Interleukin-2 and the regulation of activated macrophage cytotoxic activities.
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Biomedical subjects
Publications and source records attributed to B J Nelson.
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Twenty-two family practice dentists, in a large metropolitan area, were recruited to act as independent examiners in a study to evaluate the compliance of their patients to accept a good oral hygiene regimen with the use of a fluoride dentifrice, containing hydrogen peroxide and baking soda, dispensed from a dual dispensing package. To evaluate compliance, the dentists attended an orientation seminar and were trained to assess gingival health using the CPITN periodontal probe. Each dentist evaluated the gingival health status of five to seven of his own patients, initially and after one and three months of product use following hygiene instruction and product assignment. One-hundred and thirty-one patients successfully completed the study. After one month of using the hydrogen peroxide/baking soda toothpaste, the mean reduction in bleeding sites was 53%; at three months the reduction was 62%. The hydrogen peroxide/baking soda dentifrice was well accepted by dentist and patient, and a discernible improvement in oral health of the patients was achieved when the product was used in a conscientious oral hygiene program.
We examined the effects of TGF-beta 1 on induction of several activated macrophage antimicrobial activities against the protozoan parasite Leishmania, and on induction of tumoricidal activity against the fibrosarcoma tumor target 1023. TGF-beta by itself did not affect the viability of either the intracellular or extracellular target in concentrations up to 200 ng/ml. As little as 1 ng/ml TGF-beta, however, suppressed more than 70% of the intracellular killing activity of macrophages treated with lymphokines. In contrast, more than 100 ng/ml TGF-beta was required to suppress intracellular killing by cells activated with an equivalent amount of recombinant IFN-gamma. Addition of TGF-beta for up to 30 min after exposure to activation factors significantly reduced macrophage killing of intracellular parasites. Pretreatment of macrophages with TGF-beta was even more effective: treatment of cells with TGF-beta for 4 h before addition of activation factors abolished all macrophage intracellular killing activity. Regardless of treatment sequence, however, TGF-beta had absolutely no effect, at any concentration tested, on activated macrophage resistance to infection induced by lymphokines or by the cooperative interaction of IFN-gamma and IL-4. Effects of TGF-beta on tumoricidal activity of activated macrophages was intermediate to that of its effects on intracellular killing or resistance to infection. Lymphokine-induced tumor cytotoxicity was marginally (25%) affected by TGF-beta; 200 ng/ml was able to suppress IFN-gamma-induced tumoricidal activity by 40%. Thus, TGF-beta dramatically suppressed certain activated macrophage cytotoxic effector reactions, but was only partially or not at all effective against others, even when the same activation agent (IFN-gamma) was used. The biochemical target for TGF-beta suppressive activity in these reactions may be the pathway for nitric oxide production from L-arginine, because TGF-beta also inhibited the generation of nitric oxide by cytokine-activated macrophages.
Although mean mitogen-induced lymphoproliferation decreases with increased age, the response of individual subjects demonstrates great heterogeneity. Results of this study clearly illustrate that individual variation is apparent not only in the level of proliferation, but also in the amount of interleukin-2 (IL-2) detectable after mitogen stimulation. Further, addition of exogenous IL-2 significantly increases proliferation in only about one third of elderly subjects. Data from inbred strains of rats housed under identical environmental conditions indicate that although genetic factors greatly influence both the level of proliferation and the rate of decline with age, variation occurs even within one inbred strain of rat.
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An antiserum raised against rat glutamate decarboxylase was used to map GABAergic boutons in the inferior olive of rabbit, cat, rhesus monkey, and human. A description of the human periolivary region is also included. The inferior olive of each species contained a dense GABAergic innervation, but immunostaining intensities varied among regions. These intensities were evaluated visually and photometrically, and the sizes and frequencies of occurrence of boutons in various olivary subnuclei were measured. The beta nucleus in all species was intensely immunostained and contained the largest boutons. The caudal subdivision of the dorsal accessory olive stained with a lower intensity than the beta nucleus, but contained similarly large GABAergic boutons. By visual analysis, the rostral subdivision and the subnucleus a of the medial accessory olive and the principal olive were stained with an intermediate intensity, and these regions contained small GABAergic boutons. Photometric analysis of focal regions of the neuropil, however, revealed species differences in teh staining intensity of the principal olive, which was lowest in rabbits and highest in primates. In all species, the lowest immunostaining intensity was observed in the subnucleus b of the medial accessory olive. Species variations in bouton sizes and regional staining intensities were observed in the dorsal cap and the dorsomedial cell column. The heterogeneous staining pattern and regional variation of bouton size argue for the existence of separate GABAergic projections to discrete regions of the inferior olive. Since glutamate decarboxylase immunostaining patterns in the olive are largely similar across species, the afferent projections producing these patterns may also be similar.
