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Summary and ConclusionsThe L. D.100dose of a solution of hen egg white by intracardial injection was determined for a group of actively sensitized guinea pigs. It was found that 5 to 10 mg of pyribenzamine or benadryl injected intraperitoneally between 10 and 30 minutes before giving the shocking dose protected the animals against approximately 8 L. D.100 doses of the antigen while injection of 10 or more L. D.100 doses resulted in rapid death with symptoms indistinguishable from the control animals. If 6 or less L. D.100 doses were given, no symptoms were noted in the protected group.These results seem to indicate that the socalled anti-histaminic drugs do exert a protective influence, quantitative in nature, against anaphylaxis in the actively sensitized guinea pig. This fact might well be expected since a similar quantitative protection is obtained with these drugs against histamine shock.1,2,3 The modifying action of these drugs again seems in accord with the theory that histamine plays a major role i...

As I thought about this subject, I was reminded of a story about Oliver Wendell Holmes. When he was in his eighties nearing the end of his distin guished career on the Supreme Court, the great jurist found himself on a train confronted by the conductor who asked for his ticket, which he couldn't find. Recognizing Holmes, the conductor told him not to worry and said he could just send the ticket to the railroad company when he found it. Holmes looked at the conductor with some irritation and replied, "The problem is not where my ticket is, the problem is where am I going?" I confess I have the same question: "Where are we going with motions for substantial assistance under section 5K1.1 and section 3553(e) of Title 18?" I began by looking at statistical evidence about substantial assistance departures and discovered that they are an enormous percentage of all downward departures. Indeed, the figures for 1989 suggest that of all downward departures, better than 40% were based on substantial assistance motions. If you look at the numbers in 1990, 54.4% of all the downward departures were generated by 5K1.1 motions. I suspect that as time goes on, and as the caseload is filled with more and more drug and firearm cases and mandatory minimum cases, substantial assis tance downward departure motions will become an even larger portion of the pie. We know then that a great deal of downward departures are being driven by motions filed by prosecutors for substantial assistance. The second question I asked myself, and one that comes up regularly in our court, is, "What standards inform the trial judges' decision-making authority about substantial assistance motions?" Once the motion is filed by the prosecutor, triggering the substantial assistance examination, you are directed to 5K1.1. They tell you there are five basic factors that you have to consider, the first three of which can be boiled down to the nature and extent of the defendant's assistance. The first one listed in

Model in vivo and in vitro experimental systems have been used to study the efficacy of specific and nonspecific immunization against Candida albicans infection induced in mice. Experiments were designed to compare the extent of resistance in specifically immunized, endotoxin treated and saline treated animals. In vitro phagocytic and postphagocytic killing (cytopepsis) of macrophages or lymphocyte-macrophage combinations from such animals were determined. In the in vitro experiments the macrophage systems destroyed the yeast cells more rapidly than did the lymphocyte-macrophage combinations. Since equivalent numbers of yeast cells were phagocytized, the differences observed were a function of cytopepsis of the organisms.

The technique of chromosomal positioning of inheritable traits (C.P.I.T.) to project relative positions of two or more traits at more than one gene locus was employed to test the validity of the Fisher-Race model of Rh structure. The results of statistical analysis of two large samples of Rh phenotype distributions suggest that all models based on vertically related, linked alleles are invalid. On the basis of further analysis, Wiener's concept of the structure of the human Rh-Hr gene locus appears most valid among current hypotheses.

Summary No bacteremia was observed in adult albino Mus musculus for 10 days following exposure to 350 r (LD0/30 days) of total body irradiation. The natural resistance of such irradiated mice to intraperitoneally induced Klebsiella pneumoniae infection was significantly depressed on the first, second, fourth and ninth post-irradiation days when the animals were challenged. The significance of host defense participation in recovery from the experimental infection was inferred from the greater mortality among irradiated and treated mice than among non-irradiated and treated control animals. The critical significance of the cellular defense mechanisms of the albino mouse has been discussed.

