzed materials. A constant dose of endotoxin was administered to a third group; It contained various dilutions of the protective factor. S. aertrycke endotoxin had the ability to reduce temperature markedly, while Impure peni- cillin previously Injected protected against lethal effects and hypothermia. 553. AUBERT, J. P. Existence of a polysaccharide In Bacillus megatherium Compt. rend. Soc. blol. 229:477-478, 1949 Methods for preparing polysaccharide concentrates from B. megatherium are described. Sporulatlon decreases the quanti- ty obtainable. The age^^ the culture^and carbon sources In the media wield Influence over the amounts produced. 195 -19 4 9- 554. BAKER, E. E. and GOEBEL, W. P. Studies on the enzymatic hydrolysis of the capsular polyr-L'i .1 saccharide of Klebsiella pneumoniae . Type B,, i:-.i- ..^..v ;.,y i-ie'i ds/-:.f:r:,_,:- '/■;::; " . - > "■ u'llv au030loincff sortBieloJ oU'ilv tioue to nor&os olcieqcdq-uxi sri^ cfD:'?'' ■"' ■ ~ ■ -■:~>VB 9ri:.J- no tb9bne,-tx9 .Federation Proc. 8:400, 19^9 sew au^lv bsctssri lo .noissraio'l tne&neqsbnl ed cj aiseqqB ol 3n^,V>'^,vv'' ' ■ .-...- .,.,,... r... ........r..-; oM bib 'An: enzyme capable of degrading capsular polysaccharide/ bns -n was Isolated from soil bacilli, A motile, gram-negative ^on spore-forming organism elaborates such an enzyme when it -Ifi grovm in the presence of 0.1^ capsular polysaccharide otii-j':! a medium containing ample sources of N but no growth factor. The enzyme specifically hydrolyzes capsular polysaccharide as shown by a change in the viscosity of the carbohydratei^f . T5cl Loss of serological activity accompanies this drop in vis- cosity. More than one enzyme may be Involved in the. phen-:^! omenon, -o-ia aoY'icftrts 'oe.t.oe'ini rno -.. £Oin2,Lls-oX'^0!:iO lo , Im snO 36 ilems 8.C E:--8ob ;::Mcfdfi'i srfJ al Q'sui^-a^qntsA nl asl's e beoub . ■ .s'yrusb wol s lo Tove'i bBOubo'iq oals , Xn 52.0 555-.V :. BENVENUTl* M.? -,3:^0^' .iojIb s'TUod S o;t il xoods nssucf eiu:t&is -9b 4i o:^ c 'i' s bertoso'j ,.rjoY'::d.a^-9 beioe'lni: 8-H'J rao-il beiuo f;i,,>>'> Su,41i un tentative dl cura assoclati vaccino-siereterapial della pollomielite anterlore acuta (A trial of the treatr.r,\f ^^oj meht of acute anterior poliomyelitis with-vaccine aia<3 jsersum rnuv..,.. therapy) ..,.,„..,,,„„..;.; j,;:* c'ly-vif',--:; b^^-Hjuo-ig cii:■'^:^^ be^o'^daeb -j-seri o;j- f)>iL!aoGxL5 ..soanoaaoi awiJrv erfd' besllBiJjjOif ,■■■ ^.•. • , -HB a-ios^Jtcl- n-tnld-ulsasmori .. ,|Riv*. clin. Pediat,. 47:137-141, .1949^ ,o^q ^I.dr,SB-.i&^d '^^^^'^^l eeiD'Jsi^aii;o:y yd b'^vc'i-7c';-^b e'law a iilsrf.d'a ':.*'-'J enj biia arj'ily ssneuii A trial was made of the use of anti^rables vaccine with ma1;ernal blood serum for five patients with severe or complete parsLlysis r, of the lower extremities. The average dose was 3 ml, of .9 vaccine per day and total dosage was approximately 25 ml* Is Arrest of the paralysis was secured in all five cases. Re- gression of the paralysis was succeeded by return of motility.. 8c'P The sequelae were insignificant, •-,.■';■- - nfiXbf^fl 196 - 1 9 4 9 - 556. BENNETT, I, L., WAGNER, R. R. and LEQUIRE, V, S. The production of fever by Influenzal viruses, II. Tolerance In rabbits to the pyrogenlc effect of Influenzal viruses J. Exper. Med, 90:335-347, 19^9 Prior Injection of certain strains of viruses (PR8 strain of In- fluenza A, Lee strain of Influenza B and "B" strain of NDV) con- ferred tolerance. In the rabbit, to the pyrogenlc effects of homologous virus as well as some degree of protection against the lymphopenlc action of such virus. The period of tolerance extended, on the average, over 11 days. The protective effect of heated virus was lost when hemagglutinins were destroyed. It appears to be Independent of specific antibody formation. No cross tolerance was demonstrable between bacterial pyrogens and viruses. Prevention of fever by antipyretic substances did not Interfere with protective Influence of previous condition- ing. No modification of the reactions could be secured with reticuloendothelial blockade. 557. BENNETT, I. L., WAQNER, R., and LEQUIRE, V. S. Pyrogenlclty of Influenza virus In rabbits Proc. Soo. Exper. Biol. & Med. 71:132-133, 19^9 One ml. of chorlo-allantolc fluid from Infected embryos pro- duced a rise In temperature In the rabbit; doses as small as 0.25 ml. also produced fever of a low degree. The rise In temp- erature began about li to 2 hours after Injection of fluid se- cured from PR-8 Infected embryos, reached a peak of 3 to 4 de- grees P. above baselines In four hours, then fell to normal levels. When normal chorlo-allantolc fluid or fluids freed from virus particles through centrlfugatlon were Injected, no fever resulted; the virus re-suspended In physiologic saline solution again produced temperature elevations. Homologous Immune serum neutralized the virus responses. Exposure to heat destroyed hemagglutinin titers and rendered preparations non-pyrogenio. Unlike heat-stable pyrogens the fever element of both PR8 in- fluenza virus and the Lee strain B were destroyed by temperatures above 62° C. The Lee strain required temperatures considerably higher for complete destruction of the pyrexlal material. Tol- erance to the substance was quickly attained but lost again In eleven days. Antibody titers Increased In the period. 558. BHARUCHA, K. Pyrogen and Its prevention Indian J. Med. Scl, 3:349-350, I949 197 -19^9- Technlques for production of nonpyrogenic solutions are outlined. Freshly distilled water should be used In preparing solutions. Adsorption of pyrogens by activated charcoal or asbestos is possible. Inactlvatlon with 0.01 N/HCl with subsequent neutra- lization of the acid eliminates pyrogen because of its carbohy- drate nature. 559. BOROFP, D. A. Study on toxins and antigens of Shigella dysenterlae . I. Tox- icity and antigenicity of whole organisms and various fractions of Shigella dysenterlae . J. Bact. 57:617-632, 19^9 Somatic fractions of S. dysenterlae or its "smooth" variant pro- duce identical antibodies and cross reactions with antiserum while the "rough" variant fractionated products do not Induce immunologic reactions. The toxic properties, present in all forms and fractions, are attributable to a single endotoxin, which may consist of a toxic protein, nonantlgenlc, a specific polysacchar- ide. Inducing antibody formation, and a lipoid. 560. BOROFP, D. A. and MAORI, B. P. Study on toxins and antigens of S. dysenterlae . II. Active pro- tection of rabbits with whole organisms and fractions of Shi - gella dysenterlae J. Bact. 58:387-39^, 19^9 Reciprocal protection against homologous strains of S. dysenterlae is afforded by either "smooth" or "rough" whole organisms or their respective toxins. Chemically purified toxins give simi- lar protection. Nontoxic variants give as effective protection as toxic parent strains. The presence of antitoxin or the leth- ality of its toxin are not determining factors in inducing im- munity. 561. BRUETSCH, W. L. Why malaria cures general paralysis J. Indiana M. A, 42:211-216, 19^9 The author revelws the literature on malarial fever therapy and concludes that in the therapy of luetic general paralysis, fever per se is a minor factor. Beneficial results depend upon the kind of fever produced and upon activation of the reticuloendo- thelial system to stimulate production of macrophages. Both malarial and typhoid fevers are most active in producing Intense macrophagic responses. Tissue immunity produced by retlculoendo- - 1 9 4 9 - thelial stimulation inhibits spirochetal growth, disintegration and disappearance. Regression and resolution of the inflam- matory processes in the brain follow. "The killing mechanism of the spirochetes in general paralysis. . .must be looked for in antibody production by the R-E cells." Any phagocytosis of spirochetes by malaria organisms or ingestion of pallida by capillary endothelial cells in the brain must be considered un- proven. 562. BUNTING, M. I., ROBONOW, C, P. and BUNTING, H. Factor affecting elaboration of pigment and polysaccharide by Serratia marcescens . J. Bact, 58:114-115, 1949 Capsule formation in A. aerogenes is encouraged when growth of the organism is restricted by excessive carbohydrate in the medium, but deficiencies of N and P. Cells assume a nuclear appearance as ribonucleotide leaves the cytoplasm. The accumu- lation of prodiglosin^ a pyrrole derivatlvej, parallels the ela- boration of polysaccharide in the cell. 563. CHAMBERS, WW,, KOENIG, H., KOENIG, R, and WINDLE, W. P. Site of action in the central nervous system of a bacterial pyro- gen Am. J. Physiol. 159:209-216, 19^9 Febrile response to a bacterial pyrogen from a Pseudomonas species (PYROMEN) appears to be mediated through the central nervous sys- tem, and the cord must be in functional communication with one or more brain centers. Such responses are prevented by transection of the spinal cord in the lower cervical or upper thoracic areas; side reactions were not Inhibited. When transection was made be- low T-5^ the development of fever was not prevented. Decortica- tion, thalamic and caudal hypothalamic lesions do not prevent fe- brile reactions, Decerebratlon at a pontile or medullary level did not prevent fever; an Integrating mechanism appears to exist in the medulla oblongata or the upper spinal cord; connections with the spinal cord below the cervical region renders the or- ganiam fully responsive to pyrexlal agents. 199 - 1 9 4 9 - 564. CHASIS, H., GOLDRING, W. and BALDWIN, D. S. Effects of febrile plasma ^ typhoid vaccine and nitrogen mustard on renal manifestations of human glomerulonephritis Proc. Soc. Exper, Biol, & Med. 71:565-56?, 19^9 No decreases in proteinuria were noted in patients with diffuse glomerulonephritis after repeated intravenous administration of plasma taken from febrile streptococcal infections » diuresis. In one patient administration of typhoid filtration rate, but not per kg. body weight) reversed the renal ulonephrltls, reducing proteinuria and, creasing urine output. patients during pneumococcal and Febrile plasma did not Induce V7ith marked renal function impairment, vaccine reduced proteinuria and the inhibition of urine flow. HN2 (0.2 mg. manifestations of glomer- in one instance, in- CREECH, H. J., HANKWITZ, R. P., JR o and WHARTON, D. R. A» Further studies of the immunological properties of polysaccharides from Serratia marcescens ( Bacillus prodlglosus ) . I, The effects of passive and active immunization on the lethal activity of the polysaccharides Cancer Res. 9:150-157, 19^9 In mice bearing dorsal implants of Sarcoma 37, passive immuni- zation with gamma -globulin fractions from serum rendered immune against strains of S_c_ marcescens protected the animal to some extent against the lethal dose of the polysaccharide of the same organism. Active immunization in tumor-bearing mice was accom- plished by the injection of small intraperitoneal doses of the polysaccharide followed by the dose ordinarily lethal to 90^ of test animals. A prolonged tolerance tovi^ard lethal activity of the polysaccharide could be established in both normal and tumor bearing mice, by a single injection of 1 per cent of the 90J^ lethal dose of polysaccharide from any of the strains studied. This appears to be a true immunological response. 566. CREECH, H, J. and HANKWITZ, R, P., JR. Further studies of the immunologic properties of from Serratia marcescens ( Bacillus prodlglosus ) . immunization against the lethal activity of the with fractions of mouse antiserum elicited hy a of polysaccharide Cancer Res, 9:589-591, 19^9 polysaccharides III. Passive polysaccharides single injection Protective antibodies multiplied rapidly in the serum of mice 200 - 1 9 4 9 - after injection of globulin fractions of mouse antiserum; the latter was elicited by single injections of S. marcescens. At a low globulin ratio (16-25) one fraction from P-10 preparation afforded a high degree of protection against an LD-tq dose of S. marcescens polysaccharide; a second preparation was less ef- fective. 567. CURRY, J. J. and SHAW, E, A. Continuous intravenous injection of typhoid vaccine in treat- ment of certain ophthalmic diseases Arch. Ophthalmol. 42:123-125, 19^9 Controlled hyperpyrexia through slow continuous intravenous injection of a suspension of killed typhoid organisms (1 billion per cc. and 1 cc. per liter of physiologic saline solution) pro- duced excellent results for I7 patients with ophthalmic condi- tions ranging from nonspecific iritis to syphilitic keratitis. The risk of reaction is believed to be reduced considerably by this method of administration. 568. DAGLEY, S. and DAWES, E. A. Factors influencing the polysaccharide content of Escherichia coli Biochem. J. 45:331-336, 1949 Glucose, lactose and galactose increase the growth of E. coli and increase likewise stored polysaccharide up to a maximum. Fructose and mannose do not produce such increases in the poly- saccharide. At a fixed sugar concentration, pH affected such storage with glucose and galactose media but not with mannose or fructose. Strain differences as to polysaccharide storage were also noted. Polysaccharide content falls during the sta- tionary phase of growth. The Sahayun method, when coupled with the Hagedorn-Jensen test for reducing sugars, was not satisfactory for the estimation of total bacterial polysaccharide. 569. DELAUNAY, A., DELAIMAY, M. and LEBRUN, J. The mechanism of lymphocytic lesions provoked by epinephrine and Salmonella typhi Compt. rend. Acad. Sci. (Paris) 288:139, I949 Vascular disturbances, destructive to lymphocytes, and not directly toxic effects upon nuclear or cytoplasmic components characterize the effects of S. typhi endotoxin or epinephrine. Hypodermic injection of lymphocytes with these substances into the guinea pig provokes the same ' lesions ' as shown by lympho- 201 -19^9- cytes in serum after injection of S. typhi endotoxin or epine- phrine only, 570. DOMBA, E. and GABOR, T. Extraction of Hormones, Viruses, Toxins and Antitoxins (Trans, title) Hung. Patent #139,965, Sept. 24, 19^9 Pyrogens may be removed from bacterial and biological prepara- tions by cyclic or heterocyclic acids. Removal with ETOH and 10^ BzOH is followed by cooling and filtration when room temperatures are again attained. 571. DORCHE, J. and BOUTHIER, G. Pyrogenes des solutions injectables (Pyrogens in injectable solutions) Ann. pharm. franc. 7:267-276, 19^9 The application and techniques of the pyrogen test of the U. S, Pharmacopeia are discussed and modifications suitable for small laboratories are suggested. 572. ELLIS, P. A. GRANT, R. and HALL, V. E. Typhoid -paratyphoid vaccine and respiratory response to the in- halation of carbon dioxide Am. J. Physiol. 158:16-20, 19^9 The hypothesis is presented that pyrogenic substances may depress respiration, and other neuronally mediated processes connected with periodicity of breathing, at medullary or higher levels. The inhalation of CO2 increased breathing, and no significantly important alterations were produced by subsequent injection of typhoid vaccine. Respiratory minute volume was increased in anaesthetized animals, 573. FELTON, L. Do The significance of antigen in animal tissues J, Immunol. 61:107-117, 19^9 In mice injection of 0,5 mg. of specific polysaccharide antigen may produce immunologic paralysis extending through the normal 202 _ 1 9 4 9 - I life of the animal; the carbohydrate may be isolated from body tissues for at least one year after immunization^ and hyper- sensitivity is exhibited toward the type-specific organism. No antibody is produced either toward bacteria or immunizing doses of the polysaccharide. Human beings may become non-reactive toward immunizing doses of polysaccharides from an initial paralyzing reaction. It is postulated that a given antigen may become firmly fixed to cell surfaces of the reticulendothelial tissues and lose capacity to act as an antigen. 57^. PRANCKENSTEIN, R„ Uber die typhosen Erkrankungen in Kindersalter und ihre Behand- lung mit Pyrifer (Enteric fevers in older children: Treatment with pyrifer) Medizin. klin. 44:199-203^ 19^9 Nerve regulatory centers affected by cyclic infection by E. typhi in children produced symptoms which were benefited by the in- jection of pyrifer, 20 to 50 units, intravenously. Temperatures rose in one-half to one hour thereafter, with mild rigors. Other syTiiptoms of a psychotic nature associated with the usual clini- cal picture were seen in 80 children infected by E. typhosa or paratyphi B. Younger children gave most rapid response to pyrl- fer and very slight reactions were followed by excellent results, with very little relation between fever production, onset of chills and the therapeutic result being evident. Pyrifer re- duced temperature elevation in a child, 18 months old, in whom encephalitis, stupor and a roseola appeared after paratyphus infection. 575. GERMAN, A, Pyrogenes (Pyrogens) Ann. pharm. franc. 6:464-479, I949 After reviewing the literature of pyrogenic phenomena and making certain comparisons between the action of known pyrogens and that incidental to vaccinotherapy and "protein shock", the author concludes that pyrogenic reactions may be responsible for bene- fits derived from vaccine injections. It is difficult to explain why antibodies appear after injection of killed bacteria in in- fections in which little antibody formation is developed by the pathogens present „ Shock may be responsible for some beneficial reactions to so-called "protein"substances, but it is noted that superior results followed the use of three strong producers of pyrogen, ie. streptococci, staphylococci and Ps. aeruginosa , in a bacterial preparation (prodidon). The initial leukopenia following the injection of pyrogens and the ensuing leukocytosis 203 -19 4 9- raay be brought about by a dual activity in pyrogen: (l) massive liberation of antibody by lymphopenia, and (2) defense reactions by the organism with the release of leukocytes in an effort to combat stress. 