Immunomodulatory Activity of A Novel Nucleoside, 7-thia-8-oxoguanosine: I. Activation of Natural Killer Cells in Mice

We reported recently that a novel immunomodulator, 7-thia-8-oxoguanosine (7T80G)² inhibited formation of pulmonary melanoma metastases (1), prevented against viral infection in mice (2) and potentiated the efficacy of a weakly immunogenic leukemia vaccine (3). Since certain tumor metastases and virus infected cells are targets to natural killer cells (NK cells), we now investigated whether 7T80G is capable of activating NK cells in mice using NK cell sensitive YAC-1 and B16 and NK cell insensitive P815 targets. CBA/CaJ spleen cells incubated in vitro with 7T80G at concentrations ranging from 0.005 to 0.5 mM responded with increased NK cell activity (32-62 %) compared to controls (4-8%) to YAC-1 targets. Similar levels of augmentation in NK cell activity were observed when 40-168 mg/kg of 7T80G was administered in vivo. In addition to the spleen, 7T80G activated NK cells in the bone marrow (BM), the lungs, the liver, and in peritoneal exudate cells (PE). Although 7T80G elicited activation of NK cells was observed as early as three hours after treatment, the maximal activity was observed after 24 h in the spleen; 12 h in the BM; 48 h in the lungs, and 72 h in PE. Administration of the drug by s.c, i.v., and i.p. routes all induced activition of NK cells in spleen, BM and PE. 7T80G was found to activate NK cells in seven inbred and an outbred mouse strain, suggesting that the induced cytotoxicity against allogeneic and syngeneic tumor cells is not strain specific as well as independent of MHC restriction. C3H/He, CBA/CaJ and BDF/1 displayed higher levels of increased NK cell activity, whereas AKR mice were low responders. Low concentrations of IL-2 (0.25-5 U/ml) that induce little or no NK cell activity, when used in combination with 7T80G, elicited significant enhancement of NK cell cytotoxicity. In contrast, IFN and 7T80G showed no such synergism.     

Enhanced myocardial necrosis induced in rats by the combined administration of hydralazine and prenalterol

The cardiotoxic effects of hydralazine and prenalterol, given alone and in combination, were assessed in rats and rabbits. Acute myocardial necrosis was induced by a single administration of each drug alone in rats. However, the incidence and severity of lesions were markedly enhanced when both drugs were given in combination. Rats that received the same treatment for 10 consecutive days showed minimal or no acute necrosis, demonstrating the development of a resistance to further cardiotoxic effects of the drugs. Rabbits showed only minimal lesions when either drug was used alone and no enhancement of lesions when they were given in combination. From these data, it is concluded that the possibility of a cardiotoxic interaction exists when these drugs are used in combination and that the heavy rat (500-600 g) is a more sensitive model than the rabbit for studies of this nature.     

Decline in human immunodeficiency virus seropositivity and seroconversion in US Navy enlisted personnel: 1986 to 1989. Navy HIV Working Group.

The US Navy administered 1,795,578 enzyme-linked immunosorbent assay (ELISA) tests to 848,632 active-duty Navy enlisted personnel during 1986 to 1989. This study identified 2438 human immunodeficiency virus (HIV)-seropositive active-duty enlisted Navy personnel, including 778 seroconverters. Three types of quarterly rates of HIV seropositivity and seroconversion were determined. All three rates declined. This decline could not be explained by changes in the population tested according to age, race, sex, occupation, or geographic location of home port.     

Role of nitric oxide in modulating neurotransmitter release from rat striatum

The effect of the nitric oxide synthase inhibitor N-nitro- -arginine methyl ester (L-NAME) on the basal and stimulation-evoked release of dopamine (DA) and acetylcholine (ACh) was investigated in rat striatum. The experiments were carried out in isolated superfused striatal slices, loaded with either [³H]-dopamine or [³H]-choline.We have found that L-NAME reduced the elecrical field stimulation-evoked release of DA, while its enantiomer N-nitro-D-arginine methyl ester (D-NAME) was ineffective. In the presence of the nitric oxide (NO) precursor -arginine L-NAME failed to influence DA release. Furthermore, treatment with the N-methyl- -aspartate (NMDA) receptor antagonist MK-801 completely reversed the effect of L-NAME on striatal DA release. In contrast, L-NAME had no effect on either the basal or the stimulation-evoked ACh release in any experimental conditions studied.Our data indicate that endogenously produced NO is involved in the modulation of striatal DA, but not in ACh release. Furthermore, it seems likely that the modulatory effect of NO is linked to activation of presynaptic NMDA receptors located on the striatal dopaminergic nerve terminals.     