Summary Following intravenous injection of Thorotrast into normal mice about 50% of the ThO2 is taken up by the liver and 17% by the spleen. While the liver is about 10 times as large as the spleen and shows a greater total uptake of ThO2, the ThO2 uptake of splenic tissue per unit dry weight is almost 4 times that of hepatic tissue. The splenic uptake of ThO2 in mice is linearly related to the amount of Thorotrast injected for doses up to 0.15 ml per mouse. With this dose each spleen contains about 6 mg of ThO2 which makes up 15% of the dry weight of the organ. With doses above 0.15 ml the phagocytic cells of the spleen tend to become saturated, while with smaller doses the ability of the cells to take up additional ThO2 does not appear to be influenced by the ThO2 already ingested. X-irradiation (350 r) caused a great reduction in splenic weight but did not influence the 72 hour splenic or hepatic uptake of ThO2 in mice. Doses from 100 r to 600 r were also without effect on the splenic uptake of ThO2. After intraperitoneal injection with Micrococcus pyogenes var. aureus, leukocytes from the peritoneal cavities of irradiated mice (350 r) contained more bacteria than leukocytes from normal animals. Adrenalectomy caused a reduction in the phagocytic activity of mouse leukocytes which was marked at two days after adrenalectomy. By the sixth day after adrenalectomy however, the control and adrenalectomized groups were not significantly different in this respect. No change in splenic or hepatic uptake of ThO2 was noted to follow adrenalectomy in mice. In rats, however, adrenalectomy caused a threefold reduction in the 24 hour splenic uptake of ThO2.

Summary Total body x-irradiation (300–350 r) resulted in increased susceptibility of mice to infections induced by the gastric instillation of Streptococcus hemolyticus (Group C), paracolon bacilli, Salmonella typhimurium and Escherichia coli on the first, third, fourth, and fifth postirradiation days. No difference in mortality was observed if mice were challenged at later dates (between the sixth and twenty-fifth postirradiation days) or 1, 2, or 3 days prior to x-irradiation. Analysis of the data indicates that increased susceptibility to infection via the oral route following irradiation is dependent upon early damage to the gastrointestinal tract in conjunction with the depression of cellular and humoral defenses which develop at later postirradiation times.

Martin, William J. (College of Medicine, University of Utah, Salt Lake City), and Stanley Marcus . Relation of pyrogenic and emetic properties of enterobacteriaceal endotoxin and of staphylococcal enterotoxin. J. Bacteriol. 87: 1019–1026. 1964.—The pyrogenic, endotoxic fraction of enterobacteriaceal organisms, isolated in a relatively impure or purified state, is both pyrogenic in rabbits and cats as well as emeticogenic in cats in microgram amounts. Employing classical methods for preparation of enterobacteriaceal endotoxin from known enterotoxic strains of Staphylococcus aureus yielded preparations with less than one-hundredth the activity of the enterobacteriaceal material. However, a purified enterotoxin material from an S. aureus strain, with protein-like rather than polysaccharidelike properties, was found to be both pyrogenic and emeticogenic in microgram amounts. These results suggest the probability that the enterobacteriaceal pyrogenemetic substance(s) is a significant part of the whole cell, whereas the staphylococcal enterotoxin is elaborated as a metabolic product which apparently does not accumulate in the whole cell.

The basis and procedure for a culture method employing membrane filters to test freshly prepared parenteral solutions for pyrogenic capacity is presented. Under the limiting conditions described, solutions which yielded counts of less than 10,000 per L. were found to be nonpyrogenic by rabbit test. On the basis of laboratory and field trial, it is concluded that the bacteriological assay for the purpose described is as specific and sensitive as the rabbit assay for pyrogenicity.

Summary The intravenous administration of heparin into rabbits caused a temporary depression in the normal serum bactericidal activity. Serum and plasma exhibited less bactericidal activity than normal if either heparin or citrate was added to the blood in vitro immediately after withdrawal and prior to coagulation. In contrast, neither heparin nor citrate had a demonstrable effect on the serum bactericidal activity when added to the separated serum in vitro. The concentrations of citrate that inhibited bactericidal activity were anticomplementary when the complement titrations were carried out in saline. The heparin concentration used did not show a measurable anticomplementary effect with the test system employed. The depression of bactericidal activity caused by the in vitro or in vivo addition of heparin to blood was partially reversed by the addition of protamine sulfate. The x-irradiation induced depression of bactericidal activity was not reversed by single or multiple injections of protamine sulfate.