576. GINSBERG, H. S. and HORSFALL, F. L., JR. A resistant variant of mumps virus. Multiplication of the var- iant in the presence of inhibitory quantities of Friedlander bacillus polysaccharide J. Exper. Med. 90:393-407, 19^9 A large single inoculum of mumps virus or serial passage of the virus in the presence of inhibitory quantities of capsular polysaccharide of Friedlander bacillus , type B may produce var- iant virus strains, with infective and agglutinative qualities identical with the parent strain, but slower to multiply and not inhibited by polysaccharide. In the absence of the polysacchar- ide, serial passage again produces the original sensitive strain. 577. GRANT, R. Nature of pyrogen fever: Effect of environmental temperature on response to typhoid -paratyphoid vaccine Am. J, Physiolo 159:511-523, 19^9 Oxygen consumption was used as a measure of calorigenesis when intravenous injections of typhoid -paratyphoid vaccine or "Pyrexln" were given to rabbits kept under constant environmental conditions, The amount given was about 100 times the minimal pyrogenic dose. In moderate and warm environments, moderate doses of TPT brought initial temperature increases, a temporary fall in about 1 hour and renewed inhibition of heat loss mechanisms toward the end of the 2nd hour. With very large doses the early course of fever is the same, but pyrexia may be prolonged. With very small doses, initial temperature rises are identical with those produced by larger amounts, but the final rise in temperature begins early. Oxygen consumption during the first hour Is not affected by temperature changes; after the first hour, hypothermia follows in the shorn cold animal. The scant evidence available suggests that pyrogens may interfere with thermoregulation at lower levels of the brain stem^ 578. GRANT, R. and ROBBINS, M. E. Effect of ethyl carbam.ate on temperature regulation Federation Proc. 8:59,1949 204 - 1 9 4 9 - Prior or subsequent intravenous Injections of urethane did not alter the inhibition of heat loss mechanisms by bacterial pyrogens; intraperitoneal injections of urethane may allow vaso dilation.^ with polypnea unaffected. 579. GRANT, R., ROBBINSj M. and HALL^, V. E. Effect of environmental temperature on the febrile reaction to typhoid paratyphoid vaccines and other pyrogens Am. J. Med. 6:395, 19^9 (Abstract) After the intravenous injection of pyrogen, the oxygen pro- duction in the rabbit increases to a maximum during the first 20 minutes, and is approximately 15 per cent higher than that of controls for the first hour. It remains slightly above normal during the second and subsequent hours of fever if en- vironmental temperatures remain moderate or warm; when exposed to severe cold, oxygen values show sharp reductions below con- trol values during the second hour and return to normal levels during the third hour. In normal environmental temperatures the second hour after a pyrogen injection brings an inhibition of heat defense mechanisms^ and fever increases are again recorded. 580. GROSSMAN, M„ I. and BLICKENSTAPF, D, Quantitative aspects of inhibition of gastric secretion by pyrogens Am. J. Physiol. 159:572, 19^9 (Abstract) A lag period between the appearance of pyrexia after intravenous injection of pyrogen and inhibition of gastric secretion has been reported. Another gap exists later in the test between tempera- ture relations and gastric secretion Inhibition. 581. HALL, V. E., FISHGOLD, J- and GRANT, R. Oxygen consumption of liver slices from febrile and normal rabbits Federations Proc. 8:66, 19^19 (Abstract) If, as suggested, heat production of the liver is increased during fever produced by bacterial pyrogens, measurement of O2 consumption in vitro of liver slices taken from rabbits 15 minutes after injection of typhoid -paratyphoid vaccine does not confirm such observations. 205 -19^9- 582. HATTA, S., AOYAMA, K., and TANJI, S. The cause of fever by Injection and Its real condition (trans- lated title) Sogo Igaku 113:887, 19^9 An article in the original Japanese text. 583. HATTA, S., AOYAMA, K. and TANJI, S. Elimination of pyrogen substances (translated title) Saishin Tgaku 41: 612, 19^9 584. HATTA, S», AOYAMA, K., and TANJI, S. Studies on the bacteria and its harmful substance of injection and internal medicine in general use II. (translated title) Jap. J. Pub. Health 5:20-23, 1949 585. HEYMAN, A., and BEESON, P. B. Influence of various disease states upon the febrile response to intravenous injection of typhoid bacterial pyrogen J. Lab. & Clin. Med. 34:l400-l403, 19^9 Malarial fever appears to render its victims resistant to later injections of typhoid bacterial pyrogen; normal febrile response was lacking. With cirrhosis of the liver, the response was in- tensified. In many infectious diseases, little or no deviation from the normal fever curve is seen, 586. HOLMAN, J. and SWINEPORD, 0., JR. Studies in bacterial allergy. II. Preparation of crude nucleo- proteln and polysaccharide fractions of bacteria J. Allergy, 20:4l8, 1949 After alcohol precipitation of crude polysaccharide from the colon bacillus, Ps , pyocyaneus . Streptococci ( hemolytlcus vlridans or fecaTIs ), and the causative organisms of respira- tory infections, nucleo protein could be separated by precipi- tation with dilute acetic acid. 206 -19 4 9- 587. HOSOYA, So, HOMMA, Y., EGAMI, F, and YAGI, Y. On the isolation of antigenic substances from Pseudomonas aeruginosa (Translated title) Jap, Jo Expero Med, 20:55-68, 1949 An antigenic nucleoproteln was prepared from the Tsuchijitna strain of Ps. aeruginosa by precipitation with ZnClo, dialysis and acetone precipitation. It was LheatTs^able (100° C,,l hr.) and contained 5.8^ carbohydrates and 11.5^ N, The nucleo- proteln was precipitable with immune rabbit sera in dilutions to 1; 250, 000. It conferred immunity to a homologous strain of living bacilli, 588. KORNERUP, To Damage to visual organs resulting from typhoid inoculations Acta Ophthalmol, 27s 311-^54, 1949 After typhoid vaccine therapy, optic atrophy, neuritis or neuro- retinitis, temporary color blindness or muscular paralysis ap- peared in certa5„n patients. Allergy or activation of latent virus infect5.on may play roles in such conditions, 589. LEESE, C. E, and GREENE, K. V. Physiological effects of bacterial polysaccharides upon the cardie vascular and neuromuscular systems Federation Proc. 8;93, I949 In the rabbit injections of polysaccharide ranging from 2 to 25 gammas per kg, were administered. At higher dosage levels, dis- turbances of nervous reflexes, convulsions, urination, defecation and vomiting preceded death. In cats, arterial blood pressure fell while venous pressures increased. A loss in autonomic con- trols was seeni the vagus, splanchnic and cardiosympathetlc nerves required increased stimuli after polysaccharide was administered. Decerebratlon was fatal when the drug was administered prior to operation. Intense cardiovascular changes with heart block and dilatation of chambers were seen in the turtle perfused with polysaccharide preparations, 590. LEHMANN, H. ?ff3""^^^^ °^ ^ chemotherapy of neoplastic ailments (Translated ult le J 207 - 1 9 4 9 - Schweiz. Apoth. Zelt. 87:741-7^3. 19^9 Pyrogens, cytostatic preparations, radioactive materials and the hormone therapeutic preparations are discussed. 591. LEQUIRE, V. S. Augmentation of the thermogenic effects of pyrogens by homo- logous plasma in rabbits. Naval Medical Research Inst. Project NM007047. Report #6,1949 See: LeQulre, J, Infect. Dis . 83: 194-206, 1951 592. LIBERALLI, C. H. Metodos de Ensaio para plrogenio (Tests for and elimination of pyrogens) Anais faculdade farm, odontol, Univ. Sao Paulo 7:129-170, 1949 Better results are secured when rabbits used in pyrogen testing are carefully checked for temperature changes 4 or 5 times a day for two to three consecutive days before the day of pyrogen administration. A group average for 5 rabbits should be computed. Pyrogens may be eliminated to varying extents by Al(0H)3, Pe(0H)3 and Cu(0H)g. 593. LONSEN, W. and LIEBERT, E, Studies on a new pyrogen fever treatment Illinois Med. J. 96:186-190, 1949 PYROMEN is a nonprotein, bacteria-free product, free from toxic substances, whose action in the treatment of neurosyphilitic patients compares favorably with those secured through malarial and typhoid vaccine fever therapy. It appears to be less danger- ous than malarial therapy, and has been used, in this study, fir older patients. Because of the small dosages used, administra- tion is not difficult. Its action in these cases appears to rest in a strong mobilization of body defense mechanisms. 594. MHONEY, V, P. and HAMMERMAN, S. Combined treatment of symptomatic paresis with penicillin and fever produced by continuous typhoid vaccine J, Nerv. & Ment, Dis, 109:133-141, 1949 208 -19 4 9- 1 Although continuous Intravenous typhoid vaccine therapy Is practi- cable for adjuvant fever therapy with penicillin, some selection of patients would improve the results obtained in these inves- tigations. The two criteria used were (1) no clinical evidence of cardiovascular disease (2) ages under 50 years. 595. MARTELLI, P. and NUROLONE.. U. La piretoterapia nel trattaraento della paralisi facclale primi- tiva con particolare riferimento alia forma inveterata (Pyreto- therapy in the treatment of primary facial paralysis, with particular reference to chronic cases) Minerva med» (Turin) 2:403-4o6, 1949 In primary idiopathic facial paralysis, but not in secondary manifestations associated with more fundamental causes, bene- fits were secured through use of agents, physical or otherwise, which elevated the temperature. Results would support the hypo- thesis that primary facial paralysis may be of allergic etio- logy^with fever acting, in these improved cases- as anti-aller- gen. 596. MCGINTY, D, A., WILSON, M. L. and RODNEY^ G. The ulcer-inhibiting action of pyrogens Proc. Soc. Exper. BioJ. & Med „ 70:334-336, 1949 Extracts from urine known to possess pyrogenic activity have inhibited ulcer formation in rats. These observations have been extended to the use of purified substances from cultures of B. prodigiosu s, Ps . aeruginosa and E. typhi , given by vein in 0.5 ml. volurae prior to pyloric ligation In the rat, or by stomach tube during the period of recovery from anaesthesia. Pyrogens from B. prodlglosus (3 to 10 gammas) protected iS of 23 rats against ulcer (index 72); the index fell to I5 when do- sage levels were raised to 35 or 50 gammas. Intraperitoneal injections were less effective and higher dosages were required (100-1000 gammas). Typhoid pyrogens inhibited ulcer formation in 75^ of the rats under therapy. Ps_. aeruginosa pyrogen was less effective than that secured from cultures of B. prodlglosus . Non-pyrogenic polysaccharides (pneumococcal carbohydrates) had no anti-ulcer acltvity. The mechanism of action by which results are obtained is not clear, but both volume and acidity of gastric secretions appear to be reduced. 597. MENKIN, V. An additional thermostable component in the mechanism of leuko- cytosis with inflammation 209 -19^9- Poderation Proc. 3:362, 19^9 The thermostable, pyrogenic factor, pyrexln, induces the Initial leukopenia. It is found in the euglobulin fraction in the acid exudates of inflammatory processes. A second thermo-^ stable component appears to be in close association with pyrexin and to play a part in the induction of high levels of leukocyte formation. 598. MORGAN, H. R. and NEVA, P. A. Tolerance to the toxic effects of somatic antigens of enteric bacilli in typhoid and paratyphoid fever convalescents, J. Clin. Invest. 28:S00, 19^9 (Abstract) Intravenous test doses of the endotoxin of S. typhosa (5 mlcro- gram.s) produced no evidences of the marked febrile responses and reactions seen in normal individuals when it was administered to convalescent patients after infections with typhoid or para- typhoid organisms. Shigella dysenteriae (7 micrograms) somatic antigen was not productive of febrile reactions after resistance had developed following spontaneous infections, 599. MUETHER, R, 0. Pyrogens in intravenous solutions Hospital Prog, 30:301, 19^9 The author briefly reviews the causes of pyrogen reactions and their sources, symptoms and treatment, and the manner in which bloassay of parenteral fluids may be conducted. 600. NECHELES, H. (Editor) 21st Annual Report, Med. Res. Institute, Michael Reese Hospital 19^9 The observation has been made that even minimal amounts of cer- tain bacterial pyrogens may depress normal functions of the stomach, le. secretion of acid and normal emptiring time. The re- duction of gastric spasm in ulcer conditions might aid healing processes. Doses of pyrogen too minute to produce fever depress secretory activity, and it is tentatively stated that these sub- stances may be responsible for therapeutic results achieved by certain preparations commonly prescribed in ulcer therapy. 210 - 1 9 4 9 - 601. OLITZKI, L, Anti-leukopenic tolerance of rabbits and antibody formation in the course of treatment with typhoid vaccine Acta Med. Orient. 8:103, 19^9 Tolerance to the leukopenic effects of typhoid vaccine developed in rabbits during treatment and was unrelated to development of antibodies in the blood serum. The tolerance was noted most frequently after intra-abdominal administration. Leukocytes collected in pulmonary areas during the period of leukopenia and were released in the succeeding phase. 602. OTT, W. H. A quantitative assay method for pyrogens J. Am. Pharm. A. (Sci, Ed.) 38:179-184, 1949 When test animals were carefully selected for similarity of re- sponse to a standardized pyrogen (a standard error variation computed on the basis of the assay values in 4 rabbits was found to be minus or plus 6o^) , a method for reducing error was de- veloped, which would greatly increase the number of animals used m assayo The standard error is Inversely proportional to the square of the number of animals used in the assay. The correctioa can be aided further by standardization procedures adapted by each testing laboratory and preparation of dosage-response curves for groups of animals tested under these conditions. 603. PAGE, I. H. and CORCORAN, A. C. "Treatment with Pyrogen." Arterial H ypertens ion. Chicago; The Year Book Publishers, Inc. 2nd Edition, 1949 ;"pp. 328-330 Thirty-five patients were treated with the pyrogenic agent PYROMEN J- or periods extending from 5 to 19 weeks. A good clinical re- sponse was shown by I9 patients. The most marked difference between Improved and unimproved groups appeared to be the pre- sence of arteriolar sclerosis. Delayed response to pyrogens m both normal and hypertensive patients Involve vasodilatation, particularly in the renal vascular bed. Increased renal blood flow usually persists for 24 to 36 hours after the pyrogenic reaction. In the above group., patients who improved averaged b2 mg, per minute per 1.73 sq, m. body surface as shown by TMPAH readings and only 26 mg. in unimproved patients. Blood pressure was reduced; there was regression of retinal hemorrhage and ab- sorption of retinal exudates. Congestive heart failure resis- tant to therapy improved in five Instances, Immediate hemodynamic 211 _ 1 9 4 9 - responses and adrenal plasma and tissue enzyme interrelation- ships may enter into the mechanism of response to pyrogens. For hypertension^ pyrogen treatment must be given under careful supervision; hospitalization is required. PAGE, I. H. and TAYLOR, R, D. Pyrogens in the treatment of malignant hypertension Mod. Concepts Cardiovasc Dis= l8:51, 19^9 PYROMEN is considered to be the most satisfactory agent in the treatment of malignant hypertension, according to the results evaluated by the authors c Twenty patients have been treated with this agent over a period of four years. All selections for this therapy were based on the presence of renal function ade- quate enough to excrete para-amino hippurate at 35 mg„/"iii^°/l»73 sq. m. body surface, or to concentrate urine at specific gravity of 1.020 or above. ' PYROMEN was administered intravenously daily for 5 or 6 days per week. The initial dose was 50 micrograms, successive doses were increased to maintain a temperature rise to 103 or 104° P. each day. When tolerance developed, treatment was discontinued for 3 to 7 days. Of 20 patients so treated, ten survived. Of five who discontinued treatment before re- sults were obtained, 4 died, four patients who exhibited early improvement developed essential hypertension later. Where cardiac decompensation existed PYROMEN therapy appeared to be of value. PATTERSON, J. L., HEYMAN, A, and NICHOLS, P. Tc Effects of fever induced by bacterial pyrogen on cerebral cir- culation and oxygen consumption Am. J. Physiol, 159:584, 1949 (Abstract) Cerebral blood flow and oxygen consumption levels were deter- mined in 16 patients with asymptomatic neurosyphilis after intra- venous injections of typhoid vaccine..: Comparisons were made with readings secured during the afebrile state. Cerebral vascular resistance was significantly decreased (average 25.4;^) as the rectal temperature increased to a mean 3.8° P. above previous readings. The blood flow was unchanged. When vascular resis- tance was above the normal in the afebrile state, values were higher. Mean arterial pressure reductions of 2.4^ accompanied cerebral vascular tension decreases. There was a high degree of correlation between^oxygen consumption and cerebral flow during fever, but these levels were unrelated to each other during afebrile periods. 212 - 1 9 4 9 - 606. PEISS, Co N„;, FIELD, J., HALL, V. E, and GOLDSMITH, M. Comparison of respiration and glycolysis In the brains of nor- mal and febrile rabbits Am, J» Physiol. 