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PubMed1980

Nicotine and amphetamine: differential tolerance and no cross-tolerance for ingestive effects.

Rats chronically treated twice daily with nicotine (0.4 mg/kg, SC) or d,1-amphetamine (1.5 mg/kg, SC) exhibited different patterns of anorexia, hypodipsia, and body weight loss. Amphetamine-treated rats developed tolerance to these ingestive effects and to weight loss, whereas nicotine-injected rats did not. There was little, if any, evidence for cross-tolerance when the drugs were switched between the two groups. These results indicate that different mechanisms underlie the ingestive effects of nicotine and amphetamine.

Amphetamine↗
PubMed1994

Improvement of glucose tolerance by bezafibrate in non-obese patients with hyperlipidemia and impaired glucose tolerance.

Glucose intolerance or diabetes mellitus, hyperlipidemia, obesity and hypertension may have a close interrelation based on insulin resistance. We selected 28 impaired glucose tolerance (IGT) patients with hyperlipidemia. The IGT patients demonstrated hypertriglyceridemia associated with hyperinsulinemia, a typical manifestation of insulin resistance. Administration of bezafibrate at 400 mg/day for 4 weeks to the IGT patients with hypertriglyceridemia resulted in an improvement of the plasma glucose level and insulin response to 75 g oral glucose loading associated with a concomitant decrease in non-esterified fatty acids. The ratio of the level of serum C-peptide to that of insulin after a 75 g oral glucose tolerance test (OGTT) was augmented after 4 weeks of bezafibrate administration. However, reduction of the cholesterol level with pravastatin did not alter these parameters. These results suggest that treatment to reduce the level of serum triglycerides, but not that of cholesterol, may have a beneficial effect for improving insulin resistance even in the non-obese subjects with IGT and decreasing the risk of coronary heart disease.

Bezafibrate↗
PubMed2003

Opioid hyperalgesia and tolerance versus 5-HT1A receptor-mediated inverse tolerance.

In addition to analgesia, opioids also produce paradoxical hyperalgesic effects following acute and chronic treatment. In this article, we review the occurrence of this hyperalgesia under several conditions, and discuss the potential mechanisms and clinical implications. We also review recent evidence that paradoxical analgesia and inverse tolerance induced by stimulation of 5-HT(1A) receptors, which is a mirror image of opioid-induced hyperalgesia and tolerance, might achieve clinically significant analgesia in chronic pain.

Analgesics, Opioid↗
PubMed2001

In vitro tolerance to inhibition by ethanol of N-methyl-D-aspartate-induced depolarization in locus coeruleus neurons of behaviorally ethanol-tolerant rats.

Intracellular recordings were made in pontine slice preparations of the rat brain containing the locus coeruleus (LC). Ethanol at 100 mM, but not at 10 or 30 mM inhibited depolarizing responses to pressure-applied N-methyl-D-aspartate (NMDA) in LC neurons of ethanol-naive rats. Ethanol (100 mM) had a similar effect in LC neurons of ethanol-naive rats, of rats treated with ethanol for 14 days (3 g/kg daily, i.p.) and of rats treated with equicaloric amounts of saccharose (5 g/kg daily, i.p.). The blood concentration of ethanol was markedly decreased at 4 h, and was below the detection limit at 24 h after the last injection. Behavioral measurements in the open-field system demonstrated the development of tolerance in rats receiving ethanol for 14 days. Moreover, an anxiety-related reaction was shown to develop when the acute effect of the last ethanol injection vanished. Therefore, in subsequent in vitro experiments, ethanol (10 mM) was continuously present in the superfusion medium in order to mimic a steady blood concentration and to prevent a withdrawal-like situation. Under these conditions, ethanol (100 mM) still continued to inhibit the NMDA-induced depolarization in slices of untreated rats, but became ineffective in slices of ethanol-treated rats at 4 h after the last injection. By contrast, a supersensitivity to ethanol developed in brain slices at 24 h after the last ethanol injection. In conclusion, in vitro tolerance between systemically and locally applied ethanol at LC neurons could only be demonstrated when a low concentration of ethanol was added to the superfusion medium to simulate the blood concentration of this compound.

Animals↗
PubMed2001

Can Langerhans cell UV injury and dendritic cell infection by immunodepressive viruses induce immunologic tolerance? Second part: immunologic tolerance in AIDS.

