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Bone marrow-enhancing factor (B-EF) is the spontaneous product of whole bone marrow cells cultured in serum-free medium for a short term (24-48 hr). The factor is prepared by ultrafiltration of BMC supernates to yield a preparation with a MW of greater than 10,000. Production of the factor is not dependent upon antigenic or mitogenic stimulation of BMC, but is inhibited by treatment of BMC with cycloheximide. B-EF augments the in vitro primary PFC response to SRBC, as well as in vitro secondary IgM and IgG PFC responses to SRBC. Enhancement by B-EF is antigen dependent, genetically nonrestricted, and maximal when present at the initiation of culture. B-EF cannot induce a polyclonal antibody response like the polyclonal activator LPS. B-EF is directly mitogenic for thymocytes, bone marrow, and whole spleen cells, but fails to act as a costimulator of thymocyte proliferation in the presence of Con A. B-EF cannot support the growth of the IL-2-dependent cell line CTLL-2. Since B-EF has not been purified, the supernatant may contain more than one activity. The factor is heat labile at 65 degrees C and is sensitive to enzymatic digestion with trypsin and neuraminidase; this implies that B-EF may be a glycoprotein.
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A number of carboxyl-substituted S-blocked glutathiones have been shown to be competitive inhibitors of yeast glyoxalase I at 25 degrees C, pH 6.6. Amidation of the glycyl carboxyl group of S-(p-bromobenzyl)glutathione has no appreciable effect on binding whilst methylation reduces binding by 8.9-fold, indicating a steric constraint and the possible presence of a hydrogen bond in this region of the enzyme. Amidation of both carboxyl groups of S-(p-bromobenzyl)glutathione reduces binding significantly by 237-fold; this result agrees with electrostatic interaction of the Glu COO- group with a group located within the enzyme surface as opposed to the Gly COO- group, previously proposed.
This article has attempted to bring the reader up to date on advances in selected facets of the area of reactive oxygen intermediate-induced ischemic injury. Specifically, we have discussed the more recent reports that provide evidence for the presence of these species in reperfused ischemic tissue. In addition, we have attempted to introduce the reader to the relatively new concept of "site-specific" formation of radicals and how the use of "push-pull" techniques, such as chelation by high-affinity chelators or displacement by non-redox-active metals such as zinc, may decrease postischemic reperfusion injury. Finally, we have identified a class of compounds that affect the oxidation state of redox-active metals, and have demonstrated how these compounds may also represent a new therapeutic modality. In conclusion, both academic and nonacademic surgeons should have profited from reading this article. For the academic surgeon, who may do research, several new cytoprotectants requiring further study in both in vitro and in vivo models have been identified. For the nonacademic surgeon in clinical practice the realization that there are several promising areas of research that may yield new therapies to mitigate postischemic reperfusion injury should have been gained.
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Based on the inhibition of nitrite formation by generating superoxide from xanthine/xanthine oxidase (X/XO) reaction system, metallothionein (MT) and other sulfhydryl containing amino acids have been selected to test their abilities to scavenge superoxide radicals. Different concentrations of metallothionein and other sulfhydryl containing molecules e.g. cysteine, N-acetyl-cysteine and glutathione, were used to assess superoxide scavenging properties. Metallothionein scavenges superoxide radical in a dose-dependent manner with increasing concentrations as evidenced by the inhibition of nitrite formation. Similar abilities to scavenge superoxide radicals were shown by cysteine, N-acetyl-cysteine. Glutathione also scavenges superoxide radical in a dose-dependent manner. In vitro experiments demonstrated that metallothionein is superior in scavenging superoxide radicals compared to other sulfhydryl molecules such as cysteine, N-acetyl-cysteine and even glutathione. The data, further, suggest that metallothionein-II has a 6-fold higher capacity to scavenge superoxide radical than metallothionein-I. In addition, metallothionein-like protein was isolated from different regions of mouse brain treated with zinc. Brain metallothionein-like protein inhibits nitrite formation as demonstrated by other scavengers; however, the extent of inhibition is different by this protein isolated from different brain regions. The present study suggests that metallothioneins and metallothionein-like proteins isolated from mouse brain act as neuroprotective agents by scavenging superoxide radicals.
Recurrent aphthous stomatitis (RAS) or canker sores occur in 20-60% of all persons. The lesion occurs because of increased viscosity of oral submucosal extracellular matrix (ECM). The lesions begin in the second decade and peak in the third decade. Sex hormones are an important influence on fibroblasts, especially in the early phase of exposure. Sex hormones are known to concentrate, to a degree, in the bucal mucosa in animals. Lesions of RAS localize clinically and experimentally at sites of trauma. In the skin, edema is known to trigger early cellular inflammation. Increased viscosity of ECM heightens the response. The histopathology of the ulcerated lesions is similar to that which occurs under sites of acute inflammation in the skin. Systemic corticosteroids completely supress the lesions. Caustics, such as silver nitrate and phenol, stop the growth and pain of lesions. Irritants are known to break ECM viscosity. The oral mucosa exerts some control on underlying ECM. Substances such as lectins influencing the mucosa could influence ECM. Soluble substances in food or organisms could also penetrate to influence ECM. A number of different foods have been incriminated as trigger agents in individual cases. This includes gluten in patients with gluten sensitive enteropathy. Gluten is known to alter the mucosa of the small intestine in persons with celiac disease.