157:283-286, 1949 In comparing oxygen consumption and anaerobic glycolysis rates in both febrile cortical tissue and normal preparations, no statistically important differences could be ascertained, nor was there support for thethesis that the cellular metabolism of the central nervous system is a limiting factor on thermic regulation of the animal. 607, PHILLIPS, K, The clinical response to vaccine in 125 cases of rheumatic disease Rheumatism 5:53-57, 19^9 Rheumatoid osteo -arthritis, myositis and flbrosltis improved , in a study covering 125 patients. A stock mixed vaccine was 1 employed . 608. PINCHOT, G. B., CLOSE, V. P., and LONG, C. H. N. Adrenal changes produced in rats by infection with E. coll Endocrinology, 45:135-142, 1949 Rats were given large doses of living E. coll organisms intra- venously. The adrenal cortical response was similar to that produced by a single injection of ACTH in its effect on adrenal size, ascorbic acid and cholesterol levels. Dosages of adrenal cortical hormone many times larger than are required for the maintenance of adrenalectomlzed animals failed to prevent a de- pletion in adrenal cholesterol or prolong survival time after infection with B= tularense . Manifestations of stress were present. 609 o ROBERTSON, H. P., KISSEN, M. D., FLOTHOW, M. W, The inherent dangers of fever therapy in the treatment of paresis Urol. & Cutan. Rev. 53:409-412, 1949 The literature on malarial therapy In paresis is reviewed, and results achieved with typhoid fever therapy assessed. With all types of therapy a 50^ Improvement may be expected, but typhoid 213 -19^9- vaccine therapy was projductlve of results 10^ better than those achieved with other forms employed. However, a decrease in plasma proteins, the onset of renal dysfunction and certain vascular changes are contraindications to further therapy. 610. ROSA, M. C. Loss of pyrogenic activity by solutions prepared for intra- venous injection (.Translated Title) Rev. brasil. farm. 31:121-127, 19^9 "...pyrogenic activity disappeared from physiologic saline solution after 71 days. Isotonic glucose solutions prepared and sealed in an atmosphere of CO2...PH 4.5-^.8, lost activity after 41 or 62 days respectively ... (when) prepared without these precautions and with pH 6.8 retained activity 53 days. pH between 4.5 and 6.8 did not influence the rate of loss of pyrogenic activity. Concentration may be a more important factor. 611. RZUCXDLO, L. Odczyn opadania cialek czerwonych jako metoda roznicowania wielocukrow bakteryjnych (Erythrocyte sedimentation rate in the differentiation of bacterial polysaccharide) Med. Doswiad. i. Mikrobiol. (Warsaw) 1:40-51, 1949 The erythrocyte sedimentation rate is increased after adminis- tration of polysaccharide-lipid -protein complexes from bacteria of the Salmonella group, or their carbohydrate derivatives. Other polysaccharides in suspension fluids do not enter into such complexes and have no effect on sedimentation rates. 612. SCHEINMAN, L. J. The use of pyrogens in the treatment of lower nephron nephrosis J. Urol. 61:1003-1009, 1949 Inconclusive results during a study of the effect of increased renal flow on symptomatology of lower nephron nephrosis suggest that the rabbit may not be the best animal for use in the study of the problem because it possesses a most efficient reticuloendo- thelial system. i 214, - 1 9 4 9 - 613. SELIGMAN, A. M. and SACK, T. Chemical alteration of polysaccharide from Serratia marcescens: Reaction of polysaccharide with radioactive paraiodo benzene- — diazonium chloride and use of product in experimental and chemical study J. Nat. Cancer Inst„ 10:105-118,. I949 The preparation of a radioactive iodobenzene azo product is described. Toxicity of the radioactive product was similar to the unmodified polysaccharide of S. marcescens as was shown by changes following the administration of the carbohydrate m three patients with malignant tumors. '''• anfE^ETT^M! r'™' "' '" ^''^^' '' ^- ^«^^^> '' ^• Serum polysaccharide levels in experimental inflammation Proc. Soc. Exper. Biol. & Med. 72:294-296, I949 J^^S^^^^'^v^'^?^^ inflammation, bacterial, or, as in this study, la?ed'hf,t^^ irritant agents such as turpentine or talJ! Tde-' recorded ^^P^^^sive increase in serum polysaccharide was to slv d^... o2r "'f^^"^""^ elevation does not appear until three iLved ?n^L ^^^'^ injury, the role of tissue destruction is be- resDonslble foi^'^h ^^^^n-f^istent . Regenerating tissue may be responsible for the elevation which is independent of tempera - ^^^* IrS^^R ^«^ R., POSTER, J. v., KELLY, K. H., SHETLAR, C. L. BRYAN, R. S. and EVERETT, M. R. ^ ^. j^. ologicarco'ndL'fSns'^'"' ''"'' '" malignancy and in other path- Cancer Res, 9:515-519, 1949 theTeak^no^Sa^^^i'^f/^^^i" ^^ neoplastic disease are higher than normal lev2^f?;.^''^i^; ^"^ ^^^^^n tumors, no production of ab- skin and Of JhrS "°^!'^' ^^^^^^ ^^^^^ 1°^^^ in carcinoma of the increased ThJ ?™^** ^^^^^ surgical removal blood levels atlon and renp?r. mS^^^^ "^^^ ^® connected with tissue prolifer- chroni? con^f?^n; ^^! ^^""""^ polysaccharide is increased in many norspecl??cal]?^ir^ "^^?^ infectious processes, hence levels are noi; specifically diagnostic for neoplastic disease. 215 -19^9- L6. WHARTON, D. R. A., and CREECH, H. J. Further studies of the Immunological properties of polysaccharides from Serratia marcescens ( Bacillus prodigiosus ) . II. Nature of the antigenic action and the antibody response In mice. J. Immunol. 67:135-153, 19^9 A tolerance which reached its height on the third day after a single injection of P-10 polysaccharide-lipid complex of S. marcescens protected mice against a lethal dose of the poly- saccharide. Heating did not diminish ability to produce anti- bodies but did reduce toxic properties. The agglutinating ' antibody reached high titer levels on the 10th day after admin- istration of the substance. Anaphylaxis was not produced (in guinea pig) . Two fractions may be present in the complex, a toxic and an immunizing component. ' 617. YAGI, Y., EGAMJ, F., HOSOYA, S., NONOBE, K., HAYASHI, T. and HOMMA, Y. Studies on the endotoxine of Salmonella enteritidis , Gartner. I. Studies on the chemical nature of the endotoxin. II. Studies of the amino acid content and the sugar component of the endotoxin Jap. J. Exper. Med. 30:2^^5-259, 19^9 A crude endotoxin was prepared from S, enteritidis and subjected to fractional precipitation. The resulting concentrate contained 2.9-3.6^ N, 1.1-1.58<^ P, 2.1^ S and 43-55^ reducing sugars. Positive reactions to the Bial and Dische tests for carbohydrates were noted. Absorption curves reached their peaks at 2400-2700 Angstrom units. Three fractions were secured by heating with acetic acid: a neucleoprotein (MLD 1 mg.), a polysaccharide, non- toxic, which contained methyl-pentose, pentose and desoxy-sugars. The methyl-pentose fraction exhibited two hydrazones and a phenylosazone which resembled those found in the breakdown of f ucose. 216 ^^ - 1 9 5 - 618. ALBOT, G. and BERNARD, BRUKER, N, Nouveau traitement des dlarrhees par les emulsions de Bacillus Subtllls (New treatment of diarrhea by emulsions of B. subtilis ) Sem, hopit. (Paris) 3^00-3^035 1950 619. ALTSCHULE, M. D,, PARKHURST, B. H., and PROMISEL, E. Effects of intravenous injections 3of typhoid vaccine on blood leukocytes and adrenal cortex A.M. A. Arch. Int. Med. 86:505-518, I95O When typhoid vaccine was injected intravenously into psychotic patients (6)^ cellular redistribution in blood was observed, with lymphocytes and eosinophils decreased by approximately 80^, and granulocytes increased from 50 to 200^ after each treatment. The lymphocyte count returned to normal after three days. No correlation with the degree of fever produced could be measured. Electirc shock therapy did not produce such startling changes (eosinophils decrreased 48^, lymphocytes but l6^) . Changes in the urinary output of 17-ketosteroids were seen. Urine uric acid: creatinine ratios varied inversely to the degree of vaccine fever, 620. ARENDSHORST, W. and FALLS, H. P. Role of the adrenal cortex in treatment of ocular diseases with pyrogenic substances A.M. A. Arch. Ophth. 44:635-642, I95O This study was planned to determine the effects of "protein shock therapy in ocular disease and as an investigation of the possible release of 11, 17-oxysteroids from the adrenal cortex. The circulating eosinophil response to injections of the antigen was taken as the most sensitive index of cortical activity. Typhoid H antigen was used as a "foreign" protein, and in dosages ranging from I5 to 25 million units initially to higher concentrations, was administered to patients with various uveal diseases. Correlation was noted between eosinopenia, fever and the general response to the pyretogenic agent. Six of 21 patients had poor eoslnopenic responses and proved to be resistant to foreign protein shock". Drop in eosinophils usually occurred about I8 hours following injection;.. Improvement in ocular tissues was seen in 14 patients. The effects of pyretotherapy were attri- buted by the authors to the initiation of an "alarm" reaction and succeeding stimulation of the adrenal cortex, but no .satis- factory explanation for the mechanism involved could be produced. 217 - 1 9 5 - When foreign protein therapy induces a refractory condition, the use of ACTH or cortisone is advised; the adrenalcortical factors are useful when pyrogenic therapy no longer produces eoslnopenia or must be prolonged for longer than one week. 621. ASHENBURG, N. J., SANDHOLZER, L. A., SCHERP, H. W.^and BERRY, G.P. The inhibition of bacteriophagy by bacterial and nonbacterial polysaccharides J. Eact. 59:^81-687, 1950 Relationships between polysaccharide and bacteriophage resemble those existing between antigen and antibody, the former existing as a surface antigen and inhibiting lytic action. Nonspecific inhibition has been credited to starches, glycogen and gums. In this study the effect of nonbacterial polysaccharides and those obtained from capsules of Aerobacter and Klebsiella was to in- hibit the lytic action of Friedlander Haclllus bacteriophage. All exhibited this activity, but inhibition was not complete; it varied with the polysaccharide used and the host organism. 622. BECK, L. V. and VOLOSHIN, T. Influence of adrenal hormones on toxic and tumor-damaging effects of certain substances A. J. Physiol, 163:696-697, 1950 (Abstract) Cortisone and adrenal extract may counteract the damage wrought by tumor-necrotizlng substances on sarcoma #37. Mice injected either intraperitoneally or subcutaneously with cortisone ex- hibited increased tolerance for arsenite administered one hour later by either intravenous or subcutaneous routes. When adrenal extract was injected peritoneally, there was an increased toler- ance for both arsenite and mapharsen, and some protection against arsenite could be secured by previous Injection of ACTH. The increase in tolerance was greater in the male and at the L5 level. Cortisone or adrenal extract, when administered before intra- peritoneal Injections of the tumor-necrotlzlng polysaccharide of S. marcescens , increased tolerance, and cortisone also afforded some protection against the Intravenously injected polysaccharide. Protective patterns differed fromthose invoked against arsenlcals. The adrenocortical factors do not protect mice against lethal or sublethal amounts of alpha peltatln or acrldines. 623. BENNETT, I. L., JR „ , and BEESON, P. B. The properties and biologic effects of bacterial pyrogens 218 - 1 9 5 - Medicine 29:365-^00, I95O In a comprehensive survey of the literature of pyrogenic substances extending from I855 to the present day^ the bacter- iology, physical characteristics and chemical properties of these substances are outlined and discussed. In turn, the application of pyrogens to therapeutic uses and physiologic re- sponse to their administration are outlined in detail. "The role of pyrogens in disease is still Incompletely understood." A bibliography containing 246 references is appended. 624. BERGSMAN, A. and HEDENIUS, P. De pyrogena substansernas betydelse via parentcralt bruk av vltskor (Problem of pyrogens in the use of parenteral solutions) Nord Med. ^3: 672-676, I95O 625. BLICKENSTAFF, D. and GROSSMAN, M. I. A quantitative study of the reduction of gastric acid secretion associated with pyrexia Am. J. Physiol. 160:567-571^ 1950 Pyrexia produced by Intravenous pyrexin or bactei-lal pyrogen was not directly responsible for inhibition of secretory activity in the dog. PYROMEN, prepared from cultures of Ps. aeruginosa, in doses ranging from 0.5 microgram per kg. to 10.0, and pyrexin, from sterile pleural exudate, 2 tc 30 rag. were administered to 'gastric pouch' dogs and secretions were collected for three or more hours thereafter, A preliminary injection of histamine, 0.0125 mg. subcutaneously, was repeated at frequent intervals throughout the test. In no test was there depression of se- cretion without a rise in body temperature. When only slight Increases in temperature were registered, secretion was not in- hibited. However, a lag of approximately one hour between onset of pyrexia and reduction of gastric secretion, as well as the extension of inhibition past the period of temperature reduction, would appear to rule out pyrexia as the primary agent in this phenomenon. The state of hydration did not affect results. 626. BLUMENTHAL, L- S. and FUCHS, M. Headache Clinics. I. What is the headache problem? Am. Pract. ? Digest Treat. 1:1012-1015, I95O Work on ACTH and PYROMEN, which appears to act in a manner slmlla? to adrenal cortical derivatives, is still in the experimental Ill - 1 9 5 - stages. Proper application of PYROMEN, the antihistamines, ACTH, potassium thlocyanate, banthine and dehydrogenated alkaloids of ergot will be described in later publications. 627. BOQUET, P. and IZARD, Y. Effect of dlbenamlne on vascular response of rabbits to typhoid vaccine Proc. Soc. Exper.-Blol. & Med. 75:25^-259, 1950 The Intense initial peripheral vasoconstriction produced in rabbits by an injection of typhoid endotoxin was noted in earlier studies. It was believed to be caused by the release of adrenalin (or adrenalin-like substances) from tissues. To confirm these findings, the role of adrenolytic agents in inhi- biting or modifying vascular response was tested by injecting 0.5 to 0.8 ml. per kg. of S. typhosa endotoxin into the rabbit and follov/ing this with intravenous dlbenamlne (6-10 mg. per kg.) Cutaneous circulation was observed by three methods, two visual and one involving the use of thermocouples. Dlbenamlne modified vasoconstriction when administered either before or after the endotoxin, but, for sustained effect, blocking was necessary be- fore and after the vaccine. 628. BOVE, E. Nogle problemer 1. pyrogenbestemmelsen (Problems of pyrogen determination) Sven. farm, tidsskr. 5^:721-726, 1950 629. CARLETTI, B. La vaccinazione aspeciflca Intradermica nella malattla di Helne- Medin, Parte I. Storla, tecnlca e meccanlsmo d'azione (A specific Intradermal vaccination in poliomyelitis. I. History, techniques and mechanism of action) G. Mai. Infett. parassit (Florence) 2:l80-l87, 1950 Intracutaneous Injection of 5OO to 5OOO million nonspecific organisms in a vaccine preparation was made every 4 to 7 days for 20 Injections. The treatment was often repeated 2 to 3 months later. The site of injection was the cutis of the lower limbs, and administration was usually made at several points in the area. Among the organisms present in the killed state in th$ -^^accine, E, coll , Pr . vulgaris , the pyogenic streptococci. Ma pyogenes and catarrhalis and , S. paratyphosa A and B are noted. Seventy of 242 patients treated improved; circulation increased and neuromuscular function was benefited. 220 - 1 9 5 - 630. CHARY, R. and ARDRY, R. Note sur le controle pyrogenique des solutions cltratees utlllsees dans le transfusion sanguine (Notes on the pjrrogenic control of cltrated solutions used in blood transfusion) Ann. blol. clin. 8:504-506, 1950 631. CLEMENTE, CD. Leukocytosis in the rat upon oral administration of a bacterial pyrogen Am. J. Physiol, 163:703, 1950 Significant leukocytosis was observed when FYROMEN, 1 gamma daily, was administered to the rat. White cell counts increased from normal levels (15,000 cells per cu. mm.) to 35,000 or 40,000 cells per cu. mm. after 1 to 4 gammas of PYROMEN, but tolerance became evident after sustained dosages at constant levels, and white counts resumec normal levels. While in- creased doses were ineffectual during the period when the leuko- cyte count was returning to normal levels, a secondary leuko- cytosis could be elicited after a rest period of 6 days; the re- sponse was of shorter duration and lower intensity than the first. The percentages of granular cells to the non-granular types did not alter with the rising count. In only two of four animals observed was leukopenia noted. In two animals, circulating eosinophils showed an initial decrease but increased during the leukocytosis along with other granular cells. Histologically, no pathologic changes could be demonstrated in endocrine, di- gestive, lymphatic or excretory organs after oral administration of PYROMEN. 632. CORELLI, P. L'importanza del pirogeno nella pratica medica e trasf usionale (contribute alia profilassi delle reazioni da trasfusione, da ipodermoclisi, fleboclisi, da endovenose di calcio, ecc.) (Im- portance of pyrogen in medical transfusion practice; contribution to prophylaxis, reactions due to transfusion, to hypodermoclysis, to phleboclysis, to intravenous calcium, etc.) Pollclinico (sez. prat.) 57:345-34?, 195O Reactions may occur even when depyrogenated solutions are em- ployed since glassware, tubes, needles, or residues of blood and plasma may produce pyrogens, which after sterilization, continue to act as "denatured" pyretogenic agents, A thorough cleaning must precede sterilization, for elimination of possible pyrexial materials. 