Search PubMed⌕ Search

Biomedical subjects

R Robbins

Publications and source records attributed to R Robbins.

At least 19 recordsLinked to original sources
PubMed1995

Metabolic requirements for induction of contact hypersensitivity to immunotoxic polyaromatic hydrocarbons.

Experiments were performed to define the metabolic requirements for induction of contact hypersensitivity to polyaromatic hydrocarbons (PAHs), environmental xenobiotics that are both immunotoxic and carcinogenic. Evidence that conversion of the parent compound to a reactive metabolite was necessary for the development of contact hypersensitivity included the fact 1) that contact hypersensitivity to the polyaromatic hydrocarbon dimethylbenz(a)anthracene (DMBA) only occurred in strains of mice that could metabolize the compound, 2) that among the PAHs, only those that could induce aryl hydrocarbon hydroxylase, the rate-limiting enzyme in the PAH metabolic pathway, were immunogenic, and 3) that inhibitors of PAH metabolism reduced DMBA contact hypersensitivity. Cells from the XS52 Langerhans cell-like dendritic cell line were able to metabolize the PAH benzo(a)pyrene to its diol, quinone, and phenol metabolites. GM-CSF augmented benzo(a)pyrene metabolism in XS52 cells. Finally, in vivo depletion of CD8+, but not CD4+, T cell populations inhibited contact hypersensitivity to DMBA. The implications of these experiments are that at least for some contact allergens, the metabolic status of the host is a key determinant of individual susceptibility to the development of allergic contact dermatitis, and the metabolic pathway of an individual hapten may have ramifications for the T cell subpopulation-CD4 or CD8-that is activated.

Animals↗
PubMed1994

A dramatic change in the interaction of Cu(II) with bio-peptides promoted by SDS--a model for complex formation on a membrane surface.

The extent of complex formation between Cu(II) and many biologically active oligopeptides has been shown to change significantly in the presence of SDS micelles, a recognized model for cell lipid membranes. Protonation constants of peptides can be increased by up to 2 log unit, especially when they contain hydrophobic side chains. Metal complex formation is generally less extensive and the conformations of peptides can be altered dramatically when compared to those in simple aqueous solution.

Amino Acid Sequence↗
PubMed1992

Regulation of plasminogen activators and type-1 plasminogen activator inhibitor by cyclic AMP and phorbol ester in rat astrocytes.

Two plasminogen activators (PAs): tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), as well as the type-1 plasminogen activator inhibitor (PAI-1) are synthesized and secreted by rat astrocytes. Preliminary studies suggest that PA activity plays a role in astrocyte development and differentiation. We have examined the regulation of the PA system by the cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) in purified rat astrocyte cultures. PKA activity was increased by exposing cultured astrocytes to forskolin or dibutyryl cyclic AMP, whereas PKC activity was stimulated with phorbol-12-myristate 13-acetate (PMA). Activation of both second-messenger pathways produced a time- and dose-dependent increase in the total PA activity. However, based on SDS-PAGE/zymography we found that forskolin increased t-PA activity and reduced u-PA activity, whereas PMA treatment caused a significant increase in u-PA activity without altering t-PA activity. Reverse zymography analysis revealed that astrocyte PAI-1 activity is decreased by forskolin and increased by PMA. Together, these results demonstrate that the components of the PA system in rat astrocytes are independently and reciprocally regulated by PKA and PKC. Our findings raise the possibility that the plasminogen activator system could be involved in some of the actions of growth factors and/or neuromodulators that modulate PKC or PKA in astrocytes.

Animals↗
PubMed1992

Involvement of protein kinase-C in the mitogenic effect of insulin-like growth factor-I on rat astrocytes.