Summary The loss or suppression of the normal bactericidal activity of rabbit serum following 650 to 725 r of whole body x-irradiation was not demonstrated to be due to a substance in the sera of irradiated rabbits which inhibits normal bactericidal activity. No decrease in the bactericidal action of normal serum was observed following the addition of serum from x-irradiated rabbits to normal serum. Titrations were carried out with sera from nonimmunized x-irradiated and control rabbits to determine natural agglutinin levels. Suspensions of sheep red blood cells and Bacillus subtilis were employed as antigens. The amount of circulating natural agglutinin was not significantly altered in the sera of x-irradiated rabbits with suppressed bactericidal activity. Complement concentrations determined at a time when the sera from irradiated rabbits showed suppressed bactericidal activity were of the same magnitude in x-irradiated and control rabbits. Addition of either E or M fractions of guinea pig complement failed to restore the bactericidal activity of sera from x-irradiated rabbits.

Summary In vitro studies on the ingestive and digestive capacities of rabbit mononuclear phagocytes from the peritoneal cavities of normal and previously immunized rabbits were made using avirulent, moderately virulent and highly virulent strains of Pasteurella tularensis. The types of serum (autologous, homologous and heterologous) present in 30% concentration and specific antibodies were not found to have any significant effects on the ingestive and intracellular destructive capabilities of these phagocytes on the three strains of the organism. Phagocytes from immune animals were found to have significantly increased intracellular destructive capacities in all cases as compared to those from normal animals. The following hypotheses have been defended: a) The degree of severity of P. tularensis infection in normal rabbits is dependent on the abilities of the phagocytic cells of the animals to destroy the organisms intracellularly; b) host resistance in acquired immunity to tularemia is primarily dependent on the altered phagocytic cells which have greatly enhanced intracellular destructive capacities; and c) humoral factors in acquired immunity to tularemia are secondary in importance.

Concern for civil rights is a necessity for every American. Stanley Marcus, president of Neiman-Marcus, presents some interesting insights into the situation from his experience as a businessman. This article, based on a speech delivered at the New Careers Opportunity Seminar, presents the difficulties that arise from the believability gap between what jobs Negro students feel are available and what ones do exist and suggests that college curricular revisions be implemented to meet the needs of modern society. Marcus also points out the responsibilities of a Negro as an employee, as well as the responsibilities of industry as an employer. He concludes his article with a presentation of his company's new policy and reactions to it from customers and suppliers. This new program is an excellent example of how private business may participate actively in the civil rights field.

Purified protein derivative of Mycobacterium tuberculosis was separated by Sephadex G-200 into 3 fractions. These fractions were tested for sensitin activity in guinea pigs sensitized to Mycobacterium tuberculosis (homologous animals) or to Mycobacterium kansasii (heterologous animals). Fraction I contained nonspecific material. The cross reactions averaging 10.6 mm were approximately equal to the homologous reactions of 9.6 mm. This fraction contained two serologically active components, both neutral in electrophoretic mobility. Fraction II was more specific; the mean homologous reaction was 12.1 mm and the cross reaction was 4.4 mm. Immunoelectrophoresis demonstrated that fraction II contained two cathodic moving components. Fraction III was also more specific with a mean homologous reaction of 9.8 mm and a 1.8 mm cross reaction. Fraction III contained a single anodic moving component. Immunodiffusion showed that each fraction contained at least one unique element. These results suggest that purified pr...

Summary An isotope assay method is described for following intracellular digestion (cytopepsis) in macrophages in vitro and in vivo. This procedure, in conjunction with morphologic and cultural methods, has been used to study cytopeptic capacities of macrophages derived from normal and immunized mice. Immunization was shown to induce a degree of auxocytopepsis which was independent of mediation by circulating or added antibody.

