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Biomedical subjects

J M Weiss

Publications and source records attributed to J M Weiss.

At least 91 records · Page 5Linked to original sources
PubMed1994

Widespread activation and consequences of interleukin-1 in the brain.

The results described herein indicate that elevation of IL-1 in rat brain, either by infusion of IL-1 into the brain or by stimulation of release of endogenous IL-1 in the brain by LPS, rapidly suppresses a variety of immune responses measured in peripheral lymphocytes. This effect can be blocked by infusion of alpha-MSH into brain, an attribute that was used to indicate that the effects of LPS infusion occurred by stimulation of endogenous IL-1 and not some other influence of LPS. That suppression of cellular immune responses indeed describes the consequences of elevating IL-1 in brain was shown by determining the time course of effects and thereby demonstrating that rebound enhancement of cellular immune responses did not occur after either IL-1 or LPS. Studies that examined the mechanisms by which brain IL-1 affects immune responses indicated that IL-1 influences peripheral lymphocytes by stimulation of CRF in the central nervous system and that CRF in turn causes suppression of cellular immune responses through activation of both the pituitary-adrenal axis and the autonomic nervous system. These findings have also been observed in another laboratory. Moreover, Brown et al. have shown that IL-1 in brain suppresses macrophage function in addition to the suppression of lymphocyte functions described herein. The physiologic significance of IL-1 actions in the brain on immune responses remains to be determined, but the demonstration that this cytokine influences immune processes by acting in brain opens for study another means by which brain and immune system interact.

Animals↗
PubMed1994

An animal model for measuring behavioral responses to anxiogenic and anxiolytic manipulations.

A method for measuring behavioral responses of rats to both anxiolytic and anxiogenic manipulations, the open field drink test (OFDT), is described. This method utilizes the concept that in the open field, appetitive behavior is reduced because of the ambient level of fear experienced in such an environment. For the OFDT, rats were given restricted access to water for 1 h per day for 3 days, and then their behavior was assessed in an open field that contained a water spout at its center. Use of the open field permitted a number of measures to be taken; of these, "time spent drinking" was most sensitive in detecting differences. Three experiments showed that the OFDT: a) permitted dissociation between behavioral responses to an anxiolytic (diazepam) and an anxiogenic (FG7142) drug, b) detected a dose-response relationship for an anxiolytic drug (diazepam), and c) detected behavioral responses to environmental manipulations designed to increase fear (presence of an olfactory cue from rats that had received foot shock). Advantages of this test over previously described methods are outlined, and several guidelines are provided to aid investigators in using this behavioral test.

Animals↗
PubMed1994

Induction of interleukin-1 in various brain regions after peripheral and central injections of lipopolysaccharide.

The presence of bioactive interleukin-1 (IL-1) in various brain regions (cerebellum, cortex, brainstem, diencephalon or hippocampus) after either intraperitoneal (i.p.) or intraventricular (i.c.v.) injection of lipopolysaccharide (LPS) was studied in the rat. To detect IL-1, extracellular fluid and cell lysate were fractionated by gel exclusion chromatography and fractions tested for thymocyte stimulation; presence of IL-1 was confirmed by blockade of stimulation by addition to the assay of a monoclonal antibody (mAb) to IL-1 receptor. When LPS was infused i.c.v., IL-1 was detected in the brainstem and diencephalon 2 h after injection, and in all the brain regions except cerebellum 6 h after injection; IL-1 was not detected in the plasma of these animals. When LPS was injected i.p., IL-1 was detected in the plasma but not in the brain 2 h after the injection, and in all brain regions but not in the plasma 6 h after the injection. In all of these cases, IL-1 was found in extracellular fluid; in some cases (cortex, cerebellum) cell lysate of the region did not produce detectable bioactivity, thereby indicating that IL-1 in these brain regions is processed to active peptide during release, as has been reported in the periphery. In those cases where bioactivity was detected in cell lysate (brainstem, diencephalon), bioactivity was not blocked by IL-1 receptor mAb, indicating presence of a non-IL-1 stimulating factor. These results further support the idea that IL-1 is secreted by cells in the brain, and indicate that it is found in the extracellular fluid of many brain regions following an appropriate stimulus in the periphery as well as in the brain.