Insulin-like growth factor-I (IGF-I) stimulates the proliferation of many cell types, including astrocytes. Astrocytes are a population of brain cells highly enriched in IGF-I receptors, which unlike neurons, retain the ability to proliferate in the adult brain. Although astrocyte proliferation in response to IGF-I is well documented, the intracellular mechanisms that mediate this phenomenon are poorly defined. Interestingly, activation of protein kinase-C (PKC) by IGF-I has been observed in several cell types. In this report we first characterized the mitogenic effects of IGF-I on highly purified type I rat astrocyte cultures. Next, we determined whether IGF-I activates PKC in our cultures. Finally, since astrocyte proliferation is stimulated by both IGF-I and the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA), we decided to test the possible involvement of PKC in the mitogenic activity of IGF-I on astrocytes. IGF-I stimulated the DNA synthesis rate in rat astrocytes. Analysis of the time course revealed that IGF-I (10 nM) induces maximal stimulation of [3H]thymidine incorporation (a 4-fold increase) 16-18 h after exposure. TPA also stimulated mitogenesis in our cultures. The dose-response of [3H]thymidine incorporation induced by IGF-I and TPA indicated that 10 nM was the lowest concentration producing a maximal effect for both agents. Analysis of proteins by Western blot revealed that 10 nM IGF-I translocates PKC(alpha), the predominant PKC isoform in astrocyte cultures, from the cytosol to the membrane fraction within 20 min. A similar activation of PKC was achieved with 100 nM TPA. When astrocytes were exposed to IGF-I (10 nM) and TPA (10 nM) in combination, [3H]thymidine uptake was significantly higher than the uptake induced by either IGF-I (10 nM) or TPA (10 nM) alone. However, the effect of IGF-I plus TPA was not fully additive. In a second experiment, the mitogenic effect of IGF-I was partially abolished in cells depleted of PKC by preincubation with high concentrations of TPA (300 nM). Finally, incubation of astrocytes with the PKC inhibitor H-7 at 20 microM, a concentration that completely blocked the mitogenic action of TPA, only reduced the ability of IGF-I to stimulate DNA synthesis by 50%. In summary, our results demonstrate that IGF-I can rapidly activate PKC in astrocytes, and that PKC activation is involved in the mitogenic effect of IGF-I on these cells. However, we conclude that IGF-I also stimulates astrocyte proliferation through PKC-independent pathways.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Pulmonary surveillance using bronchoscopy and bronchoalveolar lavage during high-dose antineoplastic therapy.

Pulmonary failure is a major contributor to morbidity and mortality during marrow aplasia following high-dose antineoplastic therapy. For this reason, we initiated a pulmonary surveillance program for patients undergoing high-dose chemotherapy for leukemia or bone marrow transplantation. As part of this program, bronchoscopy with BAL was performed prior to therapy and at the onset of granulocytopenia. Thirty-three of the first 57 patients managed in this program developed some evidence of pulmonary complications. Twelve patients died in aplasia; all had pulmonary failure. Forty patients had clinically significant abnormalities on the bronchoscopy before treatment including 12 of 19 patients who had normal findings on chest x-ray films, physical examination, and pulmonary function testing, and no fever. Twenty-seven patients had clinically significant abnormal bronchoscopy or BAL at the onset of granulocytopenia. Thirteen patients required additional bronchoscopy. No patient required an open lung biopsy. Pulmonary surveillance using bronchoscopy with BAL is useful in the detection of pulmonary disease prior to the initiation of and following high-dose antineoplastic therapy.

Adult↗
PubMed1991

The role of endogenous opiates in athletic amenorrhea.

We hypothesized that menstrual disturbances in female athletes arise from opioid-induced abnormalities in gonadotropin and/or prolactin (PRL) secretion. To investigate this hypothesis, we measured luteinizing hormone, follicle-stimulating hormone, and PRL levels in eumenorrheic and amenorrheic athletes during thyrotropin-releasing hormone and gonadotropin-releasing hormone tests at baseline, after naloxone infusions, after exercise to exhaustion, and after similar exercise during naloxone infusions. Contrary to our hypothesis, amenorrheic runners did not have significant alterations in basal, postexercise, or stimulated hormone levels compared with eumenorrheic runners. In addition, opioid blockade by naloxone did not enhance gonadotropin release by amenorrheic athletes.

Adult↗
PubMed1990

Functional loss of chemotactic factor inactivator in the adult respiratory distress syndrome.

The adult respiratory distress syndrome (ARDS) is often characterized by a neutrophilic alveolitis, which may be mediated in part by the neutrophil chemoattractant, C5a. Chemotactic factor inactivator (CFI) can decrease C5a-directed neutrophil chemotaxis. Thus, a loss of CFI activity in the ARDS lung could lead to an increased ability of C5a to attract neutrophils. Lung CFI levels were measured antigenically and functionally in bronchoalveolar lavage (BAL) fluid obtained from 29 patients with ARDS and in 14 normal control subjects. Antigenic levels of CFI were found to be markedly elevated in ARDS BAL fluid (1,855 +/- 437 ng/ml) compared with that in normal BAL (29 +/- 10 ng/ml, p less than 0.005), but, in contrast, CFI functional activity was markedly decreased in ARDS BAL fluid compared with that in normal BAL fluid (31 +/- 7% inhibition versus 76 +/- 5% inhibition, p less than 0.01). Furthermore, although purified CFI readily inhibited the ability of C5a to attract neutrophils (92% inhibition), this activity was decreased when BAL fluid from patients with ARDS was incubated with CFI (47 +/- 10%, p less than 0.01). These findings suggest that patients with ARDS are functionally deficient in CFI, leading to an increased ability of C5a to attract neutrophils.