221 - 1 9 5 - 633. DORCHE, J., and CASTAING, M. Sur la recherche des substances pyrogenes dans les solutes In- jectables; les essais bases sur la leucocytose du lapln (Re- search on pyrogenic substances in injectable solutes; tests based on leukocytosis of the rabbit) Ann, pharm, franc, 8:353-357, 1950 The leukocyte count is too variable in the rabbit for use as a test factor for pyrogens in solutions intended for parenteral injection. Injection of pyrogen-free solutions and observa- tions of the increases in the poljmorphonuclear cell count should precede the administration of pyrogenic solutions. Differences between the grades of polynucleosis should be recorded for use as a test control measure, 634. DORCHE, J, and CASTAING, M. Sur la recherche des substances pyrogenes dans les solutes in- Jectables; attenuation des proprietes pyrogenes au cours de la conservation des solutes (Research on pyrogenic substances in injectable solutes. Reduction of pyrogenic properties during the storage of solutions) Ann. pharm. franc, 8:365-368, 1950 Prolonged storage of solutions reduces the pyrogenic factors in most solutions. Glucose solutions are exceptions, 635. DORCHE, J., BOUTHIER, G,, ARDIET, M. T., and CASTAING, M. Sur la recherche des substances pyrogenes dans les solutes in- Jectablesj Commentaires et application de I'essai de la Pharma- cop^e francaise (Research on pyrogenic substances in injectable solutes. Commentary on and application of the bio-assay according to the French Pharmacopoeia) Ann. pharm. franc, 8:358-365, 1950 Factors which influence the bio-assay may be physiologic or cheraic in nature. Hypotonic solutions may yield false positive readings for pyrogenic content. The sensitiveness of the rabbit to handling is noted; special precautions must be taken in plac- ing the rectal thermometer during the test, 636. FARR, R. S. and LEQUIRE, V. S. Leukocytic and pyrogenic effects of typhoid vaccine and augmen- tation by homologous plasma 222 - 1 9 5 - Proc. Soc. Exp. Biol. Med, 75:661-666, 1950 These experiments were designed to study the correlation be- tween the magnitude of leukocytic and thermogenic responses to pyrogen in the rabbit and the amount of pyrogen administered. Vaccines from 2 strains of E. typhosa were used. Fifty-eight male rabbits were divided into four groups; in each group one of the following was injected intravenously: physiologic saline solution; saline pius typhoid vaccine; normal rabbit plasma; normal plasma with typhoid vaccine. Animals were observed for six consecutive hours, during which total and differential leukocyte counts and rectal temperatures were frequently measured Saline and homologous plasma alone were without effect. Plasma - typhoid injections produced high fever, initial heterophile leukopenia and secondary heterophile leukocytosis. Saline- typhoid solutions produced only initial heterophile leukocytosis. Both these groups developed mononuclear leukopenia with the plasma -typhoid combination producing a more pronounced drop. By increasing the number of organisms in the saline suspension tenfold, it was possible to produce a response similar to that seen after plasma-typhoid injections, and conversely, reduction of cells in plasma -typhoid suspensions brought an initial hetero- phile leukocytosis. Five variables must be considered when using the leukocyte count as an index for the pyrogen test: amount of pyrogen; time at which the observation is made; differ- ential composition of the leukocyte population; the type of bacteria in the source; the media used for suspensions. 637. Fever therapy i« asthma Queries and Minor Notes. J. A.M. A. I44:l4l9, I950 "The salutary effect of acute febrile disease on allergic mani- festations has been known for centuries. Chronic and intractable asthma frequently becomes more completely relieved by inter- current non-respiratory infection than by almost any other means." The mechanism by which benefits are achieved is not clearly de- fined. Typhoid vaccine, colloidal sulfur and malarial therapy have been employed as has high frequency current. "More recently a pure carbohydrate constituent obtained from certain bacteria and known as PYROMEN has been used to produce fever." 638. PLENSBORQ, E. W. General reactions following treatment of asthma in children with ' bacterial vaccine (English) Ugeskr. f. Laeger 112:392-399, 1950 223 -19 5 Reactions to administration of the common pathogenic respiratory bacteria in the treatment of asthma of childhood become more severe during extended treatment. These are considered to be late reactions occurring, on the average, after two days. They may continue from 6 hours to 6 days. Repeated overdosage may induce prolonged temperature increases or status asthmaticus. Best treatment is prophylactic application of a minute dose, careful increases in dosage with attention to even slight reactions, and frequent temperature recordings during the first four days. 639. FLENSBORG, E. W., NEERBORG, G. and SAMSJ2fE- JENSEN, T. Probable bacterial-allergic asthma in children and its treatment (English) Ugeskr. f. Laeger 193:387-392, 1950 Children, one to four years of age, with asthma, but giving a negative cutaneous reaction to usual allergens, may have a bacterial allery as an aftermath of early infection in the upper respiratory tract. Clinically, symptoms are identical with those seen in patients who have positive cutaneous reactions. Eosino- philia is noted in both groups. The authors have used a special standard vaccine prepared by the State Serum Institute with better results than are seen after specific desensitization in children with positive cutaneous reactions. General reactions, however, may be marked even with small doses of vaccine. Treatment should be continued one year after disappearance of the clinical symptoms. 640. FRANZOLIN, C. Sulle raodificanzioni leucocitarie provocati della piretoterapia nelle m. inf iammatorie acute e chroniche (Leukocytic modifications induced by pyretotherapy in acute and chronic inflammatory diseases) Acta med. (Patav.) 11:19^-199, 1950 FREIMULLER, F,, and RHOMAKO, M. Tiber die Frubehandlung der poliomyelitis anterior acuta mlt pyrogenen substanzen (Pyrogenic substances in the early treatment of acute anterior poliomyelitis) Wiener Ztschr. inu. Med. 31:501-506, 1950 22^ - 1 9 5 - 642c GOSSELIN, W. Effets des polysaccharides sur le sarcome de la sourls (Effects] of polysaccharides upon the mouse sarcoma) Rev, brasll Cancer 3;27-505 1950 While mice tolerate dosages of the polysaccharides of S. marces -l cens 1000 times higher per unit of body weight than do human beings^ 25 to 50^ of the animals die with 24 hours. A method of reducing toxicity of the material is a prerequisite for its use in extensive cancer therapy. Antihistamines do not reduce toxicity, nor does vitamin B^. Rutin (1.0 ml. of 0.1^ to 50 gammas of the polysaccharide) brought about the survival of 11 out of 12 animals, and did not affect the hemorrhage-inducing and necrotic qualities^ which suggests that the hemorrhagic action of the polysaccharides does not depend on capillary fragility o 643. GRANT, R. Emotional hypothermia in rabbits Am. Jc Physiol. 160:285-290, 1950 A transient hypothermia may be induced in rabbits by light restraint as well as by any activity which may activate heat loss mechanisms. Cold, applied or environmental, may inhibit the phenomenon, as do pyrogen injections. When 5 gammas of PYROMEN, prepared from Ps, aeruginosa ., were given intravenously to a re- strained anlmaT~that had recently regained its normal temperature after a hypothermic period, interruption of the fever began about 1 hour after injections as shown by ear vasodilation and polyp- noea. The temperature fell to 1.25° below normal then stabil- ized at this level o In the unrestrained animal an initial drop in temperature was succeeded by an intense febrile state with no subsequent hypbthermia. Modification of cerebral cortical con- trol upon thermoregulation is postulated. Pyrogens may act on the motor mechanism of thermoregulation and not on higher centers of control, Anlm.als used in pyrogen testing should not be re- strained, 644, GRANT, R, and HIRSCH, J, D. Pyrogen fever in rabbits; Effects of adrenalectomy Am, J„ Physiol o 161j 528-533, 1950 In a preliminary study, changes in rectal and ear temperature and 225 - 1 9 5 - in the respiratory rate of the adult rabbit were recorded after the intravenous injection of 0.1 ml. per kg. of PYROMEN, con- taining 50 gammas per ml. of purified pyrogen. Seven days later a comparable amount of PYROMEN was injected and the effect on oxygen consumption observed in a part of the group. Bilateral adrenalectomy was then performed in two stages, 2 to 6 weeks apart and DCA implanted subcutaneously. After stabilization of rectal temperature and body weight, the effect of PYROMEN was again studied. When animals were maintained in a healthy state through use of DCA, adrenalectomy affected the course of pyrogen-induced fever but little. It is suggested that the re- moval, by adrenalectomy, of inhibition exerted on shivering by epinephrine may underlie a mechanism which leads to calorigenesis. 645. GRANT, R., HIRSCH, J. D. and HIRSCH, B. B. Pyrogen fever in rabbits: Effects of adrenalectomy and thyroid- ectomy Federation Proc. 9:50, I95O Shivering appeared to increase oxygen consumption following adrenalectomy with subsequent maintenance on DCA. No other effect on the normal responses to pyrogen injections could be remarked. Thyroxine, after thyroidectomy, had no effect upon normal re- sponses to pyrexial agents. While neither the adrenals nor thyroid are essential intermediaries in fever production, the mechanism by which heat is produced may be altered in the adrenal- ectomized animal; increased shivering with subsequent thermal response may be caused by shivering precipitated by the removal of the inhibition normally exerted by epinephrine. 646. HARKNESS, W. D., LOVING, W. L, and HODGES, F. A. Pyrexia in rabbits following injection of filtrates of typical mold cultures J. Am. Pharm. A. 39:502-504, 1950. Abstract, Federation Proc, 9:282, 1950 When injected intravenously, preparations from I6 out of 31 species of mold cultures brought elevations in the body temper- ature of the rabbit. A medium containing dextrose and peptone (Sabouraud) was required for production of pyrogenic characteristic inorganic salts and N sources in the medium restrained its develop- ment. 647. HARKNESS, W. D. and VOS, B. J. Comparison of the effects of injection of pyrogenic solutions by 226 - 1 9 5 - Intravenous and Intramuscular routes J. Am. Pharm. A. (Sci. Ed.) 39:^13-^14, I95O Rabbits were given intravenous injections of a pyrogenic solution prepared by the method of Welch in amounts ranging from 0.001 cc. per kg. to 0.1 cc, and the same dosages in more concentrated aliquots of solution were administered intramuscularly. The ratio of the intramuscular to the intravenous response to the . same amount of pyrogen was computed. Six rabbits were used at each dosage level and a rise of 0.6° (U.S. P. XIII assay) was considered significant. All pyrogen dosages gave signifi- cant temperature rises when administered intravenously. At any given dose this route produces higher rise in temperature. Re- sponses to intramuscular doses of pyrogen were graded and lower for any given dosage. "When the temperature response is plotted against the logarithm of the dose a linear relationship is seen to exist within certain limits," 648. HATTA, S., AOYAMA, K., and TANJI, S. Studies on the bacterial pyrogenic substances Jap. Med. J. 3:125-135, 1950 A simplified method for detecting pyrogens in Solution is des- cribed. Pyrogens were extracted from pyrogen-positive strains of bacteria (sarcinae and micrococcus sp.); from three strains of fungi ( penicillium sp., fusarium and macrosporlum ) and from S. typhi and S. paratyphi . Pyrogenic materials were found in both mycelia and metabolic products. When mycelia were crushed, extracted, and filtered and the filtrates condensed and cry- stallized, a yield of 80 to 100 mg. was secured from 50 Gm. of cultured mycelia. The crystals were colorless and had melting points of 163°, Tests for protein and for sugar (Fehling and Molisch) were negative. There was a C content of 37.7^, of H, 8.12^. Pyrogens fluoresced blue and were dialyzable through semi-permeable membranes. When injected into rabbits I5 mg. per body weight, they produced temperature increases ranging from I.5 to 2,0°C., but 30 mg. injected intravenously in the mouse did not prove lethal. The bacterium. Micrococcus s^. GIO produced two types of sub- stances one absorptive and one nonabsorptive on chromatographic partition. Both fluoresced blue and were dialyzable. Pyrexia in rabbits was produced by I5 mg. per kg. of the absorptive portion and and by 10 mg. per kg. of the nonabsorptive. Thirty mg. was not a lethal dose for mice. Phenol extraction of S. typhi and _S_. paratyphi cultures, water precipitation, followed by dialysis and precipitation of super- natant fluid, produced yields of 70 to 100 mg. of pyrogenic 227 - 1 9 5 - material from 5000 cc . S. t yphi cultures and l6 to 200 mg. from S, paratyphi cultures. Both Mollsch and Fehllng tests were positive. Both preparations fluoresced blue. Fifty gammas per kg. of S. typhi pyrogen and 75 gammas of the paratyphi prepara- tion produced febrile reactions In rabbits. The fluorescence of pyrogens In ultraviolet light was applied to a method for detecting these substances In solution. Solutions of dextrose, fructose. Invert sugar, CaClgj 10^ sodium citrate, Salso-brocanon solution and Glynogen, were subjected to U.V. light. Three per -cent of the tubes exhibited fluorescing phen- omena; only eight of twenty such tubes were pyrexia -producing for the rabbit. When compared with negative solutions, only 4^ of the latter produced fever. The pyrogen zone appears to be around 2650 and absorption spectra at this wave length remain consistent. 649. HEIDELBERGER, M., MACLEOD, CM., MARKOWITZ, H. and ROE, A. S. Improved methods for the preparation of the specific polysac- charides of pneuraococcus Neutralization of acidity in developing bacterial cultures should be avoided if one wishes to Isolate certain cell constituents in their native states. The specific polysaccharides of Type I and V pneumococcus may be damaged by alkaline environmental conditions and on precipitation yield smaller amounts of anti- body-carrying materials. Degradative processes may also be Initiated by bicarbonate disodium phosphate. 650. HEILBRUNN, L. V., and WILSON, W. L. Effect of bacterial polysaccharide on cell division Science, 112:56-57, 1950 Recent experiments with a polysaccharide extracted from S. marces - cens (Shear's polysaccharide) would tend to prove that it exerts a heparin-like action on cell division. Both polysaccharides have similar inhibiting Influences upon fertilization, although such inhibition may be overcome by additions of sperm in excess amounts. Both act to prevent mitotic gelation which may be pre- liminary to cell division. The bacterial polysaccharide also resembles heparin in preventing coagulation of human blood but high concentrations are necessary. Its potency is about 1/300 that of heparin. In one experiment outlined, Chaetopterus eggs were immersed in dilute solutions of bacterial polysaccharide (0.058^-0.125^) before and after fertilization. The polysaccharide enters egg cells more rapidly than heparin. A solution of Shear's P-25, 228 - 1 9 5 - 0.15^, reduced cleavage from 100^ (In seawater) to 0.5^. Excess sperm additions reduced the degree of Inhibition. The Increase in protoplasmic viscosity before mitosis was also prevented. Use of the polysaccharide or dicumarol in cancer therapy is discussed. 651. HEILMEYER, L. Angange einer Chemotherapie neoplastischer Erkrankungen (Chemotherapy of neoplastic diseases) Schweiz. med . Wchnschr. 79:530-5^7, 19^9 and Naturwissenschr. 37:58-65, 1950 In reviewing the literature dealing with the Effects of chemical cytostatics upon the cells of tumors, other active substances are considered. In addition to cell nucleus toxins (colchicine, trypaflavine, the urethanes, mustard gases, stilbamidine, aminop- terln and metallic salts) other active materials, including the polysaccharides and pyrogens, hormonal substances and radioactive preparations, are effective under certain conditions. 652. HEISTJZr, H. Pyrogene reaksjoner, med saerllg henblikk pa deres forebyggelse (Pyrogenlc reactions with special considerations of their ore- vention) '^ Tidsskr. norsk. laegerfor. 70:264-266, 1950 In parenteral therapy dangers of unpleasant reactions exist when pyrogens are present. Prevention may rest in careful production of material destined for injection, in elimination of pyretic substances after production and the cautious approach to initial therapeutic application. 653. HEYMAN, A., PATTERSON, J. L,, JT^ . and NICHOLS, F. T., JR. The effects of induced fever on cerebral functions in neuro- syphilis J. Clin. Invest. 29:1335-13^1, 1950 Fever was induced in 27 patients thro pyrogens, malaria parasites or induce function changes in dementia paralytl syphilis were assessed. Pyrogenlc ma organisms per cc. or 0.1 cc . each inj ranged between 101.0 and 104.0 degree response, cerebral blood flow, oxygen ugh use of typhoid bacterial d hyperthermia. Cerebral ca or asymptomatic neuro- terlal averaged 1 billion ection. Rectal temperatures s. At the height of pyrexia! consumption and arteriovenous' i 229 -19 5 0- oxygen differences and vascular resistance were determined. Paretic patients with the greatest amount of mental deterioration had the lowest oxygen concentration in this area; with fever, the optimum increase expected was approached. There was no correlation between the degree of fever and O2 consumption. Mean arterial blood pressure fell during fever. Patients with asymptomatic neurosyphilis had normal oxygen consumption in the afebrile state which was not altered during fever. In dementia paralytica subnormal oxygen consumption was evident before fever (2.1 cc per 100 Gm. per minute); during fever a 24^ in- crease was registered (2.6 cc). It is believed that, in the normal individual, cerebral blood flow and oxygen consumption are likewise altered during pyrogen hyperthermia. 