Autonomic dysfunction in women with mitral valve prolapse syndrome.

Autonomic cardiovascular regulation was evaluated in 35 women, 19 with mitral valve prolapse and 16 healthy controls. Heart rate responses to the diving reflex and to phenylephrine infusion were diminished in patients. Noninvasive measures of cardiac output, heart rate, blood pressure, forearm flow and leg volume during lower body negative pressure (LBNP) showed that patients had less lower extremity pooling of blood and had lower forearm conductance. Blood pressures during LBNP rose or remained unchanged despite decreases in cardiac output of 20--25%. These data indicate that mitral valve prolapse patients have an increased venous and arterial vasoconstrictor activity. Cardiac output at rest and echocardiographic indices of contractility were normal. Patients with a history of significant ventricular arrhythmias had higher heart rates and lower forward stroke volumes than the other patients or controls. The combined data demonstrate autonomic dysfunction in women with the mitral valve prolapse syndrome and suggest decreased parasympathetic, increased alpha- and normal beta-adrenergic tone and responsiveness.     

ON THE RELATION OF PRODUCTS OF ACTIVATED LYMPHOCYTES TO CELL-MEDIATED CYTOLYSIS

Experiments have been designed to test the hypothesis that soluble mediator production and T-cell-mediated cytotoxicity are necessarily related phenomena, and that soluble mediators may be involved in the mechanism of cytolysis. To this end, agents known to inhibit T-cell-mediated lysis in vitro have been studied for their effects on the production of two lymphocyte-derived mediators, lymphotoxin (LT) and migration inhibitory factor (MIF). A clear dissociation between mediator production and cell-mediated cytolysis was found using inhibitors of protein synthesis. Pactamycin and emetine, in doses of 10^–7 M to 10^–6 M, suppressed production of MIF and LT with only slight effect on killing of mastocytoma cells by immune T cells. On the other hand colchicine and vinblastine inhibited T-cell-mediated cytolysis in a dose-related manner but had no significant effect on either MIF or LT production, A striking dichotomy was also observed after augmentation of intracellular cyclic 3'5' adenosine monophosphate (cAMP) levels with cholera enterotoxin. Increased cAMP levels were associated with abrogation of direct lytic activity, but were without significant effect on MIF or LT production in guinea pigs or mice. These findings indicate that mediator production and direct lymphocyte-mediated cytolysis can be experimentally dissociated and represent independent cell-mediated immune functions.     

Demonstration of IL-1 alpha, and IL-1 beta secretion by the monocytic leukemia cell line, THP-1

This study examined the secretion of IL-1 alpha and IL-1 beta by THP-1 leukemia cells following activation with mezerein and promotion of synthesis by interferon (IFN-gamma). Interleukin-1 (IL-1) was not detected by co-mitogenic thymocyte assays of crude supernates. Isoelectrofocusing of concentrated medium showed that all biologically active IL-1 migrated at a pH of 6.8-7.2, indicating that the major secreted form was IL-1 beta. Double antibody ELISA confirmed the presence of IL-1 beta, but failed to detect IL-1 alpha in isofocused fractions. Although it appeared that THP-1 cells do not secrete IL-1 alpha; an inhibitor of thymocyte response to IL-1 was present in conditioned medium, migrated in an acidic pH range and masked the expression of biologically active rIL-1 alpha and rIL-1 beta. In contrast, IL-1 alpha was detected using a cell blotting assay. This technique permitted visualization of subpicogram levels of IL-1 when secreted by cells attached to an immunoblotting paper. Cell blotting showed that a greater proportion of attached cells incubated for 24 h in medium containing mezerein and IFN-gamma secreted IL-1 than cells in control medium. In conclusion, the amount of immunoreactive or biologically active IL-1 alpha secreted by stimulated THP-1 cells appeared to be much lower than that reported for human peripheral blood monocytes.     

Subcellular localization of transforming growth factor-alpha in human eosinophil granulocytes

Eosinophils are involved in the inflammatory response seen in allergy and helminthic infestations. Eosinophils synthesize transforming growth factor-alpha (TGF-alpha), which may play a role in the development of the characteristic fibrosis seen in longstanding high eosinophilia. Using immunoelectron microscopic techniques, eosinophils from peripheral blood of healthy individuals and from one patient with high eosinophilia showed presence TGF-alpha in matrix of the specific crystalloid-containing granules. In cryosections, TGF-alpha was also visualized in a vesicular compartment of the cytoplasm. In double- labeling experiments, the TGF-alpha of this latter compartment did not colocalize with CD63, a marker for lysosomes, nor with albumin of secretory vesicles. In extracts from eosinophils, obtained from healthy donors, immunoreactive TGF-alpha could be detected by enzyme-linked immunosorbent assay-technique. In addition, sera from two patients with high eosinophilia showed TGF-alpha concentrations of 1.5 ng/mL and 164 pg/mL, respectively, whereas TGF-alpha could not be detected in serum from healthy controls. In conclusion, TGF-alpha is present in the specific granules, and in an additional vesicular compartment of the cytoplasm of eosinophils.     