Aminopeptidases↗
PubMed1986

Somatostatin receptors are biologically active before they are inserted into the plasma membrane.

We have examined the biological activity of intracellular somatostatin (SRIF) receptors in cultured rat anterior pituitary cells. We used digitonin-permeabilized cells to introduce free SRIF intracellularly and chloroquine-treated cells to promote intracellular accumulation of SRIF via a receptor-mediated pathway. At a concentration of 0.001%, digitonin (3-min incubation at 37 C) allowed [125I]SRIF to enter the cells without affecting cell viability. Autoradiography of [125I]SRIF demonstrated its association with secretion vesicles (28%), nuclei (25%), and other intracellular organelles. An acid wash technique that removes cell surface-bound ligand revealed that both digitonin-permeabilized cells and chloroquine-treated cells accumulated approximately twice as much intracellular SRIF as did control cells. The biological activities of intracellular SRIF accumulated via two different pathways, receptor mediated and through digitonin-produced pores in the plasma membrane, were different. In chloroquine-treated cells, the accumulation of intracellular SRIF did not result in its additional biological effect. SRIF inhibited GH-releasing factor-induced GH release from 578 +/- 12 to 168 +/- 9 ng/10(6) cells X 30 min, which did not differ from the control value. Cells incubated with digitonin demonstrated normal basal (160 +/- 9 ng/10(6) cells X 30 min) and GH-releasing factor-stimulated GH release (564 +/- 11 ng/10(6) cells X 30 min). However, the inhibitory action of SRIF in these cells was approximately 30% greater (98 +/- 8 ng/10(6) cells X 30 min) than that in either control or chloroquine-treated cells, suggesting that SRIF freely admitted intracellularly produces additional biological activity. These observations confirm the presence of the intracellular receptors and suggest that these receptors exist in a biologically active form.

Animals↗
PubMed1985

Somatostatin and the cerebral cortex.

A unique subset of interneurons which are rich in immunoreactive somatostatin (IRS) exists in the cerebral cortex. The regulation of IRS secretion by these cells is reviewed. Acetylcholine, glutamic acid and several neuropeptides including VIP, CCK, and metenkephalin have been identified as IRS secretagogues. The types of molecules which stimulate IRS release, the electrophysiologic effects of somatostatin, and the recognition of abnormal IRS levels in human CNS diseases were all used to formulate a working model of the role of the somatostatinergic cell in ongoing cerebral cortical function.

Amino Acids↗
PubMed1985

Early extubation after high-dose fentanyl anaesthesia for aortocoronary bypass surgery: reversal of respiratory depression with low-dose nalbuphine.

To investigate the possibility of selective reversal of narcotic-induced respiratory depression following fentanyl anaesthesia, we studied 20 patients after aortocoronary bypass surgery. All patients were anaesthetized with fentanyl, 40 micrograms . kg-1 and oxygen, with isoflurane as indicated. In a random double blind fashion either incremental doses of nalbuphine, or normal saline were administered approximately four hours after cardiopulmonary bypass. Respiratory depression was evaluated using blood gas and end tidal CO2 (PETCO2) measurement, and in addition, a ventilatory response to CO2 was obtained preoperatively and at selected intervals postoperatively. Despite randomization, patients with more respiratory depression were assigned to nalbuphine. There appeared to be a reversal of respiratory depression with nalbuphine, indicated by a fall in the resting PETCO2 value. This apparent reversal of respiratory depression was associated with a significant increase in pain, requiring treatment in three patients. We conclude that low-dose nalbuphine is not an acceptable method of antagonism of respiratory depression in this group of patients. Many patients who did not receive nalbuphine were able to breathe adequately at an earlier stage than was previously suspected. Close monitoring of the respiratory system may permit earlier extubation without the requirement of a narcotic antagonist after this dose of fentanyl.