Animals↗
PubMed1994

Depression and anxiety: role of the locus coeruleus and corticotropin-releasing factor.

Based on studies of depression and anxiety using animal (rat) models, it is suggested that, contrary to a widely accepted theory, increased activity of locus coeruleus (LC) neurons does not appear to potentiate anxiety; instead, the influence of LC activity may be opposite to this. First, studies are described that indicate that behavioral changes resembling what is seen in human clinical depression occur in rats exposed to highly stressful conditions, and the research is then traced, which links this stress-induced depression to disturbance of normal noradrenergic regulation of LC activity. Second, the potential role of corticotrophin releasing factor (CRF) in stress-induced behavioral depression is explored. CRF infused into the LC did not produce behavioral depression in the swim test but did increase anxiety; by comparison, CRF infused into the parabrachial nucleus lateral to LC increased both depression and anxiety. Finally, to further explore the relationship between LC activity and anxiety, drugs were infused into LC region to attempt to specifically activate or depress firing of LC neurons. In contrast to expectations, infusion to decrease firing of LC cells increased anxious behavior, while infusion to increase firing decreased anxious behavior. Several other studies are discussed that point to a similar conclusion. It is suggested that, at least in rats, the capacity of stress-inducing or aversive stimuli to activate LC neurons does not potentiate anxiety under environmental conditions that elicit this response, but, rather, the increased activity of the LC/dorsal noradrenergic system under such conditions may exert a counterbalancing, antianxiety influence.

Animals↗
PubMed1991

Human immunodeficiency virus glycoprotein (gp120) infused into rat brain induces interleukin 1 to elevate pituitary-adrenal activity and decrease peripheral cellular immune responses.

Intracerebroventricular (i.c.v.) infusion of glycosylated recombinant gp120, the envelope protein of human immunodeficiency virus, in various doses (100 ng to 4 micrograms) resulted in detection of interleukin 1 (IL-1) activity in a high percentage (61%; 33 of 54) of rat brains, whereas IL-1 was very rarely detected in brains of animals infused with several control substances (4%; 1 of 28). To detect IL-1, clarified glial lysate of diencephalon plus brainstem was subjected to gel exclusion chromatography and fractions were assessed for thymocyte stimulation. IL-1 was seen 2, 6, and 24 hr postinfusion. i.c.v. gp120 also produced known effects of IL-1 in brain, elevating steroid concentration in plasma and decreasing cellular immune responses [natural killer (NK) cell activity and mitogenic response to Con A] of blood and splenic lymphocytes. When gp120 was infused together with alpha-melanocyte-stimulating hormone (20 ng), which blocks many biological actions of IL-1, gp120 no longer elevated steroids or decreased NK cell activity. After intravenous gp120, IL-1 was not found in brain or plasma, indicating that stimulation of IL-1 in brain by i.c.v. gp120 was not due to gp120 affecting infiltrating cells from blood or to elevated circulating IL-1. That induction of IL-1 in brain might have resulted from lipopolysaccharide (LPS) in the gp120 solution was ruled out by studies showing that (i) heating of the infusion solution, which does not affect the capacity of LPS to induce IL-1, eliminated the ability of gp120 infusion to induce brain IL-1, and (ii) gp120 induced IL-1 in brains of LPS-resistant C3H/HeJ mice. Injection of gp120 directly into the hippocampus stimulated IL-1 more readily than i.c.v. infusion. Thymocyte stimulation produced by active fractions of gp120-infused brains was blocked by monoclonal antibody to IL-1 receptors. These findings indicate that elevation of IL-1 in brain can result from infection with human immunodeficiency virus and may be responsible for certain abnormalities (e.g., elevated activity of pituitary-adrenal axis) seen in AIDS patients.

Animals↗
PubMed1991

Effects of interleukin-1 infused into brain are antagonized by alpha-MSH in a dose-dependent manner.