654. HILL, A. G. S., DEANE, H. W. and COONS, A. H, Localization of antigen in tissue cells, V. Capsular poly- saccharide of Frledlander's Bacillus , type B, in the mouse J. Exper. Med. 92:35-^4* 1950 The fate of a capsular polysacchatide (that of Priedlander bac- illus. Type B) was studied by means of homologous antibody lab- elled with fluorescein. When injected intravenously into the mouse, this acid polysaccharide is rapidly taken up by phago- cytes In body tissues. It was seen in collagenous fibers of all organs, in capillary endothelium, in the hepatic epithelium and bile, the Juxtaglomerular segment of the distal renal tubule and in a few casts. It had penetrated epithelium in uterine glands, the hormone-secreting tissues of the ovary, the suprarenal corr? tex, and lymph nodes and lymphocytes of the spleen. Synovial membranes contained large amounts, "The polysaccharide was ^ found in high concentration in pulmonary macrophages" after Inhalation. 655. HOWE, E. E. and TISHLER, M. U. S. Patent #2.532,^03, Dec, 5, 1950 A method for removing pyrogens from aqueous solutions of the acid salts of streptomycin. 656. HOWIE, J. E. Pjrrexial treatment of ulcerative colitis The Lancet 25:827-8s8 (#6642), 1950 The author presents a brief case report of a patient suffering from ulcerative colitis for two years, who, after a course of - 1 9 5 - twelve intravenous injections of pyrlfer, has been free from any clinical signs of chronic colitis despite two attacks of dysentery In other similar cases it is said that results were somewhat com- plicated by the fact that this preparation produced less fever; wartime processes may have been responsible. 657. JACOBS, P. A. Damage produced by Pseudomonas aeruginosa fraction in sarcoma 37 Canad. Res. 10:227, 1950 Cultures of Ps. aeruginosa R, grown on semi-synthetic media con- taining glycerol and fatty acids, contained a fraction capable of inducing damage to Sarcoma 37. Intraperitoneal administration of fractions from either culture fluid or cell pack of the or- ganism produced macroscopic hemorrhage and succeeding necrosis of tumor tissue in mice. The tumor damage was confirmed micro- scopically. Fractionation of the culture fluid showed that the activity was resident in a water-soluble, alcohol-insoluble polysaccharide. The method of measuring tumor response to treatment is described. 658. KAPLAN, M. H., COONS, A. H. and DEANE, H. W. Localization of antigen in tissue cells. III. Cellular distri- bution of pneumococcal polysaccharides. Types II and III in the mouse J. Exper. Med. 91:15-30, I95O Distribution of pneumococcal polysaccharides in the tissues of the mouse was followed histochemically by means of the fluores- celn-antibody technique (Coons, et al. ) or the periodic acid method (Schiff; McManus). Preparation of tissues was spaced at intervals ranging from 1 day to 6 months after a single dose of the polysaccharide under consideration. Polysaccharides were found in most constant and striking concen- trations in the cells of the reticuloendothelial system, the capillary endothelium and in fibroblasts throughout the body. They were detectable in monocytes and lymphocytes, hepatic, cardiac and smooth muscle cells, in uterine epithelium, the steroid -forming cells of the adrenal cortex, in testes and ovaries They were persistent for 75 days in macrophages of the lymphoid organs, the Kupffer cells of the liver, interstitial macrophages of the myocardium, in lung septal cells, capillary endothelium and renal glomeruli. After six months, they were still present 231 - 1 9 5 - in macrophages of the spleen, liver and heart and in peritubu- lar capillary endothelium of the kidneys. The smallest dose of polysaccharide to produce a positive preci- pitin reaction in serum and detectable quantities in cells in 24 hours was 0.03 mgo A comparison of the distributions of polysaccharide, acid dyes and suspensoids is made. Possible relationships between distribution, antigenicity and toxicity may exist. 659. KASS, E. H., and. FINLAND^ M„ Effect of ACTH on induced fever New England J, Med. 243:693-695^ 1950 Varying numbers of killed typhoid bacilli were injected intra- venously in two patients with chronic rheumatoid arthritis, prior to or after Administration of ACTH. The duration and intensity of the febrile response was reduced by administration of ACTH in advance of the pyrogen. That the antipyretic effect of ACTH is not to be credited to tolerance developed toward pyrogens has been confirmed in the rabbit. The mechanism by which ACTH exerts the antipyrexial effect is not known. There is no alteration of the fundamental pathologic process of the illness under treatment. It is necessary to differentiate between antipyretic and antipathologic results after the use of ACTH. 660. KIERLAND, R. R, and KULWIN, M, H. Clinical evaluation of a new pyrogenic agent A.M. A. Arch. Dermato & Syph, 62:571-572, 1950 The pyrogenic agent, PYROMEN, was used clinically in 46 derma- tologic patients suffering from a number of diseases. The usual initial dose was 25 micrograms given intravenously; subsequent dosages were based on the production of oral temperatures of 102,0 degrees F. The drug was administered on alternate days. The largest amount given in a single injection was 125 micro- grams; the greatest number of injections given to one patient was ten. Results showed PYROMEN produced a sa-tisfactory "therapeutic" fever. Individual duration of temperature elevation was fairly "constant and . . „independent of the dose of the material injected." Untoward side reactions were few and mild. The authors conclude that PYROMEN "is a Safe agent for use in producing therapeutic fever" since the results compared favorably with those obtained by the use of typhoid vaccine and lacked certain unpleasant side effects noted with the latter preparation. - 1 9 5 - 661. KIRKENDALL, W. M., HODGES;, Ro E. and JANUARY, L. E. The ACTH-like effect of fever In man \ J. Lab. Clin. Med. 36:845-846, I950 1 A marked drop in circulating eosinophiles regularly occurs four to eight hours after injection of a pyrogenic agent in patients with malignant hypertensive conditions. The phenome- non has been reportedlin humans after typhoid vaccine injections and in animals after induced fever. Since eosinopenia occurs also after administration of ACTH, the hypothesis that fever- producing agents may stimulate production of ACTH was tested. PYROMEN^ typhoid vaccine and physically-induced fever were employed for 2? human patients, all with normally functioning pituitary and adrenal glands, but with hypertensive disorders. The circulating eosinophil and total leukocyte counts, and the ratio of multi-nucleated cells to Ttiononuclear types and of uric acid to creatinine were determined; excretion of corticosteroids was measured in five patients. i In response to fever an initial leucopenia occurs; the decrease is mainly one of mononuclear cells. Eosinopenia follows fever in three to eight hours. Occasionally chills precede the marked leukocytosis (increased polymorphonuclear elements) which follows in 12 to 24 hours after injection. The administration of therapeutic doses of an antihistamine, of aspirin or dibenamine did not prevent such changes. No changes in the uric acid/creati- nine ratio or in corticosteroid excretion followed fever pro- duced by the three agents employed. It was believed that these would be altered if the leukocyte response reflected release of the adrenocorticotropic hormone. However, the short period of stress occasioned by the administration of pyrogenic materials may be only long enough to alter the blood picture alone. It is concluded that "in persons with normal pituitary glands, fever causes the relase of small amounts of ACTH." 662. LEESE, C. E., POEL, W. E. and BERMAN, H. Effects of the Shear bacterial polysaccharides upon cardio- vascular response Fed. Proc. 9:76, 1950 When 100 to 1200 gammas per kg. body weight of the Shear poly- saccharide was administered to the rabbit, the circulation time increased. A depressive action was seen with blood pressure falling to one-third to one-half the normal levels; a slow rise began within five to ten minutes. Once the blood pressure re- gained the normal level, subsequent injections had no influence. The depressive effects of the polysaccharide was not prevented by an antihistamine. The EKG was indicative of tachycardia with Inversion of both P and T waves; there was an abnormally high S-T takeoff which disappeared within six hours. I 233 - 1 9 5 - 663. MENKIN, V. Further studies on thermostablle leukocytosis factor of exudates Federation Proc. 9:338, I950 A thermostable leukocytosis factor may be Isolated from exudates which contain the pyrogenlc (thermolablle) factor. The thermo- stable factor does not produce fever or leukopenia but Induces leukocytosis through stimulation of the discharge of young granulocytes Into, the circulation. It Is not a polypeptide but contains at least one carbohydrate group. It Is believed that the thermolablle leukocytosis factor may be a polypeptide. 66^^. MTOIK, P. Zur Fleberbehandlung der akuten Poliomyelitis ( Pyretotherapy of acute poliomyelitis) Therap. Gegenwart 89:274-275, 1950 The author examines the results obtained In poliomyelitis through the use of temperature-elevating substances. In his own services, vaccine, pyrlfer and nucleohexyl have been utilized, as reported by R. Muller and H. Arens (Therap. Gegenw. 19^7- 1948) . 665. NESSET, N. M., MCLALLEN, J., ANTHONY, P. Z. and GINGER, L. G. Bacterial pyrogens. I. A pyrogenlc preparation from a Pseu - domonas species J. Am. Pharm. A. (Scl. ed.) 39:456-459, 1950 A relatively non-toxic bacterial pyrogen has been obtained from a culture of a Pseudomonas organism. After growth over a period ranging from one to ten days, cellular materials were digested by trypsin, centrlfuged, washed and lyophlllzed. Digestion by the tryptlc method employed was compared with proteolysis by papain, pepsin, polldase-S, pancreatin, a fish enzyme, duodenal powder, ictozyme, protease and an intestinal preparation; none yielded satisfactory results. Nine enzyme preparations with dlastatlc activity failed to produce detectable decreases in the pyrogeniclty of cells. Other solvents and fractionation methods were studied. Approximately 50 per cent of the concentrate obtained was pyro- genlc polysaccharide. Seven per cent was hexosamine and 27 per cent deaoxyribonucleic acid. Ribonucleic acid was present (8.1^). Protein content was negligible. The ash constituted - 1 9 5 - 12.9^ of the concentrate. Per the rabbit the MPD was 0.3 gammas per kilogram of body weights The LD50 ^'^ ^^^ mouse was 75^000 gammas per kilogram of body weight, 666. NEVA, P. A. and MORGAN, H. R. Tolerance to the action of endotoxins of enteric bacilli in patients convalescent from typhoid and paratyphoid fevers J. Lab, Clin. Med, 35:911-922, 1950 Initial dosages of 5.0 micrograms of typhoid antigen ( or alter- nate doses of S. dysenteriae antigen and typhoid antigen) were administered to convalescents recovering from typhoid or para- typhoid A fevers. The antigens had been prepared by the method of Morgan. When compared with healthy subjects who received the same amounts of the two antigens, a definite tolerance or resistance to the pyrogenic activity of toxic somatic antigen was demon- strated after convalescence; this was unrelated to the amount of circulating antibody. No tolerance was exhibited toward the toxins following recovery from other infections (bacillary dysenr tery, gonococcal arthritis, pneumococcal pneumonia and tularemia). Other investigators have advanced the theory that increased activity in the reticuloendothelial system may underlie the mechanism by which tolerance develops. 667. New light on endotoxins Editorial Note. The Lancet 1:722, I95O The somatic antigen or endotoxin which may be extracted from members of the colon-typhoid-dysentery group (possibly excepting S^. shlgoe) is attributable to a polysaccharide and nitrogen complex. It produces circulating antibodies, a terminal circulatory hypertension n hyperthermia^ transient hyperglycaemla and succeeding hypoglycaemia. Its hemorrhagic action on the placenta is followed by abortion; similar activity occurs in transplanted tumors. Adrenal cortical extract appears to prevent certain toxic effects, which are more lethal for the guinea pig than for mice; the ratio was 17.5 to 1 when guinea pigs were injected subcutaneously with a suspension of heat-killed B. coll organisms. Mice received intravenous doses. The gross appear- ance of lesions suggests that capillary hemorrhages are pro- duced by a terminal hypertensive action. Antibodies in serum from a mouse immunized with endotoxin were 30 times more potent than commercial B. coli antiserum in protecting others of the species against B. coll infection. I 235 - 1 9 5 - 668. NOOJIN, R. 0,, PACE, B, P. and PRAYTOR, H. B. Prolonged fever produced by three injections of typhoid vaccine Am. J, Syphilis 3^: 153-160, 1950 The advantages Inherent in typhoid vaccine fever therapy are: (1) easy administration, (2) controllability, (3) development of natural resistance, (4) simplicity, (5) inexpensiveness, (6) no after-treatment as with malarial therapy and (7) mini- mum side effect. Some of the disadvantages are: (1) hospi- talisation is required, (2) timing of fever is needed, and (3) some hypersensitivity may be exhibited. If the rise in fever is considered as proportional to the benefits derived, 20 million organisms should be injected intravenously, follovx^ed by subsequent injections at two-hour intervals for the first two doses, then three times per day for the duration of the course of treatment. 669. PIORKOWSKI, G. VJirkungssteigerung fiebererzeugender Mitt el bei gleichzeitiger intravenb'ser and intracutaner Anwendung (Increased efficacy of fever-producing drugs by using combined intravenous and intra- cutaneous application) Med. Klin. 45:630-631, 1950 670. RALL, D. P., and WELLS, J. A. Inhibition of thermal panting by bacterial pyrogen J. Pharmacol, cc Sxper, Therap. 9-3:27, 1950 Failure of the dog to pant in response to pyrogenic fever is interpreted as being, in part, due to inhibition of the thermal canting mechanism. Chronic cord transected dogs responded to environmental temperature elevation with fever (103.5-105^'?. ) and panting. The latter was inhibited by introduction into a running venoclysis system of purified pyrogens from Pr. vulgaris or Ps. aeruginosa (PYROMEN). The degree of inhibition closely followed increases in dosage, and respiratory rate decreased sharply after injection of 0.04 to 1.2 xng, pyrogen; average re- duction in 15 to 30 minutes ranged between 15 and 53 per cent. 671. RANDOLPPI, T. G. and TOLLINS, J. P. Pyromen in the treatment of perennial allergic symptoms Ann. Allergy 8:626-640, I95O 236 - 1 9 5 - A group of 150 patients has been treated with PYROMEN, Intra- venously, orally or by a combination of the two routes, over periods ranging from 10 days to 8 months. Subpyrexial doses of 0.5 to 10.0 gammas have been employed. The frequency of ad- ministration has been dependent on the allergic manifestation treated and the degree of control obtained. PYROMEN therapy has been found to be most efficacious in treatment of those patients for v.'hom partial or complete specific diagnosis had been made; a combination of PYROMEN therapy with Inhalant desensitizatlon has resulted in excellent management of peren- nial allergic symptoms. The authors believe that beneficial effects obtained during this study may be the result of stimu- lation of the pituitary-adrenal system. Side effects with this therapeutic regimen have been infrequent and mild in nature. 672. REINHARD, E. H,, GOOD, J. T. and MARTIN, E. Chemotherapy of malignant neoplastic diseases J. A.M. A, 142:383-390, 1950 In a lengthy discussion of chemotherapeutic agents used in the treatment of neoplasms, the authors discuss the potency of S. marcescens polysaccharide, the reticuloendothelial cytotoxic sera and other biologic antineoplastic agents. Toxicity is the limiting factor in application of the polysaccharide of S. marcescens . 673. RODBARD, S., SACI, H. and MALIN, A. Body fluid redistribution in induced hypothermia and hyperthermia Federation Proc. 9:107, I950 Actual fluid volume and fluid shifts in hyperthermia and hypo- thermia were determined in both rabbits and chicks. The data suggest that there is a marked shift from plasma and interstitial spaces to the intracellular phase during hypothermia, but hema- tocrit and specific gravity do not show equivalent Increases. It is suggested that both blood cellular elements and plasma proteins may be stored. This phenomenon is reversed during hyperthermia as water leaves the cells of tissue and releases plasma protein and red cells into the circulating blood. 237 - 1 9 5 - 674. RODNEY, G., and DEVLIN, H. B. Chemical composition of some bacterial pyrogens Federation Proc . 