Anesthesia, General↗
PubMed1985

Insulin receptors on cultured hypothalamic cells: functional and structural differences from receptors on peripheral target cells.

We have studied the functional and structural characteristics of insulin receptors on cultured rat hypothalamic cells. The receptors on these cells are specific for insulin, but have a lower binding affinity than that measured in nonneuronal tissues. Neither acute (2-h) nor long term (24-h) exposure of the hypothalamic cells to high insulin concentrations resulted in receptor down-regulation. However, insulin is internalized in these cells and accumulated in the presence of the lysomotropic agent chloroquine. Acute exposure to insulin does not alter initial rate of 2-deoxyglucose transport in hypothalamic cells, but does cause a stimulation of aminoisobutyric acid uptake. Photoaffinity labeling of the receptors of the hypothalamic cells with a biologically active photosensitive insulin revealed a major specifically labeled band of 115K mol wt and a minor band of 40K mol wt under disulfide-reducing conditions compared to bands of 125K and 90K mol wt seen after labeling of the insulin receptors of adipocytes. The receptor proteins in hypothalamic cells under nonreducing conditions (420K, 370K, and 310K mol wt) were also smaller than those in adipocytes. Thus, the insulin receptors of cultured hypothalamic cells differ from insulin receptors on peripheral target tissues in both functional and structural aspects.

Adipose Tissue↗
PubMed1984

Perceived vulnerability in adolescents to the health consequences of cigarette smoking.

Adolescent feelings of vulnerability, an aspect of the Health Belief Model and Elkind's concept of adolescent egocentrism, were examined in two groups of white, middle-class 6th to 12th graders. Feelings of vulnerability were examined with respect to developmental course, antecedents, and relationship to the specific risk-taking behavior of cigarette smoking. Feelings of vulnerability to the negative consequences of smoking were found to decrease rapidly from sixth to eighth grade and to increase slowly thereafter. Experience with illness and accidents was correlated with the general vulnerability measure. However, experience with illness due to smoking was not related to smoking vulnerability. This may have been because few adolescents were found to have had personal experiences with the health consequences of smoking. Feelings of vulnerability with respect to the negative consequences of cigarette smoking were correlated with adolescent smoking behavior. General feelings of vulnerability were unrelated to cigarette smoking.

Adolescent↗
PubMed1984

Differential effects of myoneural blocking drugs on neuromuscular transmission in infants.

Equipotent, paralysing doses of pancuronium and tubocurarine were administered to 40 patients, aged from 1 day to 12 months, during nitrous oxide, oxygen and fentanyl anaesthesia. Neuromuscular activity was measured during onset and recovery from paralysis using train-of-four stimulation. At the same depression of the first stimulus of the train, the train-of-four ratio was decreased more during recovery than during onset with each drug and more with tubocurarine than with pancuronium. These results are qualitatively similar to those found in adults, but the decrease in train-of-four ratio was less in infants. Thus, it is concluded that prejunctional neuromuscular activity, recognized as fade in response to train-of-four stimulation, can be detected after administration of pancuronium or tubocurarine to infants, but that it is less marked than in adults.

Anesthesia, General↗
PubMed1984

Treatment of inoperable non-small cell carcinoma of the lung with radiation therapy, with or without levamisole. A randomized trial of the Southeastern Cancer Study group.

In a randomized trial, 251 patients with inoperable non-small cell lung cancer received radiation therapy (RT) with or without levamisole (2.5 mg/kg twice weekly for 1 year, or until progression). Radiation therapy was delivered to 6000-6500 rad for Stages I and II, and 4000-4500 rad by continuous or split course for Stage III disease. Responses were observed in 40% of patients receiving placebo, and in 29% of patients taking levamisole. Relapse occurred at local sites only in 53% of the placebo- and 75% of the levamisole-treated patients. The frequency of relapse in distant sites was lower (25%) in the levamisole group as compared with the placebo group (47%). No significant difference in survival was observed between the placebo and levamisole-treated groups (median survival, 48.2 and 45 weeks, respectively). Responders to radiotherapy survived significantly longer than nonresponders (median survival, 73 vs. 33.3 weeks, p = 0.001). Among responders, the median survival of patients treated with levamisole was shorter (63.9 weeks) than that of patients receiving placebo (92.7 weeks). Toxicity attributable to levamisole included severe granulocytopenia in five patients and severe nausea and vomiting in nine. It is concluded that levamisole is without significant benefit in this setting.

Adenocarcinoma↗