Interleukin-1 (IL-1) in the brain stimulates the pituitary-adrenal axis and markedly suppresses cellular immune responses. alpha-Melanocyte-stimulating hormone (alpha-MSH) introduced into the ventricular system simultaneously with IL-1 blocked these effects of IL-1 in a dose-dependent manner, with 10 ng of alpha-MSH totally blocking the elevation of plasma ACTH and corticosterone and suppression of Natural Killer (NK) cell activity produced by a dose of IL-1 (100 pg) that otherwise causes maximal effects. In that IL-1 has been shown to promote production of alpha-MSH, these results suggest that actions of IL-1 in brain are under negative feedback control and, consequently, that the effects of this cytokine in brain are of biological significance.

Adrenocorticotropic Hormone↗
PubMed1991

Immunohistochemical investigation of dermal capillaries in chronic venous insufficiency.

Skin biopsies from the area of the medial malleolus of 24 patients with chronic venous insufficiency, of 5 patients without signs or history of chronic venous insufficiency and of seven corpses without manifestation of chronic venous insufficiency, were sectioned and stained with hematoxylin and eosin and with Ki-67, a monoclonal antibody expressed in the nuclei of proliferating cells. Hematoxylin- and eosin-stained sections of all specimens were assessed blindly to determine the state of capillary increase in stasis dermatosis. Twenty-four patients were found to have different stages of stasis dermatosis. During the examination of the Ki-67 frozen sections, close attention was paid to the capillary bed of all sections for any Ki-67-positive nuclei in capillary cells. None of the three groups showed positive staining of nuclei in capillary cells. This finding proves that there is no capillary proliferation, but an elongation and distension of the capillaries.

Adult↗
PubMed1991

Immunohistochemical investigation of pericytes in chronic venous insufficiency.

Patients with chronic venous insufficiency show typical glomerulum like alterations of cutaneous capillaries. Objective of this study was to determine any changes of the alignment of pericytes around cutaneous capillaries in CVI patients. Skin biopsies from the area of the medial malleolus were taken from 42 patients with CVI, 5 healthy individuals and 11 cadavers without history of CVI. Sections were stained with HHF35, anti alpha and gamma muscle actin with the avidin-biotin-peroxidase method (ABC) and anti vimentin with the alkaline phosphatase anti-alkaline phosphatase technique (APAAP). The stage of stasis dermatosis was assessed and sections were examined for pericyte changes. Among the collective of 42 patients with CVI, 31 patients showed slight or severe pericyte changes, 11 patients were without changes. None of the sections from cadavers or healthy patients showed any pericyte changes. Pericytes are among other functions possibly involved in microvasculature regulation and wound healing. Thus destruction of the pericyte envelope might lead to microcirculatory dysfunction. This could be one of the causes that lead to leg ulcers in CVI.

Actins↗
PubMed1990

Brain IL-1-induced immunosuppression occurs through activation of both pituitary-adrenal axis and sympathetic nervous system by corticotropin-releasing factor.

Intracerebroventricular infusion of femtomolar quantities of interleukin-1 (IL-1) or stimulated release of endogenous IL-1 in the brain suppresses various cellular immune responses, decreasing natural killer cell (NK) activity, response to mitogen, and interleukin-2 production of splenic and blood lymphocytes (an effect hereafter called "brain IL-1-induced immunosuppression"). The present study examines mechanisms by which IL-1 produces this effect. First, because IL-1 in the brain activates the pituitary-adrenal axis by stimulating release of corticotropin-releasing factor (CRF), the role of CRF was investigated. To block CRF, affinity-purified antibody to CRF was infused into the lateral ventricle 30 min before introduction of IL-1. When this was done, suppression of cellular immune responses that normally follow IL-1 infusion was completely prevented. Infusion with an equal quantity of non-CRF IgG prior to IL-1 was without effect. Second, the role of sympathetic nervous activity was examined. To block neural transmission at sympathetic ganglia, chlorisondamine (3.0 mg/kg) was injected intraperitoneally 60 min before IL-1 infusion. When this was done, suppression of immune responses by IL-1 was partially blocked. These results indicate that IL-1 in the brain suppresses various cellular immune responses by activating both the pituitary-adrenal axis and the sympathetic nervous system, and that these systems are both activated through the influence of IL-1 on CRF.