Summary Pretreatment with ACTH or cortisone alters the Shwartzman phenomenon induced by Salmonella aertrycke filtrate. The size and the degree of edema of the inflammatory reaction in hormone-treated animals was decreased and small petechiae appeared within 24 hours following the intradermal injection of the bacterial filtrate. ACTH and cortisone inhibited the Shwartzman phenomenon; the degree of inhibition was proportional to the amount of hormone administered. Both hormones were more effective in inhibiting the Shwartzman phenomenon when hormone treatment was started prior to the intradermal injection of bacterial filtrate than when treatment was started after this injection. Significant inhibition of the various components of the inflammatory reaction was noted. This inhibition varied with the hormones used as well as with the time and dose schedules.

SummaryMultiple tests on solutions to which have been added known numbers of various bacterial species, suggest that 1000 or more organisms/ml must be present before the U.S.P. rabbit pyrogen test will yield a positive result. The potentiality is inferred of a simple culture procedure as a screen test for pyrogenicity of solutions to be employed for parenterl infusion.

1.There is need for uniform criteria for the classification of shock following acute myocardial infarction. 2.2. Levarterenol is the vasopressor drug of choice in patients with severe coronary shock. Compared to non-specific therapy, levarterenol is beneficial and may be life-saving in an additional 20 per cent of these patients. 3.3. Neither intravenous nor intra-arterial transfusion alone reduces the mortality rate in severe coronary shock. 4.4. The mechanism of coronary shock is obscure and present day therapy is empirical. Additional data are needed on the hemodynamic changes and mechanism of this syndrome.

Summary Immunization with Salmonella typhimurium or Bacterium tularense, prior to near LD50 radiation, statistically increased resistance to oral challenge with the homologous living organism when the immunizing procedure conferred a sufficiently high degree of immunity. Antibiotic therapy in conjunction with preradiation immunization was more effective in increasing resistance than either of these methods used alone. A large total dose (900 r) given in regular small increments was found to be far less detrimental to the host defenses of the mouse than single exposure to smaller lethal doses.

Summary Immunization with Klebsiella pneumoniae prior to x-irradiation increased the resistance of mice to challenge with an aerosol of the living organisms. This protective effect of preradiation immunization was not destroyed at sublethal to near midlethal levels of exposure (levels at which mortality resulting from overwhelming infections are implicated as an important cause of death). The results presented show that a large total irradiation dose, given in increments, is far less detrimental to the host defenses than the same dose acutely administered.

Summary The role of cellular immunity in tuberculosis was studied by using in vitro techniques to observe cellular capacities for phagocytosis and bacterial inactivation. Peritoneal exudates were stimulated and collected and alveolar phagocytes were harvested using standard techniques. Normal and BCG-immunized guinea pigs were used as phagocyte donors. Two strains (H37Rv, H37Ra) of Mycobacterium tuberculosis were used for infecting the phagocytes. Suspensions of these tubercle bacilli consisting of single cells were prepared by filtration. Plate counts were used to indicate the amount of ingestion and cytopepsis by the phagocytes. It was shown using the H37Rv strain of tubercle bacilli that phagocytes from BCG-immunized animals had increased cytopeptic activity when compared to phagocytes from normal animals. Also, the alveolar phagocytes were more active in cytopepsis than were the peritoneal exudate cells.

Cells were separated from tissue specimens of human malignant melanoma and grown in tissue culture on coverslips. After 8 days of growth the explanted cells were fixed and stored until used. Sera from 15 patients with malignant melanoma were reacted with the fixed melanoma cells and a variety of other cells. The indirect immunofluorescence method was used to test for presence of antibodies. Sera from all 15 melanoma patients reacted with fixed melanoma cells giving intense fluorescence of intracytoplasmic granules. The fluorescent material appeared to be independent of melanin granules. Homogenate of fresh melanoma but not of other neoplastic or normal tissue absorbed out the anti-melanoma antibodies. The human antimalignant melanoma antibodies did not react with live malignant melanoma cells or with fixed or live cells from benign nevi or fixed guinea pig kidney, human kidney or HeLa cells. The evidence suggests that these antibodies are unable to penetrate living cell membranes.