The binding of glu- and lys-plasminogens to fibrin and their subsequent effects on fibrinolysis

The affinities of glu- and lys-plasminogens (plgn) for totally crosslinked fibrin were compared in two systems: a) incorporation into fibrin during clotting and b) direct adsorption onto fibrin immersed in plgn solution. Over a wide range of concentrations of plgn, uptakes were greater with incorporation than immersion, and in purified than in plasma systems. In all cases lys-plgn showed a greater affinity for fibrin than did glu-plgn. The potencies of glu- and lys-plgn were also compared in lysis systems using ¹²⁵I-labelled fibrin. The lysis achieved increased in proportion to the plgn concentrations to which clots were exposed. Fibrin to which plgn was adsorbed by immersion lysed slowly and incompletely when transferred to streptokinase (SK), irrespective of the type of plgn used. However, more lysis was achieved after incorporation of plgn, in which system prior exposure to lys-plgn gave more lysis in SK than did glu-plgn. In contrast, a third and slightly more potent lysis system (adsorbing SK-activator to washed fibrin then transferring the fibrin to plgn solution, called the SK→plgn regimen), produced marginally more lysis in glu- than lys-plgn. The molecular species of fibrin degradation products obtained with different lysis regimens were not altered by interchanging glu- and lys-plgns. Again, with either type of plgn, the binding to fibrin (in both incorporation and immersion systems) and the lysis rates of fibrin (in the SK→plgn regimen), were both decreased in the presence of plasma or serum. The pertinence of these test-tube data to $\text{in vivo}$ requirements for thrombolytic therapy is speculative, but they support both current theories that the impetus to fibrinolysis is provided a) by intrinsic plgn and b) by the adsorption of plgn activator to fibrin. It cannot be assumed that lys-plgn must be more effective than glu-plgn in lysis systems because of superior affinity for purified fibrin, and in these studies the most active lysis was achieved when either type of plgn percolated the fibrin and was activated to plasmin in situ.     

Correlation between human cell growth response to interleukin 1 and receptor binding

Human recombinant interleukin 1 alpha (IL-1 alpha) and IL-1 beta inhibited the replication of the mammary tumor cell line, MDA-MB-415; stimulated division in the colon carcinoma, SW-48; and had no effect on the growth of the milk mammary line, HBL-100. Inhibition of growth was reflected in a significant decrease in DNA synthesis accompanying a transient increase in RNA synthesis. Specific binding of 125I-labeled recombinant IL-1 beta by MDA-MB-415 and SW-48 reached a maximum by 2 h of incubation, and an equivalent amount was bound by each cell type. Binding was inhibited in a dose-dependent manner by unlabeled IL-1 alpha or IL-1 beta. Scatchard plot analysis revealed that MDA-MB-415 cells expressed approximately 700 binding sites with an apparent dissociation constant of 8.8 x 10(-10) M. Reversibility of growth inhibition was independent of dose or time of incubation, but DNA synthesis did not return to control values. Flow cytometric analysis of DNA content showed that growth inhibition was cell cycle phase nonspecific with a slight reduction in the proportion of cells in S phase. The major conclusion from these studies was that inhibition or stimulation of malignant cell growth by IL-1 was related to the presence of receptor sites.     

Is there familial transmission of pedophilia?

A naturalistic, double-blind, family history comparison of sexual deviancy in the first degree relatives of inpatients with pedophilia and nonpedophilic paraphilia was done. Both proband groups were similar in demographic characteristics, except that pedophiles had a later onset of illness and were older during hospitalization. All patients were men. Sexual deviancy was found in 18.5 per cent of the families of paraphiliacs; only 3 per cent of a psychiatric control group had a family member with sexual deviancy. The preponderance of affected relatives were men. The types of sexual deviancy found in the families of the groups differed. Sexual deviancy among the pedophiles' families consisted of pedophilia. In families of nonpedophilic paraphiliacs, sexual deviancy was predominantly a paraphilia not involving children. These data suggest that pedophilia is familial; however, further studies are needed to delineate the manner of transmission. Nonetheless, pedophilia is found more frequently in families of pedophiles than in families of nonpedophilic paraphiliacs. This indicates specificity in the familial transmission. Thus pedophilia may be independent of the other paraphilias.