Animals↗
PubMed1990

Corticotropin-releasing factor produces fear-enhancing and behavioral activating effects following infusion into the locus coeruleus.

The present series of experiments tested the hypothesis that the behavioral activating and anxiogenic effects produced by intraventricular administration of corticotropin-releasing factor (CRF) may be mediated by noradrenergic neurons in the brain-stem locus coeruleus (LC). Results showed that infusion of CRF into the LC (100 ng) significantly increased nonambulatory spontaneous motor activity measured in photocell cages; ambulatory (i.e., locomotor) activity was not altered. In the modified Porsolt swim test, which examines arousal and agitation in a stressful situation, significant behavioral activation (i.e., decreased floating) was seen following infusion of CRF (10 ng) into the LC; a 500 ng dose of CRF was necessary to produce similar effects following infusion into the lateral ventricle. The results of these 2 tests suggest that the behavioral activating effects of CRF in the LC may be related to arousing or stress-related effects, rather than to increased locomotor activity per se. Anxiogenic activity was assessed in animals placed in an open field containing a small, darkened compartment. Infusion or CRF into the LC (1-100 ng) significantly increased the time spent in the compartment and decreased the amount of time spent exploring the outside of the compartment or venturing into the inner squares of the open field, all indices of anxiogenic behavior. Biochemical studies showed that bilateral infusion of CRF into the LC produced significant increases in the concentration of the norepinephrine metabolite 3,4-dihydroxyphenylglycol in such forebrain projection areas of the LC as the amygdala and posterior hypothalamus. These data, taken together, suggest that CRF produces its behavioral activating and anxiogenic effects, at least in part, by increasing the activity of LC noradrenergic neurons.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Peripheral, but not local or intracerebroventricular, administration of benzodiazepines attenuates evoked activity of locus coeruleus neurons.

To determine whether benzodiazepine receptors in the locus coeruleus (LC) regulate the firing of LC neurons, the effects of systemic, intracerebroventricular, and local administration of various benzodiazepines on LC activity were compared. Systemic administration of diazepam, chlordiazepoxide, and alprazolam in anesthetized rats markedly attenuated sensory-evoked activity of LC neurons while also suppressing, but to a lesser degree, spontaneous LC firing rates. When microinfused into the LC region, diazepam, chlordiazepoxide, and alprazolam reduced spontaneous LC firing rates to the same extent observed following systemic administration; however, unlike systemic administration, infusion of benzodiazepines into the LC failed to attenuate evoked LC activity. Similarly, intracerebroventricular administration of diazepam and chlordiazepoxide suppressed spontaneous, but not evoked, LC activity. These findings indicate that benzodiazepines suppress spontaneous LC firing by stimulating benzodiazepine receptors in the LC while attenuating evoked LC activity by stimulating benzodiazepine receptors that are neither in the LC nor accessible to benzodiazepines introduced into the ventricular system.

Action Potentials↗
PubMed1989

Blockade of alpha 2-adrenergic receptors, but not blockade of gamma-aminobutyric acidA, serotonin, or opiate receptors, augments responsiveness of locus coeruleus neurons to excitatory stimulation.