In relating measures of therapeutic commitment (TC) in a sample of Australian rural town generalist health and welfare workers to their urban counterparts (modelled on Cartwright's study) it was confirmed that the former lacked the knowledge, training and support required to function as effective interventionists in alcohol related problems. Rural generalists were worse off than urban generalists when it came to gaining greater access to the variables that predict a positive TC.
Drugs of abuse share with conventional reinforcers the activation of specific neural pathways in the CNS that are the substrate of their motivational properties. Dopamine is recognized as the transmitter of one such neural pathway, being involved in at least three major aspects of motivation: modulation of motivational state, acquisition (incentive learning) and expression of incentive properties by motivational stimuli. Drugs of abuse of different pharmacological classes stimulate in the low dose range dopamine transmission particularly in the ventral striatum. Apart from psychostimulants, the evidence that stimulation of dopamine transmission by drugs of abuse provides the primary motivational stimulus for drug self-administration is either unconvincing or negative. However, stimulation of dopamine transmission is essential for the activational properties of drugs of abuse and might be instrumental for the acquisition of responding to drug-related incentive stimuli (incentive learning). Dopamine is involved in the induction and in the expression of behavioural sensitization by repeated exposure to various drugs of abuse. Sensitization to the dopamine-stimulant properties of specific drug classes leading to facilitation of incentive learning of drug-related stimuli might account for the strong control over behaviour exerted by these stimuli in the addiction state. Withdrawal from drugs of abuse results in a reduction in basal dopamine transmission in vivo and in reduced responding for conventional reinforcers. Although these changes are likely to be the expression of a state of dependence of the dopamine system their contribution to the motivational state of drug addiction is unclear.
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Feline defensive rage is a form of aggression occurring in nature in response to a threatening condition and is elicited under laboratory conditions by electrical stimulation of the medial hypothalamus or midbrain periaqueductal gray (PAG). Since it has recently been shown that cytokines can modulate neurotransmitter release, the present study was designed to determine the effects of administration of interleukin 2 (IL-2) into the PAG upon defensive rage elicited from the medial hypothalamus. Microinjections of relatively low doses of IL-2 into the dorsal PAG significantly facilitated defensive rage behavior elicited from the medial hypothalamus. The specificity of this phenomenon was supported by the following findings: (1) IL-2 induced effects were dose- and time-dependent, (2) the facilitative effects of IL-2 could be completely blocked by pre-treatment of the injection site with either anti-IL-2 or anti-IL-2 receptor antibody and (3) IL-2 administration into the PAG showed no effect upon another form of aggression, namely predatory attack, elicited from the lateral hypothalamus. The findings further demonstrated that the effects of IL-2 were mediated by an NK(1) receptor mechanism since pre-treatment of the PAG with an NK(1) receptor antagonist completely blocked the facilitating effects of IL-2. Immunocytochemical observations supported these findings by demonstrating an extensive pattern of labeling of IL-2Ralpha in the dorsal PAG. The present study thus demonstrates that IL-2 in the dorsal PAG potentiates defensive rage behavior and is mediated through an NK(1) receptor mechanism.
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Eighty-three subjects were asked to solve a series of 15 mathematical problems after having been randomly assigned to an easy (5 problems) or to a difficult (9 problems) performance challenge. In addition to this, in order to create a sense of threat, subjects were told that a loud noise would be contingent upon failing to attain the performance challenge. Goal self-efficacy was computed from calculating the difference between self-efficacy level and the performance challenge. Intrinsic incentive value was derived from a six-item scale measuring the intensity of negative affects expected by the subject to be contingent upon a hypothetical failure to attain the goal. Systolic and diastolic blood pressure, and heart rate were collected during both the task performance and a prior rest phase. Anxiety-state was measured during the task performance as well. Statistical analyses revealed that interaction of goal self-efficacy and intrinsic incentive value partially predicted systolic blood pressure and heart rate reactivity. A main effect of self-efficacy was found on diastolic blood pressure. Overall, data best fitted to non-linear, quadratic functions in which either very low or very high self-efficacy, jointly with high incentive value, led to an enhanced cardiovascular reactivity. These findings are partially consistent with those previously obtained, and point to a complex model in which self-efficacy exerts specific effects on each cardiovascular parameter, usually in a non-monotonical way. Again, incentive value appeared as a moderator, but anxiety-state did not appear as a mediator of the relationship between goal self-efficacy and cardiovascular reactivity.
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The effects of phosphate and acylphosphonate phosphate transporter inhibitors were investigated on inositol 1,4,5-trisphosphate (InsP3)-induced Ca2+ release from cerebellar microsomes. Although neither changing the phosphate concentration nor adding phosphate transporter inhibitors affected the percentage (extent) of InsP3-induced Ca2+ release, they did, however, affect the transient kinetics of this process. InsP3-induced Ca2+ release is biphasic in nature, arising from two populations of InsP3-sensitive Ca2+ stores which either release Ca2+ in a fast or slow fashion. Altering phosphate concentration or adding phosphate transporter inhibitors appeared to affect only the fast phase component. We therefore suggest that these observations could be explained by the possibility that phosphate transporters only reside in the fast releasing InsP3-sensitive Ca2+ stores.