Studies on the maturation of immune responsiveness in the mouse. II. Role of the spleen.

Experiments were designed to investigate the role of the spleen in the development of the murine immune system. By using mice splenectomized within 24 hr of birth, as well as mice with a hereditary, congenital absence of the spleen, the primary immune response to sheep erythrocytes was examined. The immunocompetence of lymph node cells from spleenless or control mice was assessed in vitro, in organ and in cell suspension cultures, and in vivo, by transfer into lethally irradiated syngeneic recipients followed by antigenic stimulation. The immunologic capacities of thymus and bone marrow cells were similarly tested by injection separately or in combination into irradiated syngeneic mice. Lymph node cells from spleenless animals appeared fully competent both in vitro and in transfer experiments. Neither neonatal splenectomy nor congenital absence of the spleen significantly reduced the capacity of bone marrow or thymus cells to participate in the immune response to sheep erythrocytes.     

Reproduction in the ferret. I. The effect of ovariectomy on the course of gestation.

The role of the ovaries in the maintenance of pregnancy was studied in the ferret. Ovariectomy at the time of implantation showed that some embryos survived for 7 days after the operation but all were destroyed after 10 days, although the trophoblast continued to grow at a much faster rate than normal. Ovariectomy performed after implantation showed that no fetal development occurred when the ovaries were removed at Day 21 post coitum, but that fetuses developed for an appreciable length of time in animals ovariectomized on Days 23 to 27 post coitum. Ovariectomy in late gestation resulted in speedy expulsion of the fetuses. An increase in the placenta:fetus ratio did not alter the response to ovariectomy in late gestation. The uteri in all ovariectomized animals showed progestational endometria when examined shortly after explusion of the fetuses.     

Progesterone in the uterus. IV. Dependence of the in vitro progesterone metabolism in the rat uterus on the progesterone concentration.

After incubation of uterine segments of normal rats with various 3H-progesterone concentrations in nutrient medium, different patterns of radioactive steroids were obtained in uterine tissue. Using hormone concentrations of less than 5 X 10(-7)M progesterone metabolites could not be detected in the tissue. A series of metabolites appeared with progesterone concentrations of 10(-6)M and higher. Six radiometabolites were identified and two were characterized.     

Studies on the circadian rhythm of phosphoenolpyruvate carboxykinase. III. Circadian rhythm in the kidney.

Phosphoenolypyruvate carboxykinase [EC 4.1.1.21] activity in rat kidney shows a circadian rhythm with the highest activity between 0200 h and 0800 h and the lowest activity between 1400 h and 2000 h. The rhythm was observed in both sexes and throughout the year. Actinomycin D and cycloheximide effectively blocked the circadian increase in enzyme activity. These findings suggest that the circadian increase in phosphoenolypyruvate carboxykinase activity is due to net synthesis of enzyme protein through newly synthesized mRNA. In experiments with kidney cortex slices, gluconeogenesis from the radioactive precursor, [14C]malic acid, was considerably higher at 0200 h than at 1400 h, varying in parallel with the change in the enzyme activity.     

Studies on the product of antigenic recognition. I. Formation of the product in recognition of alloantigens.

A product of antigenic recognition (PAR) was produced whenever receptors for alloantigens from T lymphocytes or a principle present in T-cell dependent alloantisera interacted with alloantigen. With two forms of the PAR assay (direct and indirect) the mechanisms underlying these interactions have been analyzed. For the interaction of T-lymphocyte receptors with alloantigen measured with direct PAR assays, the following conclusion emerged: upon confrontation with alloantigen, receptors (if not already present in secreted form) had first to be released from T-cell membranes. Shed T-cell receptors interacted with alloantigens by solubilizing them. Both processes could be prevented by fixing cells with formaldehyde. Release of T-cell receptors was temperature-dependent, solubilization of alloantigens was not. Because in mixed cell cultures receptors had first to be shed, this process was considerably slower and, in concordance with temperature dependence of receptor release, took place only at 37 degrees C. Titration of T lymphocytes with 'bound' receptors by the direct PAR test revealed that in the presence of excess alloantigen 10(2) T cells sufficed to give measurable responses. Supernates of parental strain lymphocytes containing numerous T-cell receptor specificities could be depleted of one of them. Alloantisera raised in presence of T helper cells ('T alloantisera') contained a principle capable of recognizing alloantigens, alloantisera incited in the absence of T helpers ('B alloantisera') did not. The recognizing principle appeared to be IgG. Like T-cell receptors, it was capable of solubilizing alloantigens form target cell membranes. B alloantisera lacked this capacity and their alloantigen-recognizing moiety was found to be monomeric IgM. The mode of interaction of this IgM with alloantigen most likely consisted in fixation to and shielding of antigen.     

Investigations on erythropoiesis in newborn rats. Dependence of erythropoiesis in newborn rats on the intensity of the haemopoietic processes in the lactating mothers.

The intensity of haemopoietic processes was investigated in 7, 9, 11, 14 and 19-day-old suckling rats in relation to the intensity of these processes in their mothers. The rate of the haemopoietic processes in newborn rats was determined on the basis of 59Fe incorporation into the blood and haemopoietic organs. The activity of the erythropoietic system in lactating rat females was stimulated by haemorrhage and inhibited by erythrocyte transfusion. Anaemization of lactating rats by haemorrhage did not stimulate erythropoiesis in the suckling rats. Posttransfusion polycythaemia in the lactating mothers inhibited erythropoiesis in the suckling rats beginning with the 9th day of life. This phenomenon became more pronounced with the age of the rats.     

Perspective on hypertension in the elderly.

More than half of elderly men and women have hypertension, leading to a significant risk of increased morbidity and mortality. The cause of hypertension in this age group is unknown. Left ventricular hypertrophy is frequently present, often associated with diastolic dysfunction. Systolic hypertension in the elderly increases the risk of cardiovascular disease, but there are no good data to show that the treatment of isolated systolic hypertension reduces the morbidity or mortality. Good evidence indicates that antihypertensive treatment in this group decreases cardiovascular morbidity and mortality up to age 80, so most elderly hypertensive patients should be treated. An empiric trial of nonpharmacologic therapy can be initiated in those with mild hypertension and no cardiovascular disease, but most patients will require drug therapy. Most elderly hypertensive patients have accompanying illnesses for which they may or may not be taking medications. Some antihypertensive drugs exacerbate coexisting diseases while others augment treatment regimens. Similarly, drugs may interact in a beneficial or adverse way. Finally, drug metabolism is altered by age, leading to problems with toxicity or diminished efficacy. The choice of medication should be based on all such considerations, including the cost and convenience of the drugs available.