Previous studies in this laboratory indicated that alpha 2-adrenergic receptors in the locus coeruleus play a major role in regulating the responsiveness of neurons in the locus coeruleus to excitatory influences. The present study points to the possibility that alpha 2-receptors are unique among inhibitory receptors in the locus coeruleus in regulating responsiveness of these neurons independently of the spontaneous firing rate. In the first part of the study, blockade of alpha 2-receptors was shown to markedly augment responsiveness of neurons in the locus coeruleus to the excitatory stimulus of compression of the contralateral hind paw at doses of an alpha 2-blocker both above and well below those necessary to increase spontaneous activity of neurons in the locus coeruleus. In contrast, blockade of gamma-aminobutyric acid and serotonin receptors augmented spontaneous firing rates of neurons in the locus coeruleus but failed to augment responsiveness of these neurons to compression of the hindpaw. Blockade of opiate receptors failed to increase either spontaneous firing rates or the responsiveness of neurons of the locus coeruleus to paw compression; moreover, in animals given an opiate agonist over a number of days to produce tonic stimulation of opiate receptors, blockade of opiate receptors augmented spontaneous firing rates of neurons in the locus coeruleus but had no effect on responsiveness to paw compression. In that blockade of each type of inhibitory receptor tested increased the spontaneous firing rates of neurons in the locus coeruleus but only blockade of alpha 2-receptors increased the responsiveness of neurons in the locus coeruleus to stimulation, without affecting the spontaneous firing rate, alpha 2-receptors may be unique among inhibitory receptors in independently regulating the responsiveness of neurons in the locus coeruleus. One possibility discussed for why alpha 2-receptors regulate the responsiveness, independently of the spontaneous firing rate, is that there are two types of alpha 2-receptors in the locus coeruleus, one of which regulates responsiveness and another which regulates the spontaneous firing rate.

Adrenergic alpha-Antagonists↗
PubMed1989

Intracerebroventricular infusion of interleukin 1 rapidly decreases peripheral cellular immune responses.

Low doses (50-200 pg or 3.1-12.4 fmol) of interleukin 1 (IL-1) infused into the brain of rats produced rapid suppression of various cellular immune responses in peripheral lymphocytes of rats. Fifteen minutes after infusion of purified IL-1 beta into the lateral ventricle, natural killer cell activity, response to phytohemagglutinin stimulation, and interleukin 2 production were markedly suppressed in lymphocytes isolated from blood and spleen. These effects were due to infusion of IL-1 into brain since they did not occur when IL-1 was infused into the cisterna magna (essentially posterior to brain) or was injected intraperitoneally. Effects of IL-1 in brain could be blocked by simultaneous infusion of alpha-melanocyte-stimulating hormone, which is known to block the biological actions of IL-1. To stimulate release of endogenous IL-1 in brain, lipopolysaccharide was infused; this produced similar effects as IL-1, and these effects also were blocked by alpha-melanocyte-stimulating hormone. At longer intervals after infusion of IL-1 and lipopolysaccharide (3, 6, and 24 hr), immune responses returned to baseline or remained suppressed; i.e., "rebound" immunopotentiation did not occur. Finally, IL-1 infusion suppressed cellular immune responses in adrenalectomized animals, thereby showing that the effects of central IL-1 on peripheral cellular immune responses were, at least in part, independent of the stimulatory effect of IL-1 on secretion of adrenal hormones. These results indicate a link from brain to peripheral immune responses by means of action of a cytokine acting in the brain.

Animals↗
PubMed1989

Behavioral and neural influences on cellular immune responses: effects of stress and interleukin-1.

A series of experiments examined effects of stressful conditions on several cellular immune responses and attempted to elucidate the physiological mechanisms underlying these effects. Initial studies showed that stressful conditions can profoundly suppress immune responses of blood and splenic lymphocytes, including T-cell mitogenesis, natural killer cell activity, production of interleukin-2 (IL-2) and interferon and IL-2 receptor expression. Subsequent studies found that (1) multiple physiological pathways mediate stress-induced suppression of these responses; (2) stress-induced suppression of these responses is produced, at least in part, by a peptide with molecular weight greater than 10 kilodaltons, which stressed animals release into circulation; (3) whereas most stressful conditions suppress immune responses, stressful conditions of moderate intensity can enhance cellular immune responses; and (4) extremely small quantities of interleukin-1 (IL-1) acting in the brain (e.g., 3.1-12.4 X 10(-15) moles) bring about suppression of cellular immune responses very rapidly and for a prolonged period of time. The relationship between the newly-discovered immunosuppressive influence of IL-1 in the brain and immunosuppression produced by stressful conditions remains to be determined.

Animals↗
PubMed1988

Pertussis toxin blocks the effects of alpha 2-agonists and antagonists on locus coeruleus activity in vivo.

