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To the Editors: Alzheimer disease is the most devastating disease of the 1990s because it destroys not only the patient but at least one caretaker. The destruction is slow—almost without end. Even ...

The case is presented that both hemorrhagic and septic shock are due to an inadequate oxygen supply to mitochondria of vascular muscle cells in peripheral circulatory beds. Mitochondria disintegrate in the presence of severe hypoxia; this is a normal response which does not, per se, indicate generalized cell damage. Irreversible shock follows when appreciable numbers of the muscle mitochondria become non-functional. The ATP available from glycolysis is inadequate to resynthesize the mitochondrial apparatus and oxygen cannot be used by the damaged mitochondria to produce the needed ATP through oxidative phosphorylation. In the absence of adequate ATP, the tone of these peripheral vessels must fall, leading to irreversible systemic hypotension and death. In hemorrhagic shock, mitochondrial hypoxia of smooth muscle cells is produced by decreased perfusion of the vasa vasorum in the constricted peripheral vessels; in septic shock there is direct competition for oxygen between bacterial cytochromes and muscle mitochondria.

Epidemiology and Pathology AS the lethal activities of man decreased in the closing months of World War I, a new lethal agent emerged that killed 20 million people around the world.1 The disease was pandemic influenza, and the agent a new influenza virus.2 In Ireland the average endemic mortality rate from influenza from 1901 through 1917 was 29 per 100,000 per year for males. The epidemics of 1892, 1900 and 1918 had mortality rates of 81, 105 and 243 respectively. The 1918 rate was highest, but much more striking was the change in age distribution of those dying. Although the . . .

Atmospheric and biological evolution progressed simultaneously and today certain cell types flourish only at oxygen tensions which were ambient 600 million years ago, i.e., at 5 to 10 mm Hg. In man, a continuous oxygen flow at these pressures is supplied in the skin where Treponema pallidum , Mycobacterium leprae and members of the genus Rickettsia grow best. In vitro studies support the microaerophilic status of these organisms and of certain other microbial and mammalian cells. Vigorous growth in pure culture will await the development of techniques which can maintain these low oxygen tensions at the cell walls of the microbes as they replicate and consume increasing amounts of oxygen. Continuing failure to consistently isolate microbes from active lesions in patients with rheumatoid arthritis or systemic lupus erythematosus may reflect the universal absence of suitable methods for isolation of microaerophilic microbes.

The evolution of aerobic organisms required the development of oxygen sensors so the organism could avoid anoxic environments. In man these oxygen sensors are known as pain receptors. The skin pain receptor includes the epidermis and the dermal papilla with its capillary and terminal nerve. A pain stimulus such as a pin prick occludes blood flow into the papilla. The epidermal cells consume enough residual oxygen to produce a fall in oxygen tension at the nerve ending sufficient to cause the nerve to fire. The maximum time required for the oxygen drop is 0.04 seconds.

An experiment was designed as an instructional method, elective class participation (ECP), in which class attendance was not re quired and the instructor tended to be a guide rather than lec turer. Ss were adult students enrolled in one of two semesters of introductory psychology. For two years data were collected on all Ss. Half the sessions were taught the conventional way; the other half used the ECP approach. Hypotheses tested were: Ss in the ECP groups would show more posttest gain over the pretest scores than those in the control groups; the ECP method would elicit favorable reactions. The criterion measure was posttest gain over pretest score. Biserial part correlations were computed be tween ECP and control groups and posttest score residualized with respect to six control variables: sex, hours attempted, semester grade point average (GPA), cumulative hours completed, cumula tive GPA, and pretest score in course subject matter. Four correla tions were positive, indicating that enrollment in the ECP group was related to a higher posttest score. In one group the relation ship was statistically significant. The data were further analyzed into the following groups: ratings of classes which consisted pri marily of lecture, demonstrations, films, and feedback quizzes. No significant differences were found among ratings of the last three, but when each of the last three was compared with the lecture classification, it was found that Ss rated ECP classes higher than the locture classes. It is apparent that Ss preferred to attend (or at least rated the quality higher) classes in which novel techniques were used. Ss' ratings of the ECP course indi cated that 59% rated it average or better and a satisfying learning experience while 41% rated it fair or poor.