Boutons presumed to use gamma-aminobutyric acid as neurotransmitter (GABAergic boutons) were detected by glutamate decarboxylase (GAD) immunocytochemistry in all regions of the rat inferior olive. The remarkably high concentration of these boutons allowed a clear visualization of olivary subnuclei boundaries. Regional variations in GAD immunostaining intensity were observed within the nuclear complex and were graded both visually and photometrically. The regional staining variations, for the most part, followed subnuclei boundaries and olivary zonal compartments that have been delineated by the topography of climbing fibre projections. Some subnuclei were grouped by similar staining intensities. The beta nucleus and a medial region in the ventral fold of the dorsal accessory olive were most intensely immunostained, followed by the subnucleus c of the medial accessory olive. Lower staining intensities were observed in the dorsomedial cell column, the dorsal fold of the dorsal accessory olive and the dorsal cap. The lowest intensities were observed in the subnuclei a and b of the medial accessory olive, the ventrolateral outgrowth, the rostral lamella of the medial accessory olive, the principal olive, and the lateral part of the ventral fold of the dorsal accessory olive. The factors contributing to the variations in immunostaining intensity (bouton size and frequency of occurrence) were investigated. The largest boutons were observed in the beta nucleus. Intermediate sized boutons were observed in the dorsomedial cell column, dorsal cap and the dorsal fold of the dorsal accessory olive. The smallest boutons were present in the remaining regions of the inferior olive, including the principal olive, the rostral lamella of the medial accessory olive, and the ventral fold of the dorsal accessory olive. The medial region of the dorsal accessory olive ventral fold contained a higher density of GABAergic boutons than other regions. GABAergic bouton size and innervation density therefore largely accounted for the variations in GAD immunostaining intensity. This study provides a map of the rat inferior olive based on the distribution of GABAergic nerve terminals, and may serve as a basis for characterizing different GABAergic afferent systems in the inferior olive.
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Two kinds of optokinetic afternystagmus (OKAN) have been studied in rabbits; positive and negative OKAN. Positive OKAN is the persistence of eye movements evoked by optokinetic stimulation following the termination of the stimulus, with the slow phase of the eye movements in the same direction as the inducing stimulus. Negative OKAN is evoked by long duration optokinetic stimulation, and has a slow phase of opposite direction to the inducing stimulus. The stimulus conditions which are optimal for inducing and maintaining negative OKAN were characterized. Rabbits were placed in an optokinetic drum for periods of 12-96 h (with appropriate intervening periods for food and water). Eye movements were recorded during and after the termination of optokinetic stimulation. The optimum optokinetic stimulus velocity for the induction of negative OKAN was 5 degrees/s. The minimum duration of stimulation for the induction of negative OKAN of maximum velocity was 48 h. Once induced, the slow phase of negative OKAN attained velocities of 50-100 degrees/s. Three conditions of restraint of the rabbits were studied after negative OKAN was induced during the intervening periods when eye movements were not being recorded. These conditions were: (1) unrestrained (full freedom of movement) without visual stimulation (in a dark enclosure); (2) restrained (horizontal head and body movement prevented) without visual stimulation; and (3) restrained with visual stimulation (in the stationary optokinetic drum). Conditions 1 and 2 caused negative OKAN to dissipate within 24 h. Condition 3 caused negative OKAN to be maintained for more than 70 h. The velocity imbalance of the horizontal vestibuloocular reflex (HVOR) was measured at different times following the induction of negative OKAN. It provided a more sensitive index of the central imbalance which caused negative OKAN, than did spontaneous nystagmus. One of the consequences of optokinetic stimulation measured over a 16 h period was a decrease in the gain of the optokinetic reflex. This reduction in gain could represent a central adaptation to maintained stimulation which in the absence of continued optokinetic stimulation is expressed as a nystagmus.
Previous studies of changes in immune responses in the elderly have been limited in both number and age of elderly subjects and have produced conflicting results. Using 260 subjects, mean age 84.6, the present study conclusively demonstrates that T cell response is decreased in the elderly. Decreases in response to phytohemagglutinin and concanavalin A were demonstrated in groups aged 70 to 79, 80 to 84, and 85 to 89, although a group 90 to 106 years old showed a decreased response only to phytohemagglutinin. None of the groups had a decreased response to pokeweed mitogen. No response to all three mitogens was observed in 13 percent of the group aged 70 to 89, but in none of the group aged 90 to 106 or in the young groups. No differences in natural killer cell cytotoxicity were observed among the elderly groups. In contrast to previous studies, these results suggest that: the decreased immune response of the elderly is not directly related to age, over age 70; and there may be a selection process in which subjects who live to the age of 90 are those in whom the least decrease in immune response is demonstrated.