9:220, 1950 Pyrogens in a purified form were isolated from strains of B. prodiglosus , B. subtllis , Ps . aeruginosa and E. typhi grown on symthetlc medTa, After digestion, nucleic acTd and pyrogens were removed, and the latter was fractionated by means of or- ganic solvents. Carbohydrates present in hydro lysates were quantitatively separated by filter paper partition chroma- tography. Analyses for nitrogenous materials and phosphorus were made. Pyrogen from different sources differed in composition both as to quality and quantity; activity also differed. The most active pyrogen was obtained from B. prodiglosus which ini- tiated reactions in rabbits in concentrations of 0,01-0,005 micro- grams per kg. body weight, 675. SCHMENGLER, R, D, Effect of fever shock therapy in acute rheumatic and allergic diseases. Its significance for acute rheumatism (Translated Title) Klin. Wchnschr, (Heidelberg) 27:1027, 1950 A vaccine produced from the colon bacillus (pyrifer) was injected in varying amounts into patients who presented the following pathologic entities: (l) acute rheumatic polyarthritis; (2) acute rheumatic fever without joint Involvement; (3) poly-symp- tomatic rheumatic conditions, often with cutaneous lesions; (4) acute allergic disorders with known antigens. Following therapy prompt defervescence occurred and the local symptoms disappeared. A sympathetic reaction is postulated; a cellular anaphylaxis may set in motion a sympathetic response ending in pathologic processes. This latter response is reversed by pyrifer. 676. SCHOLTZ, H. G. Physlkallsche Hyperthermle Oder Pyrlferfieber? (Physical hyper- thermia or fever Induced by pyrifer?) Arch, phys, Therap. 2:53-56, I950 677. SMITH, J. McC. and MIRICK, G. S. The inhibitory effect of bacterial suspensions on pneumonia - 1 9 5 - virus of mlee Bft«t. Px>oo. (19gQ) 6tSf Orii«-n«CAtlve b«eillax»y eellt h«d an Inbibltory eff««t on the In- flaamatory an4 lethal aetlvlty of the pnf uftonla virus when ap- plied intpanasailly to mice, befors Infection or two days day after. Species employed Included S. t yphosa and paratyphi , k, Band C. S. t yphlmCirlum , E« coll , ?. dysenterlae (Shiga and Piejaaer) and Proteus 0X19. Preparations given intraperltoneally exhibited no activity. Filtrates of broth were Inactive. The agent was not a polysaccharide, since a trypsin digest was like- wise Ineffective. Activity of cells was not affected by aUto- oalvlng, phenol or acetone ejctraction. A similarity to the auclnase from V. coTOma described by Burnet Is dlscussSd. 678. arUART, ?. a. Alterations In connective tissue mast cells Induced! by bact;erlal pyrogens Am. J. Physiol. 163j754, 1^0 In ooilnectlye tissue ijiast cells In abdominal skin of the mouse, a concentration of granules around a central nucleus may be seen with a few cells exhibiting some dispersion of granules when cell boundaries are Indefinite. Aft^r peritoneal «»nd oral PYROMQf In dosages ranging between % and 5Q giammas per kg. body weight, akin biopsies were taken at "intervSls varying from 15 minutes to 30 ^ays after injection. A response to PYROMEN was elloltedf which reached its peak In severt to i;en days after s single (5 fammas per H|5.)dose. ''Numerleall.y, laorphologlcally and spatially t followed a definite pattern dependent qn the dosage, elapsed time and stra^lh of experimental nice employed" Opanules of many mast cells (dispersed, the dispersion beginning in the vlolnlty of small venules and capillaries beljween ^ to 15 mlhutes after administration, according to Ijhe dosage given. Groups of mast cells some distance from blood vesaeis were less rapidly changed; there was an alteration in shape away from the ovoid* granules spread out from the cell center. Many of the perlcaplllary cells assumed a spindle shape. 679. STUART, E. Q. The mast cell response to admiiilistratlon of a bacterial pyrogen J. Nat. Cancer Inst. 10:1375-1376, I95O After 5 to 50 gammas of PYROMpi per kg. body weight had been ad- ministered to mice by intraperitoneal Injection or the oral route, skin biopsies were taken at intervals between I5 minutes and 24 239 -19 5 0- hourso Dispersion of granules of mast cells began between 2 and 15 minutes after administration of PYROMEN with most rapid alterations evident in areas near small blood vessels. 680. STUTTGEN, Go Pyrifer als antigen im rahmen der baktercellen autoallergic (Pyrifer as an antigen in the picture of autoallergy of the bacterial cello) Zeitschro Haut u. Geschleetskr, 9:17-20, 1950 681. SWINEPORD5 0,5 JRo Observations on the use of bacterial antigens in the treatment of asthma. A brief critical review Am. Pract. I:6l2~6l8, 1950 The author presents summarized data from twenty-eight authors who have reported on the treatment of asthma with bacterial antigens. Characteristics, clinical and laboratory, of atopic and tuberculin allergies and of the Arthus reaction are enumer- ated. The treatment by such means is empirical but of definite value. 682. TAKOS, Mo J, and MOE, G. K. Prevention of pyrogen-indueed renal hyperemia in the dog by dihydroergocornine Proco Soc, Expero Biolo & Med. 75:51-52, 1950 After control periods in which glomerular filtration rate and the effective renal plasma flow were determined, dihydroergocornine (DHO) was administered to female dogs (0.01 rag, per kg. intra- venously and a like amount subcutaneously) and followed by a pyrogen derived from Shigella organism. Rectal temperatures were recorded. Comparisons were made with controls receiving pyrogens alone, and all experiments were repeated » In animals treated with pyrogen alone, the renal plasma flow Increased 27 to 79 per cent while the glomerular filtration rate remained within normal limits. DHO is an alkaloid known to interfere with certain central autonomic mechanisms. Premedi- cation with this drug brought a great reduction in renal hyper- emic response, with a range of -4 to plus 25^» It did not affect the glomerular filtration rate or inhibit fever. The antagonism between pyrogen and DHO is presumed to indicate a blocking action on the central nervous system by the alkaloid. 683. TAL, C, and GOEBEL, W. P. - 1 9 5 - On the nature of the toxic component of the aomatlc antigen of Shigella para^yaenterlae type Z (Pl#xner) J. Bxper. Med. 92:25-3*, 1950 The toxic component of the sonatlc antigen of dysentery bacilli appears to he neither the lipid, protein or carbohy- drate of the complete antigen. Fractions disassociated from the complete antigen yielded a protein component nearly as toxic as the original antigen; carbohydrates were still bound to the protein complex. A milder procedure yielded a product almost . protein free; further treatment eliminated 505^ of the total I lipids but did not change serologic, antigenic or toxic proper- ties. The U.V. absorption was approximately 2600<^ for one component, primarily polysaccharide In nature. Further hydrolysis yielded a polysaccharide, serologically active but non-toxic, and an Insoluble precipitate, not Identifiable as protein or lipid . 68^. WAGNER, R. R., and BEMMETT, I. L. The production of fever by Influenzal viruses J. Exper. Med. 91:135-1^5, 1950 Toxic bacterial filtrates which have an affinity for and de- structive effect upon the cell receptors for influenzal viruses diminished the febrile response to PR8 and Lee strains of influenza virus and that of Newcastle disease. Both Cholera vibrio and Clostridium welchii filtrates had antlpyrexlal in- fluence, but near lethal amounts were necessary to demonstrate a protective effect. However, the ability of animals to re- spond to the pyrogenlc effect of typhoid vaccine was unimpaired by injection of receptor destroyers. "These findings give support to the hypothesis that union of virus and host receptor substance plays a part in the production of fever by these viruses." Chemical substances (le; sodium perlodate) may be neutralized by normal serum and allantoic fluid, since the cell receptor activity was not blocked by their use; glucose is also believed to neutralize the action of sodium perlodate. 685. WALKER, L., OLSON, W. H. and NECHELES, H. Depression of gastric secretion with pyrogens and antipyretics without fever Am. J. Physiol. 163:758, 1950 (Abstract) Increases In the temperature of the body may cause a partial or complete inhibition of hydrochloric acid secretion by the 241 -19 5 0- stomach. Injection of pyrogens can produce temperature eleva- tions with inhibition of gastric secretion and, may be capable of depressing secretory ability when subpyrexial quantities are administered. After histamine stimulation, pyrogens in sub- pyretic dosages were injected into dogs with total gastric pouches „ The inhibitory effect was not constant. When larger pyrogen increments were utilized, consistent inhibition of se- cretion was obtained even after the temperature elevation was abolished by antipyretics o Sixty per cent reduction in total voluem of gastric juice and 72 per cent reduction in total mEq, of free HCl accompanied this Alteration, produced by in- jection of 50 gammas of PYROMEN, and 10 grains of aspirin given orally, A latent period of 30 to 60 minutes preceded these findings. 686. WAUER, D, Innere Abteilung des Stadtischen Behring-krankenhauses Berlin- Zehlendorf a Zur Pyrifertherapie akuter und chronischer Leber- parenchyraschaden (Treatment of acute and chronic involvements of the liver parenchyma with pyrifer) Deutsche Gesundheitsw, 5:489-^92, 1950 Nonspecific desensitization with pyrifer as anti-allergic agent was beneficial in both acute and chronic hepatic parenchymatous conditions. Allergy may be etiological in many hepatopathies, and pyrifer activity is considered one producing a change in cap- illary permeability. 687. WINDLE, W. P. Changes in the hypophysis and suprarenal glands induced by a bacterial pyrogen Anat. Recc 106:94-95, 1950 Histologic studies were made of the organs of 32 virgin female rabbits previously treated with a new purified bacterial pyrogen, P.V. PYROMEN, and these were compared witt or^ns from six controls. The average dose of PYROMEN was either 1 or 5 gammas per kg. body weight. Six animals received 0.01 to 0.1 gammas per kg, J six others received very high dosages (500 to 20,000 gammas per kg,). The LDcq is 80,000 gammas per kg. Tissues were prepared with perfusion formalin fixation and hematoxylln- eosin staining procedures, PYROMEN appeared to act as a mild stress stimulus, but no animal exhibited lesions resembling those seen in exhaustion stages of the general adaptation syndrome. Changes in endocrine organs 242. - 1 9 5 - were not related to dosage levels. Within 12 to 2k hours a panendocrlne response was manifested with vacuolation of cell cytoplasm in the suprarenal medulla, hypophyseal basophil and chromophobe cells^all zones of the suprarenal cortex, the parathyroid, islets of the pancreas and ovarian stroma cells. Leucopenia and eosinopenia appeared within one hour and reached their peak levels in four hours. Lymphocytosis followed. In contrast to the action of ACTH, no suprarenal hypertrophic changes were seenj in the mouse mast cells show marked granu- locytic dispersion after PYROMEN. Prolonged administration of PYROMEN stimulated growth of the suprarenal cortex, with in- creased width of the reticularis but decreases in other zones. Capsule cells appeared to be transformed to glomerulosa cells. Prolonged high doses led to a reduction of anterior lobe baso- phil population associated with involutional changes. 688. WINDLE, W. P. Endocrine and connective tissue cellular responses to adminis- tration of a bacterial pyrogen Abst. of Communications, XVIII Inter. Physiol. Congress (Copen- hagen) Augp 15-18, 1950- p. 518 Events following PYROMEN administration were studied in various species. One to 5 gammas per kg. induced leucopenia and eosino- penia within one hour in the rat, cat, dog and human. The low point was reached in 4 hours, and lymphocytosis followed. In- creased output of urinary corticoids was not detected in rabbits and cats, but pronounced temporary increases in dogs and man have been reported by others. In the mouse, connective tissue mast cell granular dispersion was noted within one hour. A pan- endocrine reaction to PYROMEN was seen in all organs of rabbits. These changes began in 12 to 24 hours, and maximal effects were present for periods up to 10 days; vacuolation of cell cyto- plasm in adrenal medulla and cortex, pituitary chromophobes and | basophils and parathyroid and pancreatic cells were seen. In- terstitial cells of the ovarian stroma became hypertrophied with- in 24 hours, with vacuolation. Prolonged administration of PYROMEN created hyperactivity of lymphatic organs, inducing hyperplasia and even metaphasia with granulocyte production in the spleen. In all organs there was increased vascularity. Proliferation of certain connective tissue cells followed. After spinal cord transection in dogs and cats, fibrous and glial scars appear to be inhibited while the cellular tissues develop- ing between cut surfaces permit the penetration of regenerating central neurons . 689. WINDLE, W. P. and CHAMBERS, W. W. Regeneration in the spinal cord of the cat and dog 243 - 1 9 5 - J. Compar, Neurol. 93:241, I950 In a series of experiments to determine the site of action of bacterial pyrogens, spinal cords of cats and dogs were trans- ected at various levels. One group was used for control purposes The rest received PYROMEN intravenously or intraperitoneally in cumulative dosages ranging from 300 to 11,000 gammas. In addi- tion one control received I50 units of hydase for 10 doses; one animal received 225 gammas of typhoid concentrate and 35 tng. "Pyrexin", and a second was given 3*856 gammas of typhoid con- centrate alone. One animal had received old and inactive pyrogen. The animals were sacrificed at intervals ranging from 8 to 139 days after administration of PYROMEN. Cords of animals living 30 to 50 days after transection revealed new growth of neurons across or into cut regions. There was some connective tissue scarring at severed ends, but no glial barrier. Rather a blending of spinal cord parenchyma with a loose tissue contain- ing non-nervous tissue cells had occurred. Through such regions nerve fibers had in some cases penetrated into or through the scar along strands of reticulum-like cells. Serial sections and staining by the pyridine-silver method revealed that they were derived from severed or injured nerve roots, nerves to blood vessels and intrinsic spinal cord neurons. No evidences of functional regeneration were seen. 690. WDTDLE, W. F. Spinal cord regeneration associated with a cellular reaction in- duced by administration of a purified bacterial pyrogen International Anatomical Congress, July 24-28, 1950. Abst., Proc. of the Congress, p. 196. Transected spinal cords of dogs and cats, when given varying dosages of PYROMEN for periods of time ranging from 8 to 61 days, revealed clear-cut evidence of neuron growth into or aoross the cut ends. Some connective tissue scarring between severed ends and the usual amount of retrograde degeneration were observed. There was no glial barrier, but a blending of spinal cord paren- chyma with connective tissue was noted; through such areas, nerve fibers could be seen growing into the scar. The nerve fibers were derived from severed or injured posterior and anterior nerve roots, vascular and meningeal nerves, and intrin- sic spinal cord neurons. Numerous blood vessels were observed at scar-cord juncture and there were many macrophages at the interstices between strands of non-nerve cells and the nerve fibers. I - 1 9 5 - 691. WINDLE, W. P., CHAMBERS, W, W., RICKER, W. A., GINGER, L. G. and KOENIG, H» Reactions of tissues to administration of pyrogenlc preparation from a Fseudomonas species Am. J. Med. Scl, 219:422-426, 1950 I Sensitivity to PYROMEN was shown In test animals In the follow- ing descending order: dog, rabbit, cat, monkey, guinea pig and rat. Administration of massive doses Induced histological changes In lymphoid and myeloid organs similar to those ob- served with other pyrogenlc substances or pyrogen-free saline so- lution. There was Increased macrophage and lymphocyte pro- duction In all species studied; where treatment was prolonged, myelocyte and granulocyte production In the spleen of the rabbit was noted. 692. WINDLE, W. P. and WILCOX, H. H. Extramedullary hemopoiesis In rabbit and cat Induced by bacterial pyrogens Am. J. Physiol. 163:762, 1950 Histological changes In the spleen after PYROMEN are related to time of treatment and 'en some degree to the size of the dose. Most marked changes were observed In the red pulp, where proli- feration of reticular cells and reduction of blood flow through sinuses were noted during the first 20 days of treatment; where treatment had been continued a month or more, phagocytosis of static blood by macrophages was noted. Groups of hemopoietic cells appeared In pulp cords. 'Islands' of hemopoietic tissue, similar to those found in embryonic states, were seen in sinuses j of the spleen. When the dosage was massive or therapy prolonged the hematopoietic picture resembled, for the spleen, that of bone marrow. The greatest Increases In spleen weight occurred in the cat, but hepatic hemopoiesis was noted in the rabbit after massive or prolonged therapy. Hepatic activity was not noted In controls nor with lower dosage levels of PYROMEN. 