Summary Data derived from the literature are presented in support of the 1912 theory of Smith and St. John-Brooks that the antigen dose-antibody response follows the form: K1c1/nAb where K1 is a constant, c is the concentration of the antigen, n is a constant between 1.9 and 3.6 and Ab is the maximum concentration of antibody. The value of n appears to depend upon the chemical composition of the antigen. For proteins, n is about 1.9, for lipopolysaccharides about 2.6, and for polysaccharides about 3.6. From limited data, this equation appears to hold only at intermediate concentrations of antigen. At low concentrations, n approaches 1, while at high concentrations n approaches infinity. On the basis of the above equation, certain values for K1 could be calculated, and these are listed. These findings are consistent with, but do not prove, the concept that the limiting step in antibody production involves an adsorption process.

Summary Three-kilogram rabbits were injected intravenously, intrasplenically and intraportally with 4 or 40 mg of alum-precipitated bovine γ globulin (BGG). At both dosage levels the peak precipitin responses were as follows: intravenous >; intrasplenic = intraportal. Antibody responses of small groups given soluble BGG were intravenous = intraportal > intrasplenic. In an attempt to determine any correlation between antigen concentration in an organ and serum antibody levels, the distribution of soluble and alum-precipitated I131 human serum albumin (HSA) was studied in certain organs of normal rabbits at 15 minutes and 24 hours after intravenous, intrasplenic and intraportal injections. No good correlation was found. An unexpected finding was that, when injected intravenously, eight times as much antigen was found in the lungs 15 minutes after alum-precipitated antigen as after soluble antigen. Splenectomized rabbits produced about 40% as much antibody as controls following intravenous injection of alum-precipitated BGG.

Summary The rate of loss of labelled antigen (I131 bovine gamma globulin) from blood has been used as a measure of the primary immune response in rabbits. Using this method, standard curves have been set up for normal rabbits and for rabbits in which the immune response has been eliminated by prior x-irradiation. The results agreed with those published by other workers. Rabbits were given daily injections of one of the following antibiotics: crystalline penicillin G (28,000 units/kg), dihydrostreptomycin (50 mg/kg), aureomycin (30 mg/kg), terramycin (29 mg/kg). The loss of I*BGG from the blood of these animals was followed. The mean values for the control vs. the experimental groups were subjected to statistical analysis, using the “F” test. All antibiotics tested produced a depression. For aureomycin, this depression was significant at the 98% confidence level, for dihydrostreptomycin at the 99% level, for terramycin at the 99.8 % level, and for penicillin at the 99.9% level. All rabbits were not affected: some showed no depression, some showed partial depression, while others were completely depressed.

Summary Spleen fragments from both primarily and secondarily injected rabbits produced antibody to protein antigens when cultured in a suitable medium. The longer the antigen remained in vivo, the higher were the antibody titers in extracts and in cultured material. The antibody produced was specifically neutralized by the homologous antigen. Antibody synthesis seemed to occur intracellularly with little or no induction phase, with release into the surrounding medium occurring at a later time. The titers of culture fluids and serums were shown to be about 8-fold higher when S. typhosa endotoxin was given 24 hr in advance of the primary antigen injection, but not when the endotoxin was given simultaneously with the antigen. In both cases, spleens were removed 2 hr after antigen injection.

Summary1) Sera from 1086 patients admitted to a general hospital and from 38 medical students were examined for antibodies to egg albumin using both a microprecipitin technic and a very sensitive hemagglutination technic. 2) Of 450 sera examined by the microprecipitin technic, all were negative. 3) Only 15 patients of the 1124 or 1.3% were found to have antibodies by the hemagglutination technic. Their HA titers ranged from 25 to 2190 with a median of 80. None of these HA positive sera contained precipitins. 4) Five of these patients with circulating antibody had abdominal complaints, 4 were pregnant and the remaining 6 had miscellaneous illnesses.