It is common to examine the cerebrospinal fluid in untreated or inadequately treated asymptomatic patients with a reactive serum fluorescent treponemal antibody absorption (FTA-ABS) test before initiating antibiotic therapy for syphilis. This prospective study evaluated the usefulness of such examination. Four hundred thirty-two patients over 40 years old, reporting for annual physical examination, had a serum FTA-ABS test. Thirty-seven (8.6%) patients and 2 of 4 spouses were reactive repeatedly. Of the 39 patients with reactive tests, 7 had a history of penicillin therapy for syphilis, 5 had received heavy metal therapy, and 27 had no history of syphilis. These 39 patients had a neurological examination, serum VDRL, Treponema pallidum immobilization (TPI), and repeat FTA-ABS tests by two other laboratories. The TPI test was reactive in 30 (77%). Four had nonspecific neurological signs. Routine CSF examination (cells, total protein, VDRL, glucose, IgG%) on 30 patients with a history of inadequate treatment had a low diagnostic yield. Two patients had an unexplained total protein elevation (57 and 61 mg/dl) and 1 had a mildly increased IgG% (15%). All cell counts, VDRL tests, and glucose levels were normal. Agarose electrophoresis demonstrated one or more CSF immunoglobulin bands in 10 (36%) of 28 patients, possibly representing an immunological marker of past or latent central nervous system infection.
Early, atypical, or progressive cases of multiple sclerosis (MS) may be hard to diagnose. Until recently, assays of the most common abnormalities in cerebrospinal fluid were not available in clinical diagnostic laboratories, but now they can be done with relative ease and adequate standardization. With the newer techniques the CSF is abnormal in more than 90% of clinically definite cases of MS, and determination of such changes can be a major aid in diagnosis. The most common CSF abnormalities are discussed: elevation of immunoglobulin G(IgG), expressed as percentage of total protein; elevation of the IgG/albumin index; and presence of oligoclonal IgG bands. Not only does assessment of these CSF proteins provide an improved aid to diagnosis, but their study may furnish important clues to the cause and pathogenesis of MS as well.
The gamma globulins in cerebrospinal fluid from almost all patients with multiple sclerosis migrate in agarose electrophoresis as abnormal discrete populations, so-called oligoclonal bands. Such bands have also appeared in cerebrospinal fluid from patients with other types of inflammatory pathology such as neurosyphilis, acute idiopathic polyneuropathy, and subacute sclerosing panencephalitis. The demonstration of cerebrospinal fluid oligoclonal bands may aid in the evaluation of patients with early or atypical multiple sclerosis. This report describes a simple method for demonstrating cerebrospinal fluid oligoclonal bands using readily available commercial reagents and apparatus. Oligoclonal bands were seen in cerebrospinal fluid from all patients with clinically definite multiple sclerosis, even though some had normal cerebrospinal fluid gamma globulin levels, and in most patients with presumptive multiple sclerosis or other inflammatory conditions of the nervous system. They were not seen in cerebrospinal fluid of control patients with a variety of other neurologic diseases.
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While renin is a highly specific protease, converting enzyme has at least two principal substrates, angiotensin I and bradykinin. Changes in the rate of formation of angiotensin II or degradation of bradykinin can influence the hypotensive action of angiotensin converting enzyme inhibitors. The present study was designed to determine if there were differences in the maximal blood pressure reduction in Na-deficient dogs after angiotensin converting enzyme or renin inhibitor treatment. Five conscious dogs received 0.1, 0.5, and 1.0 mg/kg of i.v. enalaprilat, a potent angiotensin converting enzyme inhibitor, which reduced blood pressure to 75 +/- 4, 71 +/- 5, and 71 +/- 5 mm Hg. Plasma immunoreactive angiotensin II levels were reduced in a dose-related fashion to 35% of control level at the highest dose. Infusion of a maximally effective dose of a statine-containing renin inhibitor (SCRIP) with the high dose of enalaprilat produced no further fall in blood pressure (68 +/- 7 mm Hg), but immunoreactive angiotensin II levels fell to essentially zero in four of five dogs. The order of drug administration was reversed in another experiment in a group of nine dogs in which SCRIP reduced plasma immunoreactive angiotensin II to 25% of control at 0.04 mg/kg/minute (n = 5), with reduction to near zero levels at higher doses. Maximal blood pressure reduction was achieved at 0.32 to 0.64 mg/kg/minute (76 +/- 4 mm Hg); 1 mg/kg of enalaprilat lowered blood pressure an additional 11 +/- 2 mm Hg (p less than 0.01) while not further decreasing immunoreactive angiotensin II levels.(ABSTRACT TRUNCATED AT 250 WORDS)