693. WINDLE, W. P., WILCOX, RHINES, R., and CLEMENTE, C. Changes in endocrine organs Induced by bacterial pyrogens Pederatloh Proc. 9:137, I950 The organs of rabbits were examined histologically for signs of stress -linked changes after administration of Ps. PYROMEN 2^5 -19 5 (100, 000-200 <, 000 gammas total dosage) :, Treatment extended from 19 to 303 days. Comparisons were made with the appearance of organs after 500-20i,000 gammas per kg,, body weight of P„Vo PYROMEN had been administered for 3 to 6 weeks. Neither group had organs typical of the exhaustion stage associ- ated with the general adaptation syndrome <, Ps, PYROMEN-treated rabbits exhibited hyperplasia ^ hyperactivity of lymphatic and reticuloendothelial tisBues^ while PoVo PYROMEN induced but slight changes In these tissues o Both preparations produced blood component alterations resembling those seen after stress or following the administration of ACTHo Changes suggestive of involution after marked growth stimulation of the adrenal cor- tex were noted. Rabbits and rats given P»Vo PYROMEN thrice weekly (to 122 days) in dosages of 1 or 5 gammas per kg, body weight exhibited in- creased cytoplasmic activity 3„n endocrlnes. Vacuolization of anterior lobe basophils and cells of the pars Intermedia of the hypophysis appeared within 12 hours <> Similar changes appeared in adrenal cortex after prolonged administration; at higher dosage levels involutional changes were seeno WIRTH^ P„ Uber Pyrlferbehandlung bei schwerer Dlphtherie (Fever therapy (pyrifer) in severe diphtheria) Deutsche med, Rscho 42 204-206, I95O Seventy-one of 133 patient© treated with antitoxin and peni- cillin were given a bacterial pyrexial agent ^ with the result that recovery was more rapid and less difficult „ Mortality appeared to be reduced by adjuvant therapy. Neurological com- plications were unchanged , - 1 9 5 1 - 695. ALGIRE, G. H. and LEGALLAIS, P. Y. Vascular reactions in normal and malignant tissues in vivo. IV. The effect of peripheral hypotension on transplanted tumors J. Nat. Cancer Inst. 12:399-^21, 1951 The transparent chamber technique was used in making microscopic observations of changes in the blood supply of transplanted tumors when peripheral blood pressure was reduced. Direct corre- lation between hypotension and reduction of circilalation in capil- laries of tumors and surrounding tissues in the host was secured. Reduction of tumor circulation was related to the duration and degree of peripheral hypotension. Necrotic changes in tumor tis- sue follow in prolonged reductions. A- polysaccharide from Serratla marcescens furnishes a mechanism which may be related to this phenomenon: progressively increasing sluggishness of flow in the arteries; stasis of blood; occlusion of capillaries in striated muscle; necrosis in sarcoma tissue. In the latter in- stance, hemorrhage follows ischemia within a few hours and tumor damage may be apparent in 24 hrs. thereafter. Work is now in pro-< gress to determine whether hypotensive effects are responsible for the therapeutic benefits achieved. 696. ARCHER, B. J. Remission in rheumatoid arthritis following fever therapy with liver damage New York J, Med. 51:2657-2658, I951 Cephalin flocculatlon tests became positive soon after initiation of therapy with injections of typhoid bacteria in a patient re- sistant to the effects of gold salts and salicylates. The ele- vated sedimentation rate returned to normal and remission of arth- ritlc symptoms followed. The cephalin index returned to normal at the time of relapse, two weeks later. 697. BECK, L. V. Reducing substances as Indicators of protection afforded by cort- isone against tumor -damaging effects of Serratla marcescens poly- saccharide Cancer Res. 11:4, I95I Marked decrease in the content of reducing substances - ascorbic acid and glutathione - accompanied hemorrhagic necrosis Induced in mouse sarcoma #37 by arsenlte, a-peltatln and P25, the poly- saccharide from S. marcescens . When 5 micrograms of cortisone per Gm. mouse weTght were Injected before P25, the minimal dose of the polysaccharide required for production of tumor necrosis I 247. - 1 9 5 1 - was doubled. It was shown that the minimum dose of P25 required to decrease ascorbic acid and glutathione content of tumors is twice that required when preceded by injections of cortisone. 698. BRIL' M T, Knokhitkin Metodke pirogennoi terappii sifilisa (Method of Pyrogenous Syphilis Therapy)" Vestnik vener. dermat. 1951(3) 28-31 CHARONNAT, R. and LECHAT, P. Investigaciones sobre el ensayo de los pirogenos en los solu- ciones inyectables (Investigations on the test for pyrogens in injectable solutions) Laboratorio, 10:545-556, I950 I 700. CHARONNAT, R, and LECHAT, P. Researches sur la nature des pyrogenes des solutes injectables. I. Substances definies d'orlgine biologique ayanat une action pyrogene (investigations into the nature of pyrogens in injec- table solutions) \ I Ann. pharm. franc. 9:17-22, I95I |J The pyrogen of Robinson and Plusser appeared to be a polysaccharide approximating 62,000 molecular weight, containing 0,29-2.38^ P but without azotes. Menkin's "pyrexine" has 11^ N, but 1^ P, gives no Molisch reaction and is considered to be a glucopeptide. In a series of experiments, pyrexial substances, both bacterial and chemical, were injected intravenously into the rabbit. Prom an opotherapeutic product, a substance was extracted which was, when purified, insoluble in water but soluble in monosodium car- bon solution, 0,1 mg,/kg,, in the rabbit, elevated temperature from 1 to 4 degrees. Nucleic acids, thymonuclelc acid, and a 7% nucleotide solution were also investigated. Adenylic acid was not pyrogenic . Adenosine (three types) had specific hyperthermic action, but it was believed that an impurity was responsible. 701. CHARONNAT, R. and LECHAT, P. Researches sur la nature des pyrogenes des solutes injectables. IIo Essais de definition quantitative des substances pyrogenes. III. Indice pyrogeniques (II. Tests of quantitative definition of pyrogenic substances. III. Pyrogenic indices) Ann. pharm. franc. 9:22-30, I95I -19 5 1- II. After extended studies It could not be confirmed that the log of hyperthermia provoked by the pyrogen of B. pyocyanae us has the relationship of a linear function to the logarithm of the dose, i III. An empiric formula is presented which may be employed to correlate the hyperthermic curve and amounts of pyrogens injected. The law involved is one far more complex than that of a straight line function. The pyrogen unit is not an index. 702. CLEMENTE, C. D. i. Production of periods of leukocytosis and tolerance by conse- cutive oral administrations of different bacterial pyrogens Federation Proc. 10:27, 1951 Tolerance to oral administration of several bacterial pyrogens J^^o" f Paeudomonas species, Pr. vulgaris and B. subtilis) fol- lowed leuKocytosis. Normal wHTte cell levels reappeared . To differentiate between a generalized effect of PYROMEN and possible existence of species differences, 1 gamma Ps. PYROMEN was fed in drinking water daily. In 2 to 5 days the total white count had ascended from an average of 16,000 leukocytes per cu. mm. to levels between 29,000 and 35,000. Normal levels reappeared in '4 2? ^^^^^' ^^^^ ^^® pyrogen employed was one obtained from either Pr. vulgaris or B. subtilis , a secondary leukocytosis was evoked and a second period of tolerance followed. In some animals the period of white cell elevation extended to 20 days. The most prolonged results were achieved with Pr. vulgaris pyrogen. '^^^' and^raOLE^V^'p ^"^'^^^^ ^' ^" GREENE, L. C, MITCHELL, S. Q. Regeneration of the transected spinal cord of adult cats Anat. Rec. 109; 280, 1951 Certain bacterial pyrogens assist in inhibiting collagenous scar- ring after complete spinal cord resection. Loose reticular and macrophage matrices are substituted for scar tissue. The pene- tration of intraspinal nerve fibers on regeneration is thereby rendered possible. Regenerative activity was demonstrated histo- logically when 20 gamma of PYROMEN per Kg. body weight were ad- Tr^^J^^®*^ initially to spinal cats and the amounts Increased (to 200 gamma per Kg. body weight) for successive periods of ap- proximately two weeks each. Treatment alternated with rest periods. When the treatment was discontinued prematurely, growth of the dense collagenous tissue was resumed. 249 - 1 9 5 1 - CLEMENTE, CD., CHAMBERS, W. W. and WINDLE^ W. F. Blending of regenerating peripheral fibers with cerebral cortex through glial barrier Inhibition Am. J= Physiol, 167:77^^ 1951 The published observations of Windle and Chambers (1950) and Cleraente and co-workers (1951) on the anatomical regeneration of severed spinal cords of adult cats have been augmented through a report of the results obtained when peripheral nerves were im- planted into the cerebrum. The proximal stump of the temporal branch of the right facial nerve was implanted into the cerebral cortex of subject and control. One animal received a bacterial polysaccharide intravenously (PYROMEN) for a period of 30 days. Sections of cerebral tissue stained with silver were examined. No sharp demarcation between peripheral nerve and brain paren- chyma could be seen in tissue following PYROMEN therapy. The regenerating fibers grew radially and blended with the substance of the cerebrum. In untreated tissue., distinct glial barriers were seen and no blending was observed o CLOUGH, P. W, Pyrogens . Editorial, Ann. Int , Med. 34:8l6-8l9r 1951 The literature on the therapeutic applications of pyrogenlc sub- stances is partially reviewed. Present use of pyrogens is, ac- cording to the author, confined to attempts to stimulate certain defense mechanisms. "This is most evident in such diseases as uveitis and other ocular infections. ,, it might be used more fre- quently than it is in certain other types of Infection for which no specific therapy is available and which are resistant to less drastic procedures,,.." Application of pyrogens in the therapy of (a) inoperable neoplasm.s (b) malignant hypertension appears to be promising but is limited by severity of the reaction. In summarizing, the editor states that "this form of treatment is., still in the early experimental stage" . The characteristics of bacterial pyrogens, clinical manifesta- tions following their administration^and the increases in toler- ance seen after continued pyrogen therapy are briefly discussed. Abolition of pyrogenlc reactions has been secured through use of antipyretics, ACTH and cortisone, or reticuloendothelial block- ading agents. FARIA, R. Post-transf usional reactions. A clinical and statistical study 250 -19 5 1- (Translated Title) Seara medica 6:359. 1951 The reactions characterized as pyrogenic may be controlled after transfusion of blood by (1) discontinuance of transfusion, ad- ministration of anti-febrile drugs, sedatives (2) substitution of plasma and other equipment for transfusion. Calcium intra- venously has been advocated as efficacious for these reactions as has novaldin in one gram injections intravenously. "Prophylaxis ot pyrogenic reactions Includes „. ,care in the collection and ad- ministration of blood and a completely closed technie" . Pyro- genic reactions may be actually pseudo pyrogenic reactions; the ro±e 01 chilling and the use of frozen preserved blood are con- ?pvn^!Si 5! ^"^52"' e^served an incidence of 3.9 per cent un- 5?MHo5 ^^^^^Tf^^^^*^ ^^^^^ 2.069 transfusions, and these in- cluded all reactions recorded, 707. PISHGOLD, J. T., GRANT, R,, FIELD, J„ and HALL, V. E, ?S^®2 consumptioa and glucose exchange in vitro of liver slices irom febrile rabbits Am. J, Physiol, 166:113-120, I95I Sm!!?!!^ ^" liver function in fever may be caused by (a) heat pro- me?abo?i^S°oJT^K"g r^!^°^^° process or (b) disturbance of the t?n?P«i dT«S^-r''^°^?^''^*^ resulting in hyperglycemia and the Tjypical diabetic syndrome, Sil??'?^«i.f?rr^*^''?J^^ measured in liver slices taken from ' found ?hirio^^ sacrificed at the onset of the chill, it was t?Dhoiri vLi?r? 5^2^"^^ ""^""^ present after pyrogen (typhoid para- Union ^n^n^t^ !?^^ ''^''^ ^^^^ ^" untreated animals. The hydro- IlLir.rnrf'rJ^'^" Zl^ ^ ^^°^°^ ^1^°^ si^°^ incubation of levels \!n rliL $^^ ?'^^^'' consumption closer to normal Of fl^^r^ ^L } It of epinephrine could be measured at the onset glucSIfwaS r^lL^S^ f ^^""^f °^ epinephrine, five times as much no^alti^^n^ !5S?J''°'" i^^^"^ suspensions after fever as from bo?S in thJ -:k.,??^^J^°" °^ epinephrine increased glucose values no?Sal P,n?Lif ^^ *^^^"^ preparations and in those taken from In^eL^iZL .T^^ suggestion is made that early hyperglycemia SatrSom ?h^ iJf^^^^v,^'' ^""^ ^y ^ =^"^^^" release of ca?bohy- that he^? n^n^.iJr'' ^^'^^"S^ sympathetic -adrenal stimulation, and no? th?ou^n?"^Ji°" "?^u^^ mediated through nervous pathways and not through direct peripheral action when pyrogens arradmiiLstered 708. FITCH, E. M, J. and WASHRTTRMr a p I The effects of PYROMEN administered intravenously in subpyrexlal ( I 251 - 1 9 5 1 - doses to depressed patients. A preliminary study- New England J. Med. 245:961-968, 1951 Among the favorable results reported after PYROMEN therapy has been the appearance of increased euphoria. To determine whether or not this response might be therapeutically useful in the treat- ment of the mentally depressed patient, and whether or not it was independent of fever, subpyrexial doses of PYROMEN were adminis- tered to 62 individuals, 31 of whom reported extreme depression. Of these, four were termed schizoid personalities and four manic depressive. Fifteen patients presented some symptoms of aller- gic disease. The average dose of PYROMEN ranged from initial injections of 0.5 to 1.0 gamraa^ to 2.0 gammas two or three times weekly for an average period of 79 days. Overdosage appeared to bring an exacerbation of symptoms but it was rarely necessary to reduce the amount given. Among the symptoms observed were head- ache, dizziness, nausea and aching. A tendency toward increased bleeding was noted; menstruation was induced in 1 patient, intra- menstrual bleeding in two. Dysmenorrhea was relieved. Caution is Indicated in the use of PYROMEN where a hemorrhagic lesion may exist. Nocturia and frequency of urination were present in the early stage of treatment; a loss of weight may have been related to loss of edema fluid. Symptoms indicative of vitamin balance disturbance, le, metallic taste, cheilosis, glossitis, and bleeding guras_, appeared in a few patients and were relieved by administration of vitamins B and C in high dosages. On the basis of 537 pairs of differential counts it was con- cluded that hematologic response could not be used for evaluation. The eosinophil count was not valid enough to be used as a gauge of response. There were no significant changes in hemoglobin, erythrocyte levels, platelets, reticulocytes, total serum protein, prothrombin time, vitamin C, calcium, phosphorus or bilirubin, A placebo (saline solution) occasionally brought a drop in eosin- ophils. Allergic states yielded to PYROMEN therapy (asthma, severe acne and chronic eczematoid dermatitis), but seborrheic dermatitis was not improved. Depression, fatigue, anxiety and insomnia disap- peared. One of the schizophrenic subjects improved but symp- toms were exaggerated in the passive variety of schizoid involve- ment. The drug appears to bring the psychiatric patient toward an acceptance of psychotherapeutic techniques. The theory is advanced that central nervous symptoms of a functional- nature may be the results of allergic states with cerebral edema, or that a shift from the parasympathetic to the sympathetic system has changed both psychic and somatic behavior. A common agent, op- posed by PYROMEN, may be Involved in these syndromes. 252 - 1 9 5 1 - 709, GINGER, L, G., NESSET, N„ M,, RIEGEL, B, and PITZSIMONS, E. J. Bacterial Pyrogens, II. Pyrogenlc preparations from various bacterial species J. Am. Pharm. A. (Scl. Ed.) 40:421-424, I95I Pyrogenlc concentrates, prepared from the cell bodies of five bacterial species by means of tryptic digestion, were charac- terized by essential chemical and biological differences. Cellu- lar materials from E. coll , Pr. vulgaris , S. typhi and B. subtilis were grown and collected by a method previously described (j. Am. Pharm. A„ 39s456, 1950) Both cellular material and concentrates were analyzed for the following constituents 1 ribonucleic acid, desoxyribonuclelc acid, hexosamine, pyrogenlc polysaccharide and tree lipid „ Total nitrogen, protein and nitrogenous residue were f%l%3\^' '^^^ smallest content of pyrogenlc polysaccharide U5oO^) was found in the concentrate from Pro vulgar is; the largest content was found in the concentrate from bT subtilis. The poly- saccharide content bore little relationship to biological actlvl- J^i 2\u°^ active concentrate was that from S. typhi . It con- rained the smallest amounts of hexosamine and unclassified reducing sugars. Proteus vulgaris concentrate, with low pyrogenlc poly- saccharide content possessed high biological activity. On the il %Z ' ^^® concentrates prepared from B. subtilis contained Ojo2^ pyrogenlc polysaccharide but had the lowest biological activity. ^^i^ll^^^^^^^^ Pyogenic polysaccharide composition may account a°Lf,?f/^^,^^Ji°^^i^ activity. »'The possibility that biological not be ?ve?looker "^ differences in molecular structure can- 710. GREENE, Lo Co Healing of thermal burns in cats treated with PYROMEN Am. J. Physiol. l67;789, 1951 thp^^,^J^f!!f^■'■°?/™° ^2 diameter, were produced on either side of riS4?^Q!Sr^ ?''^™ °f the cat by the method outlined by Peters ^ ?.n^^l^ZV;..J ? f^''^®^ °^ ^2 animals, intravenous injection of at^seiei^i ^nllT^^^ polysaccharide (PYROMEN) were administered at several dosage levels. Pour animals received initially 20 oinL'^fn ot P^^^^y ^teadily increasing to 60 gammas per kg. 8? da?s tSo «^?^^ M^i^t^^ance doses were 10 gammas per day for men? wSs ron?inMi;?^^%^?''^^^?? °<"2 gamma three times a day. Treat- ment was continued until healing was complete. efanfmalf Jn^^nn^^^'^r ''°l^'^ ^^*^^^" ^^^^ appearance in the treat- ed animals and controls. For the former, scab formation was rapid, 253 - 1 9 5 1 - and sloughing took place in a fragmentary fashion, leaving smooth surfaces, small scars and textures resembling those of normal skin. Sloughing and healing were completed 15 to 25 days earlier in the treated animal than in the untreated . 711. HALLMAN, N., LAG US, K. Pyrogeenireaktioista eri tavoin valmlstetullla Injektiolluok- silla (Pyrogen reactions to solutions prepared by Finnish method as prescribed by U.S. P.) Duodecim. 