Ten µg. of the lipopolysaccharide endotoxin of Salmonella typhosa was given to rabbits intravenously to enhance the subsequent antibody response to an unrelated substance. The spleens were removed 24 hours later, diced, and incubated 1 hour with the antigen, bovine-γ-globulin (BGG), in a protein-free medium. After washing, the tissues either were extracted at once or planted and the fluids and tissues harvested 1 to 3 days later. Antibody was determined by a modification of the Boyden hemagglutination technique. Small amounts of antibody were synthesized as early as 1 hour after the addition of antigen. The antibody formed could be specifically inhibited with BGG, was not dialyzable, and did not sediment at 105,000 g for 2 hours. Dose-response studies revealed no antibody formation when the BGG concentration was 0.005 or 0.05 mg./ml. The best responses were obtained at concentrations of 0.5 to 5.0 mg./ml. These results were found irrespective of whether the animal had previously received BGG in vivo. Forty per cent autologous serum increased antibody formation about 9-fold over that secured with protein-free medium or with 40 per cent homologous serum. Antibody formed with this system could be detected by 50 per cent complement fixation test, although at much lower titer than found by hemagglutination. While spleens from rabbits previously given BGG did not produce more antibody than spleens from normal rabbits, they differed in that they produced antibody without the involvement of endotoxin. Under appropriate circumstances, endotoxin was effective in vitro in enabling spleen fragments to produce antibody to BGG. Cortisone acetate administered to rabbits prior to the removal of the spleen severely inhibited antibody production in vitro. Sodium prednisolone phosphate added in vitro showed a similar irreversible effect at concentrations as low as 2 x 10–5 M. Nitrogen mustard inhibited antibody formation at concentrations as low as 10–4 M.

Cells from peritoneal exudates of rabbits sacrificed 3 days after an intraperitoneal injection of sterile mineral oil were grown in tissue cultures in medium 199 (75 per cent); normal rabbit serum (25 per cent). Antibody produced by the cells was assayed by an hemagglutination technique in which the antigens used were adsorbed to formalinized tanned sheep erythrocytes. These sensitized cells agglutinate in the presence of antibody specific to the adsorbed antigen. It has been demonstrated that: Peritoneal exudate cells produced hemagglutinating antibody to bovine gamma globulin (BGG) in a replicating tissue culture system for approximately 3 weeks when taken from animals given either primary or secondary injections of BGG. The mean hemagglutinating titer was 30 for the primary and 32 for the secondary systems. Since the other cell types did not persist, it is felt that monocytes were responsible for these results. Monocytes taken from normal rabbits and exposed to either BGG or egg albumen (EA) in vitro produced titers of 28 for about 2 weeks. Monocytes taken from rabbits given hyperimmunizing injections of BGG produced titers of 147 for about 1 week. Endotoxin from Salmonella typhosa caused the monocytes to form antibody as if they had been taken from hyperimmunized rabbits. This was true both when the antigen was given in vivo together with the endotoxin as well as when the cells were exposed to antigen in vitro. The titers were 223 and 97, respectively. Neither freshly harvested nor cultured monocytes were phagocytic for carbon particles or bacteria in vitro. Monocytes in tissue culture appeared to assume the morphology of fibroblasts, but did not stain with the characteristics of fibroblasts. The morphologic changes and staining characteristics of monocytes in tissue culture have been described. The implications of these findings have been discussed and an attempt made to integrate them into general biological theory.

The Cdk12/CycK complex promotes expression of a subset of RNA polymerase II genes, including those of the DNA damage response. CDK12 is among only nine genes with recurrent somatic mutations in high-grade serous ovarian carcinoma. However, the influence of thesemutations on the Cdk12/CycK complex and their link to cancerogenesis remain ill-defined. Here, we show that most mutations prevent formation of the Cdk12/CycK complex, rendering the kinase inactive. By examining the mutations within the Cdk12/CycK structure, we find that they likely provoke structural rearrangements detrimental to Cdk12 activation. Our mRNA expression analysis of the patient samples containing the CDK12 mutations reveals coordinated downregulation of genes critical to the homologous recombination DNA repair pathway. Moreover, we establish that the Cdk12/CycK complex occupies these genes and promotes phosphorylation of RNA polymerase II at Ser2. Accordingly, we demonstrate that the mutant Cdk12 proteins fail to stimulate the faithful DNA double strand break repair via homologous recombination. Together, we provide the molecular basis of how mutated CDK12 ceases to function in ovarian carcinoma. We propose that CDK12 is a tumor suppressor of which the loss-of-function mutations may elicit defects in multiple DNA repair pathways, leading to genomic instability underlying the genesis of the cancer.

Antibodies to human seminal plasma (hsp) were assayed by a haemagglutination technique in 618 sera from hospitalized patients. Thirty per cent of the sera had low antibody titres (1:20 to 1:320). Further studies indicated that the antibody measured was a natural isoagglutinin which reacted with the blood group substance found in hsp. However, immunization of rabbits with hsp produced antibody which reacted with other antigens of hsp but not with blood group substance.