Summary Exposure of mice to total body x-radiation in doses of either 300, 400 or 500 r does not affect the phagocytosis by reticuloendothelial cells of spleen of intravenously injected ThO2 when determined 2 days following radiation. However, similar investigations carried out on the seventh postradiation day indicated that 1) x-radiation in a dose of 300 r did not affect the localization of ThO2 in spleens; 2) a 400 r dose of x-radiation causes a transient depression of localization of ThO2 at 2 hr but 6 and 24 hr splenic uptake values were not different from the controls; and 3) x-radiation in a dose of 500 r significantly depressed the uptake by the mouse spleen of ThO2 at 2, 6 and 25 hr after injection. Whole-body x-radiation in a dose of 550 r suppressed the phagocytosis by reticuloendothelial cells of LAf1 mice when tested on the seventh postradiation day. Chronic exposures of mice to x-radiation in doses of 25 r three times per week until accumulated doses reach as high as 825 r did not affect the phagocytic function of the reticuloendothelial cells.

The specificity of the first or “presumptive” portion of the USP rabbit pyrogen test was investigated by use of a new absolute standard of reference. The reference standard was a 0.9% sodium chloride solution prepared to be pyrogen-free. Details of the preparation were described. The hypothesis was explored that the temperature response of rabbits after intravenous injection of the standard solution was independent of exogenous pyrogen. Reactions observed among the rabbits in our colony allowed a classification of these animals ranging from “consistently reliable” to “consistently unreliable.” Details of the experimental results and implications for pyrogen testing are discussed. The recommendation was made that all rabbit test animals be “screened” in sham and actual tests before being used for pyrogen testing.

Summary Total body x-irradiation suppresses intracellular digestion of chicken erythrocytes by the peritoneal phagocytes of mice and rabbits. Such digestive function was normal on the second and eighteenth postirradiation days but was depressed on the sixth through the fourteenth day following 350-r total body irradiation of mice. When the irradiation dose was increased to 450 r, digestion of chicken erythrocytes by mouse phagocytes did not return to normal until the twenty-sixth day. The inhibition of phagocyte digestion of Candida guilliermondi followed the same pattern as observed with chicken red blood cells. Immunization with chicken erythrocytes caused an increase in the digestion of these cells by the phagocytes from mice and rabbits. The immunization-induced increase in digestive capacity was reversed by irradiation procedures that did not appreciably alter serum antibody titers. In vitro tests carried out in the presence of serum from immunized and immunized-irradiated rabbits revealed that the beneficial effect of immunization and the detrimental effect of irradiation on phagocyte digestion were due to alterations in the phagocytic cell and not due to the humoral changes that follow irradiation or immunization.

Conclusions1. A reliable biological method for the quantitative assay of small quantities of hyaluronidase or hyaluronidase inhibitor in the presence of body fluids is described.2. Presumably, the conjugates of salicylates as well as salicylate itself in therapeutic concentrations have no inhibitory effect on testicular hyaluronidase in vitro.3. Thermolabile hyaluronidase inhibitor has been found increased in a significant proportion of the sera of human malignancies in a small series studied.4. Rheumatic states do not differ from the normal with respect to this inhibitor toward testicular hyaluronidase.

Martin, William J. (University of Utah, Salt Lake City), and Stanley Marcus . Detoxified bacterial endotoxins. I. Preparation and biological properties of an acetylated crude endotoxin from Salmonella typhimurium . J. Bacteriol. 91: 1453–1459. 1966.—Acetylation of a crude endotoxin prepared by the Roschka-Edwards (RE) procedure from a strain of Salmonella typhimurium yields a product with reduced pyrogenicity in rabbits as well as one which is nontoxic in mice. A reduction in pyrogenicity of approximately 100 times was noted with this acetylated crude endotoxin when compared with the parent RE preparation. A comparison was made of immunogenicity with mice of Boivin, RE, and acetylated Roschka-Edwards (Acet-RE) preparations with a heat-killed, phenol-preserved (HP) vaccine prepared from the same strain of S. typhimurium . Less than pyrogenic doses of all vaccines were not protective. The least pyrogenic preparation (Acet-RE) was immunogenically effective in about five times the minimal pyrogenic dose. The data suggest that the Acet-RE preparation should be considered further in the search for enteric fever vaccines with lowered potential for undesirable systemic responses.