This study assessed the effects of pertussis toxin, which is known to inactivate G proteins and therefore to block receptors linked to G proteins, on electrophysiological activity of the locus coeruleus in vivo. Pertussis toxin was injected into the lateral cerebral ventricle of rats, and locus coeruleus activity was then recorded. Compared to vehicle-injected control animals, pretreatment with pertussis toxin markedly increased the spontaneous firing rate of locus coeruleus neurons. In addition, the alpha 2-antagonist idazoxan was no longer able to augment either spontaneous or evoked locus coeruleus activity after pretreatment with pertussis toxin. Finally, pretreatment with pertussis toxin made locus coeruleus neurons resistant to inhibition by the alpha 2-agonist clonidine. These results are consistent with the view that pertussis toxin blocks alpha 2-receptors, receptors linked to G proteins, in vivo.

Adrenergic alpha-Agonists↗
PubMed1988

Neurochemical and electrophysiological events underlying stress-induced depression in an animal model.

This paper has described an animal (rodent) model of depression in which depression-like characteristics are produced by exposure of animals to stressful events that they cannot control. This model, called "stress-induced depression," appears to be mediated by stress-induced changes in brain norepinephrine (NE), and evidence now indicates that a large depletion of NE in the Locus Coeruleus region of the brain stem (LC) is critical for producing the behavioral disturbance seen in this model. To explain the functional significance of NE depletion in the LC, it has been suggested that this change results in decreased stimulation, (i.e., functional blockade) of alpha-2 receptors that normally inhibit firing of LC neurons. Consequently, LC neurons should be disinhibited in stress-induced depression. The final part of this paper describes findings from electrophysiological measurement of LC activity. Prior to measuring changes occurring in stress-induced depression, studies examined the basic role played by alpha-2 receptors in LC activity. These receptors were found to regulate the responsivity of LC neurons to excitatory stimuli, so that pharmacological blockade of these receptors increased the firing of LC neurons to excitatory input. When LC activity was then measured in stressed animals showing behavioral depression, responsivity of LC neurons to excitatory input was elevated in comparison to animals not exposed to stress. Also, administration of an alpha-2 blocking drug could not increase responsivity of LC neurons in stressed animals, which further indicated that alpha-2 receptors in the LC region were functionally blocked in these animals. Finally, the amount that LC neurons increased their firing to an excitatory stimulus (i.e., an index of alpha-2 receptor blockade) was highly correlated with the amount of behavioral depression seen in an activity test conducted just prior to electrophysiological measurement. These electrophysiological findings indicate that LC neurons are disinhibited in stress-induced depression, and that this disinhibition is particularly characterized by increased responsivity of LC neurons to excitatory input, which is indicative of alpha-2 receptor blockade. These findings further support the view that the LC is involved in stress-induced depression, and are consistent with a proposed mechanism that attributes behavioral disturbance in the model to disinhibition of LC neurons arising from subnormal activation of inhibitory alpha-2 receptors.

Animals↗
PubMed1988

Transthoracic needle aspiration biopsy following negative fiberoptic bronchoscopy in solitary pulmonary nodules.

To evaluate the utility of transthoracic needle aspiration biopsy (TTNAB) following negative fiberoptic bronchoscopy (FOB) in a patient with a solitary pulmonary nodule (SPN), we reviewed the records from 262 patients who had undergone TTNAB over an eight-year period. Fifty-eight patients had a SPN and met the criteria for inclusion in this series. Twenty-five of these (43 percent) were diagnosed by TTNAB; 24 had malignant lesions; one had M tuberculosis. Of the remaining 33 patients, 18 went on to definitive diagnostic procedures (surgery, repeat FOB or TTNAB). Nine of these patients had a malignancy. Fifteen patients were followed long-term; one was diagnosed with carcinoma two years after the initial work-up. Carcinoma was not found in any patient under 40 years of age. A benign lesion was diagnosed by TTNAB in only two patients. We conclude that TTNAB is a valuable procedure in the evaluation of patients with a SPN and negative FOB. While a negative FOB and TTNAB do not assure that the lesion is benign, a complex of variables influences the decision regarding thoracotomy vs careful follow-up.

Adult↗