Retarded myelination in the lumbar spinal cord of piglets born with spread-leg syndrome

Piglets born with spread-leg syndrome, a congenital weakness of the hindlimb adductors, were investigated to determine the site of lesion leading to limb impairment. Histological and immunohistochemical studies of the motor neuron unit showed no alterations but quantitative analysis revealed a reduction of axonal diameter and myelin sheath-thickness of the fibres innervating the adductors of the affected limbs. In the lumbar spinal cord a lack of myelination was observed in the tracts descending to the lower motor neurons. Recovery from the syndrome was accompanied by a catching-up of myelination with that of the controls. The spread-leg syndrome is due to a nutritional deficiency in the sow; thus it is assumed that the deficient maternal substances, mainly choline and methionine, are essential for the normal myelin production by spinal white matter oligodendrocytes of the fetus.     

The persistence of interleukin-6 is regulated by a blood buffer system derived from dendritic cells

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High sensitivity to autoxidation in neonatal calf erythrocytes: possible mechanism of accelerated cell aging

The suspension viscosity, formation of methaemoglobin and production of malondialdehyde (MDA) associated with the non-enzymatic oxidation of polyunsaturated fatty acids during auto-oxidation conditions in vitro have been compared in erythrocytes from young calves (2, 4 and 6 weeks of age) and mature cattle. The autoxidation conditions were designed to simulate the oxidative stress to which neonatal erythrocytes are exposed in vivo. Characterisation of lipid peroxidation was also undertaken by a combination of lipid fluorescent measurements and quantification of the superoxide dismutase (SOD) activities of the erythrocytes. The results demonstrated that high SOD activities in the erythrocytes of the neonatal calf was insufficient to afford protection against the increased autoxidation of haemoglobin and subsequent accumulation of lipid peroxidation products. High levels of methaemoglobin formation and lipid peroxidation were able to provide an explanation for an observed reduction in rheological adaptability (increased suspension viscosity) and an accelerated aging of the neonatal cells under in vivo conditions.     

The use and image of mature adults in health care advertising (1954-1989)

Health care professionals who treat older (over 65) patients are influenced by the journals they read. Advertising directed at health care professionals during the period 1954 to 1989 was subjected to a content analysis. Advertising in health care journals was expected to reflect the demographic changes in American society with increasing numbers of older models and to present positive images of older people. Contrary to content analyses of magazine cartoons (Smith 1979) and general readership magazines (Bramlett-Solomon and Wilson 1989; Gantz, Gartenberg, and Rainbow 1980; Ursic, Ursic, and Ursic 1986), this study did find a significant use of older people in health care advertising and positive role portrayal.     

Detection of dopaminergic supersensitivity induced by neuroleptic drugs in mice

We investigated the sensitivity of dopaminergic receptors in mice fed neuroleptic drugs. Groups of mice were fed daily doses of approximately 10% of the LD50 of haloperidol, clozapine, chlorpromazine, trifluoperazine, or thioridazine for 2, 4, or 8 weeks. Four days after withdrawal of the neuroleptics, thozalinone, a dopaminergic stimulant, was given ip at 50 mg/kg to elicit gnawing behavior. Increased gnawing behavior was seen in mice after 4 weeks of administration of haloperidol (80%), chlorpromazine (80%), trifluoperazine (100%), and thioridazine (100%) compared with control values (50%). The gnawing behavior in mice treated with clozapine was the same as that for control mice. Levels of gnawing behavior after 2 or 8 weeks of administration of the same drugs were lower than those reported above. Alcohol increased the thozalinone-elicited gnawing behavior 2 weeks after dosing with haloperidol and trifluoperazine. After 4 and 8 weeks of administration of the drugs, the locomotor activity of mice was increased from 29-113% (4 weeks) to 37-110% (8 weeks) compared with controls. The study of neuroleptic drug-induced dopaminergic supersensitivity may serve as a method for detection of tardive dyskinesia-inducing effects.