67:335-343, 1951 712. HIRSCHMANN, J. Konstitutionelle Unterschiede von Temperatur und Leukocyten- kurven unter Pyriferbelastung (Constitutional differences in temperature and elukocyte variations during pyrifer adminis- tration) Nervenarzt 22:260-264, 1951 713. GUTHRIE, T. C. Effects of artificially-induced fever on the electroencephal- ograms of patients with multiple sclerosis Trans. Ne\\r York Neurol, Soc . and New York Acad. Med. (Sect, on Neurology and Psychiat.) Meeting, May 8, 1951. A.M. A. Arch. Neurol, and Psychiat. 66:660-66l, 1951 (Abstract) Under the experimental conditions outlined, increased heat ap- pears to affect multiple sclerosis adversely. When the temper- ature was increased from 0,8 to 5.4 F. through the injection of 20 million killed typhoid organisms, electroencephalograms re- corded for five patients were indicative of unfavorable activi- ty; there was decreased strength of grip, a loss in visual acuity and increases in dysarthria. The permanence of these changes is discussed and a further consideration of such therapy is suggested, 714. HAYl^IES, B, W., DEBAKEY, M. C. and DENMAN, F, R. Renal function studies of severely burned patients Ann, Surg,, 134:617-625, 1951 During a study of renal function in eight severely burned patients. - 1 9 5 1 - who were receiving adequate hemotherapy and fluids, the renal plasma flow, glomerular filtrate rate and fraction excretion were determined. An analysis of both arterial and venous blood was added. There were changes in plasma protein concentration. The possibility that there is increased thyroxine production in burns was suggested, and certain similarities to results obtained through DOCA were noted. In fevers, the maintenance of glomerular fil- tration is accompanied by effective increases in blood plasma flow. Reduction of filtration factors has been reported. Pyrogen, without actual production of fever, increases the renal plasma flow but does not affect glomerular filtration. Filtration fractions are decreased, 715. KIRKENDALi, W. M,, HODGES, R, E, and JANUARY, L. E. The ACTH-like effect of fever in man Jo Lab, & Clin, Med, 37,' 771-779, 1951 ^ In studies planned to determine whether or not eosinopenia ob- served after induced fever is caused by liberation of ACTH, elevation of temperature was induced in 27 afebrile patients, all with normally-functioning adrenal and pituitary glands. Fever was Induced by either (1) I5 to 100 million typhoid or- ganisms in vaccine (2) moist air fever cabinet or (3) an endo- genous polysaccharide of Proteus vulgaris (PV PYROMEN) . The last-named was administered intravenously in 25 to 100 gamma doses. The effects of aspirin, dibenamlne and chlor-trimeton before and after injection of Pv PYROMEN were observed in four patients. Determinations of uric acid/creatinine ratios, circulating leuko- cytes, corticosteroid excretion and rectal temperatures were em- ployed in evaluating the results obtained. The blood leukocyte changes following fever induced by all of the methods employed simulated those produced by ACTH with three major differences (1) neutrophilia and lymphopenia were greater after induced fever (2) eosinopenia occurred later than when ACTH was administered, particularly when typhoid vaccine was the pyrogenic agent, (3) leukopenia produced by typhoid vaccine was prolonged to 48 hours. The leukocyte response following fever cabinet pyrexia most nearly resembled that seen in ACTH therapy. Aspirin minimized the pyretic effects of Pv PYROMEN but did not affect leukocyte changes. Neither dibenamlne or chlor-trimeton had capacity to alter febrile or leukocytic responses. None of the agents provoked consistent Increases in uric acid/creatinine ratios or corticosteroid excretion. Pv PYROMEN gave a 210^ increase in leukocytes within 8 hours; levels returned to normal in 24 hours. There was a sharp rise in 255 - 1 9 5 1 - polymorphonuclear cells to levels above those secured with other hyperthermic agents. It is possible that both immunization and toxic effects (not mediated through the anterior pituitary) occur with Pv PYROMEN therapy, Pv PYROMEN does not increase urinary corticosteroid excretion, but this may merely imply that the renal threshold is high, " , , .with normal oituitary glands, fever and pyrogenic substances may cause the release of small amounts of ACTH..." the authors believe, 716. LEQUKE, V. So The augmentation of the thermogenic effects of pyrogens by homo- logous plasma in rabbits J. Infect, Dis., 83; 194-206, 1951 Mechanisms involved in the augmentation of pyrogenic response by use of homologous plasma were demonstrated through studies of the minimal and moderate febrile reactions in the rabbit after in- jection of saline or plasma suspensions of pyrogens from E, tv- phosa , P. aeruginosa , Aerobacter cloacae and PR-8 Str . influenzae . Thermogenic response and duration of reaction were heightened when plasma was the suspending fluid. The latent period before initial temperature elevation was shortened.. An exception v,'as noted when influenza virus A was injected; the febrile reaction proceeded to peak levels regardless of the material used for sus- pension, although time of onset and duration were extended through the use of plasma. The pyrogens from E, typhosa were completely removed from the blood stream within 15 minutes when a saline med- ium was used for the suspending fluid; with plasma, fever was pro- longed for two hours. Heparin decreased the pyrogenic activity of E, typhosa and restored a latent period; heparin itself was pyrogenic. With plasma in combination with heparin a febrile re- sponse could be obtained. When plasm.a pyrogens were pretreated through suspension in this medium, clearance time was prolonged. The activity of pyrogens appears to be a selective precipitation of fibrin and aggluti- nation of the bacterial coat. It is believed that pyrogens do not act directly on the temperature regulation centers,, when com- bined with plasma but alter the surfaces of bacteria or react with certain blood constituents. It was noted that influenza virus A immune serum abolishes leukocytosis and pyrogenic activity. 717. MARTIN, S, P, Effect of a group of bacteria and their carbohydrates on human leukocytes Am, J, Med, 11:246, 1951 (Abstract) - 1 9 5 1 - Since the somatic carbohydrates of S, typhosa appear to prevent diapedesls of leukocytes from blood vessels. Inhibiting cell mi- gration, the effects of bacteria (S. typhosa and P. aeruginosa ) , of their carbohydrates (purified) and of heparin upon the oriented migration of leukocytes were studied. The slide cell was em- ployed . 718. MCDONALD, R. K., SOLOMON, D. H. and SHOCK, N. W. Aging as a factor in the renal hemodynamic changes induced by a standardized pyrogen J. Clin. Invest. 30:^57-^62, 1951 Changes in the function and anatomical structure appear in the kidney of the aging individual. Alterations in renal function are shown in decreased urea clearance and rate of filtration, the reduction of the effective plasma flow and tubular transfer. Some intimal thickening is seen in renal arteries and arterioles even in the nonhypertensive individual. The standard pyrogen test was applied to 5^ male subjects divided into three groups: young, middle-aged and old. Decreases in renal function were not significant until after the age of 50. When 0,05 cc. TAB vaccine was administered and analyses made of albumin, globulin, inulin, PAH, blood urea N, total serum protein, hematocrit and blood pressure, it was noted that the baseline C declined with advancing age, but no changes were attributable to the pyrogen test itself. Effective plasma flow mean baseline declined with age and, for all ages, pyrogen injections increased flow. Systolic pressure fell in middle-aged and aged subjects; diastolic pressure reductions were approximately the same for all age groups. Renal afferent resistance was highest in older groups, and the fall was more abrupt. Minimal efferent resistance was highest in older subjects. While the filtration factor de- clined at the peak of the pyrogen reaction in all groups without distinction, the largest absolute decline occurred in aged sub- jects. The responsiveness of the renal vascular system to pyro- gen at older ages would indicate persistence of arteriolar di- latation under such conditions and a certain reversibility of the usual functional alterations. The purified carbohydrates (PYROMEN-in a concentration of 0,25- 5,0 gammas per ml.) and the organisms themselves produced similar inhibitions of human cell migration. The profound effects they exert may be basic to the phenomena of leukopenia and fever, "In addition to the shock these agents produce it would appear that they have a direct effect upon the leukocytes," 257 - 1 9 5 1 - 719. MENCZEL, E. A note on the depyrogenizatlon of infusion solutions by hydrogen peroxide J. Am. Pharm. A. 40:175-176, 1951 The Taub and Hart method for depyrogenizing infusion solutions has been slightly modified by workers of the Government hos- pital, "Yarkon" , One modification replaces the Soxhlet appara- tus with large pyrex boiling flasks. After boiling, contents are readjusted to the original volume. The usual standard ti- tration with permanganate is replaced by other methods; fair re- sults were obtained with the spot test of Pelgl. The reagent used, a mixture of 0.4^ ferric chloride solution and 0.8^ po- tassium ferricyanide solution in equal parts, is sensitive to 0»08 gamma of hydrogen peroxide in a drop. Sensitivity of the test may be further increased if a 10 drops per 100 cc. solu- tion ratio is maintained. Dextrose causes no interference. Both oxidizable substances and pyrogenic contamination may be de- tected through use of the test. It may be applied to parenteral dextrose solutions. Elimination of detectable hydrogen peroxide by boiling with manganese dioxide for 15 minutes (0.1^) or the use of activated charcoal (1^) for saline and dextrose combina- tions is to be recommended. 720. MITCHELL, S. Q., and STUART, E. G. Role of adrenal gland in mechanism of leucocyte changes upon administration of PYROMEN Am. J. Physiol. l67:8lO, 1951 PYROMEN, a purified bacterial polysaccharide, was injected intra- venously into cats in dosages ranging from 0.5 to 35.0 gammas per kg. body weight. The leucocyte reaction was studied in both nor- mal and adrenalectoraized animals. When adrenalectomy was uni- lateral, no significant changes were elicited in the leucocyte counts until the second or third day after the operation when the typical response was observed. The remaining gland was unable to compensate fully. After bilateral adrenalectomy with maintenance on DCA or cortisone, no leucocyte changes could be noted at any dosage level employed. When portions of the adrenal gland were transplanted into the adrenalectomized animal and desoxycortico- sterone discontinued, PYROMEN again induced leucopenia on the 5th, 6th and 7th days; on the 8th and 9th days the initial rise in leucocytes was recorded. 258 - 1 9 5 1 - 721. MOST, S. Effect of Shear's Polysaccharide on plasma clotting Nature, 168:3^2, 1951 It has been previously suggested (Heilbrunn, Wilson and others) that the polysaccharide extracted from the bacterium, S. marces - cens may have heparin-like structure and activity » The action was presumed to involve prevention of mitotic gelation or clot- ting before division o Like heparin, the substance gives a meta- chromatic reaction with toluidine blue, A solution of polysaccharide P25, containing 36 mg, per cc,,was diluted with distilled water and added to freshly oxalated human plasma containing 1 cc , of 0,1 M sodium oxalate to 9 cc . of blood. The clotting time at 37°C, of total volumes of 0.1 cc. plasma and equal amounts of polysaccharide and M calcium chlor- ide (0.025) was computed from the time of addition of the last- named chemical until complete clotting had taken place. Shear's polysaccharide inhibited the clotting of recalcified plasma in a manner resembling that of heparin, but commercial heparin had an activity : 138 to 320 times more effective for the purpose stated. 722. PAGE, I. H. Treatment of essential and malignant hypertension J. A, M. Aos 147:1311-1318, I95I In a review of the present status of therapy and of the possible additions to the therapeutic armentarium in essential and malig- nant hypertension the use of pyrogens is held to be "the treat- ment of choice" in the latter condition. The author considers it to be a "harsh" treatment as applied in malignant hypertension., but a life-saving procedure o An Infusion of PYROMEN is employed in amounts sufficient to raise the body temperature to 101.0 or 102,0° P, Saline solution is preferred as a diluent, and 200 cc, are infused dally^ f or six days a week^over a period of three to four months. Since toler- ance may develop, dosages may increase to very high levels and a rest period of 3 to 5 days is required. In the treatment of some patients it is possible to fix a maintenance level early in the treatment period. Reactions to PYROMEN may be diminished through preliminary Intravenous injections of amobarbital (0,2 Gm.) or tolserol (Oo5 Gm.) before Infusion. Tolserol should be well- diluted to reduce dangers of venous thrombosis resulting from its use. I 259 - 1 9 5 1 - 723. SAETHER, J. Pyrogener (Pyrogens) Nord. Med. 5^:501-504, 1951 724. SCHOCH, A. G. (Editor) Clinical experience with PYROMEN. PYROMEN for the treatment of chronic dermatoses Current News in Dermat. and Syphilol., November, I95I PYROMEN therapy was evaluated from the results obtained in a group of 52 patients presenting stubborn dermatoses. The most frequently given dosages were 0.5 or 1.0 gamma initially, in- creased as tolerance developed. Three or four intravenous in- jections were given per week. Improvement was seen in 39 patients. After interruption of therapy for one to two months, improvement was still evident in 25 patients. Six cases of psoriasis improved but exacerbations were noted. The importance of the psychotherapeutic features of the treatment was stressed by the reporting clinician. who found spontaneous major environ- mental changes coincident with the fluctuations in about one- half of the patients and "psychic catharsis" where reactions to treatment occurred. Temporary favorable results from PYROMEN and psychotherapy in combination are reported. Two indivi- duals became conditioned to pyrogenic injections and reacted similarly to injections of saline solution. Astonishing im- provement was shown by certain patients. "Although the useful- ness of the drug, per se., remains to be determined, it seems that the results would usually not have been as good without PYROMEN" . The Editor quotes Dr. Kierland (Mayo Clinic), "PYROMEN. . .is of value but not specifically so in the treatment of many. .chronic dermatoses. . .unresponsive to the usual therapeutic measures. There is evidence that subfebrile doses are effective." He considers the action a nonspecific one, similar to that noted in foreign protein therapy, but raore controllable than that of TAB vaccine or other pyrexia -producing ageate. 260 - 1 9 5 1 - 725. SCOTT, D., JR. and CLEMENTS, C. D. Conduction of nerve impulses In regenerated fibers of the spinal cord of the cat Am. J, Physiol, 16? s 825, 1951 (Abstract) The growth of severed nerve fibers and a return of their capa- city to transmit nerve impulses were observed in the cat after re- section of the spinal cord and treatment with a bacterial poly- saccharide, PYROMEN. Responses to stimuli in rapidly conducting descending fibers to the site of the lesion and below the point of severance were recorded. In the animal receiving PYROMEN ther- apy, impulses conducted to the site of the lesion at 25 to 40 meters per second were registered at a distance some 20 mm. below the lesion. Neural activity below the site of resection was undiminished in velocity. No activity could be demonstrated be- loyr the site of the lesion in the control group. Approximately 15J^ of the total number of nerve fibers normally present appeared to be capable of conducting impulses after PYROMEN therapy, 726. SHTAKEL 'BERG, N. A. Raziotle likhoradochnol reaktsil u zhivotnykh prl razlichnoi lokallzatsii vvedeniia pirogennykh veshchestv. (Development of fever reaction in animals in relation to injection sites of pyrogenous substances) Pizlol. Zh. SSSR (Moskva) 37:195-205, 1951 727. SOYLEMEZOGLU, B,, and WELLS, J. A. Studies on the mechanism of the leukocyte response to bacterial pyrogen J, Pharmacol, & Exper. Therap. 101:33-3^, 1951 The relationships between pituitary-adrenal discharge, appear- ance of the alarm reaction and the activity of bacterial pyro- gens, ACTH and cortisone were examined. Intravenous and intra- muscular Injections of ACTH (10 mg.) or PYROMEN (500 micrograms) in the dog produced widely differing results. While changes after Intravenous administration of pyrogen were essentially the same as those produced by ACTH given by the same route, ititramuscularly ACTH induced leukocytosis and PYROMEN did not. The responses to ACTH were modified by adrenalectomy. It is concluded that pyro- gen-induced changes take place throu^ some mechanism differing wholly or in part from that of pituitary-adrenal discharge. 26l - 1 9 5 1 - 728. SOYLEMEZOGLU, B. and WELLS, J, A. Compari50n of leukoctye response to ACTH and bacterial pyrogen Proc. Soc. Exper. Biol, and Med. 77:43-^7, 1951 Removal of the adrenal gland substantially reduced the eosino- philic response In the dog to ACTH but did not affect the re- sponse to pyrogen. Normal animals received either 500 micrograms of Ps. PYROMEN or Pv PYROMEN Intravenously or 10 mg. ACTH, Bilaterally adren- alectomized animals received pyrogen-free saline to establish a non-febrile condition, then one or the other of the preparations by vein. Blood samples were examined in 5 minutes, after 15 minutes, 30 minutes and at hourly intervals thereafter for 6 hours. Differences between leukocyte responses were observed. In the normal a