In the first part of the present editorial [1], we recalled experimental and clinical data demonstrating that 1) UV, via their effects on Langerhans cells, and 2) some so-called immunodepressive viruses, such as measles, lymphocytic choriomeningitis agents, and some animal retroviruses, via their action on dendritic cells, can induce tolerance in some conditions concerning immunologic parameters and/or the antigen(s). We present in this second part of the editorial a commentary on patients treated at the AIDS phase of HIV-1 infection for 3.5 to 8 years. Among them, one has been submitted before and at the beginning of our treatment, for a psoriasis, to a PUVA irradiation, at the dose of 214.5 J (spectrum 230-320). We were present at the end of this irradiation to see the disappearance of his blood CD4 and of his suppressor T cells. Comparing his data with those of other patients of the cohort similarly treated, we have found arguments to consider that this UV-victim patient has presented for the 6 years of his clinically excellent survival and still presents manifestations of immunologic tolerance towards a fraction of his HIV-1 population.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Relation of C-reactive protein to features of the metabolic syndrome in normal glucose tolerant, impaired glucose tolerant, and newly diagnosed type 2 diabetic subjects.

OBJECTIVE: To determine the relationship between CRP levels and the components of MS in normal glucose tolerant (NGT), impaired glucose tolerant (IGT), and Type 2 diabetic subjects. MATERIAL AND METHODS: A based cross-sectional population study was performed. Eligible subjects, men and non-pregnant women, 30 to 64 year of age, were randomly recruited. Subjects with acute or chronic diseases were excluded. Only newly diagnosed type 2 diabetic or hypertensive subjects were included. Disorders related to CRP increase, also were exclusion criteria. In accordance to WHO proposal, components of MS were: High Blood Pressure, Dyslipidemia, Obesity, and Microalbuminuria, and MS was defined, for the NGT, if at least two of the criteria were fulfilled and in addition the subject had insulin resistance. The MS in IGT and DM subjects was defined if at least two of the criteria were fulfilled. RESULTS: CRP was significantly associated with MS for the NGT (Odds ratio -OR- 3.8, CI(95%) 1.6-14.8), IGT (OR 4.9, CI(95%) 1.2-15.5), and diabetes (OR 5.6, CI(95%) 1.9-10.2). For NGT, after adjustment for obesity, CRP was not longer associated with MS. After adjust for obesity and fasting glucose (FG), the relationship between CRP and MS for IGT was lost. Finally, after adjustment for obesity, FG, and microalbuminuria, CRP was not longer associated with MS for diabetic subjects. CONCLUSIONS: This study show a significant relationship between CRP and MS which is maintained only by obesity in the NGT, by obesity and FG in the IGT, and by obesity, FG, and microalbuminuria in the newly diagnosed diabetic subjects.

Adult↗
PubMed2002

Post-liver transplant Crohn's disease: graft tolerance but not self-tolerance?

Inflammatory bowel disease (IBD) rarely occurs de novo after liver transplantation, and when it does usually presents as ulcerative colitis in patients transplanted for primary sclerosing cholangitis. We present two patients who developed de novo Crohn's colitis two and three years after liver transplant for primary biliary cirrhosis (PBC) and chronic hepatitis B infection, respectively. Both were on maintenance immunosuppression with a calcineurin inhibitor and azathioprine with no evidence of allograft rejection. Investigations for enteric and opportunistic infection were negative. In the nontransplant setting, the development of IBD is likely multifactorial with an immune origin. In our cases, the immunosuppression was titrated to minimal levels when IBD developed. Clearly, although a significant degree of allograft tolerance can occur, autoimmune diseases can still develop elsewhere, suggesting selective immune tolerance.

Colon↗
PubMed2004

Transformation of copper oxychloride fungicide into copper oxalate by tolerant fungi and the effect of nitrogen source on tolerance.

Aspergillus niger and Penicillium chrysogenum were able to grow on Czapek Dox medium amended with elevated concentrations [up to 500 ppm active ingredient (ai)] of the fungicide copper oxychloride. Solubilization of the fungicide in solid medium was evident by the appearance of a clear (halo) zone underneath and around the growing colonies. The halo formed with A. niger, grown on fungicide-containing nitrate nitrogen medium, was found subsequently to enclose concentric rings of newly crystalline precipitate. These crystals were extracted, examined by scanning electron microscopy and IR, and identified as copper oxalate. The supplemented nitrogen source to the medium greatly affected both fungicide solubilization and fungal tolerance. Ratios of fungicide solubilization rate (R(S)) in relation to the colony growth rate (R(G)) were significantly higher on ammonium than on nitrate nitrogen medium for both fungal strains. Growth ratios (the colony extension rate in the presence of a given concentration of the fungicide in relation to the control colony growth rate) of A. niger were markedly lower on ammonium than on nitrate nitrogen medium. The cellular copper contents, taken up from the fungicide, and the medium titratable acidity were higher in ammonium than in nitrate medium for both fungi. These results suggested fungal possession of variable tolerance mechanisms to this fungicide by complexation and/or precipitation of copper in the medium. Additionally, this work emphasizes the activity of fungi in transformation of insoluble inorganic metal-containing fungicides into insoluble organic metal compounds, which has a potentiality in metal cycling in biogeochemical and environmental context.

Biodegradation, Environmental↗
PubMed2002

The oral glucose tolerance test reveals a high frequency of both impaired glucose tolerance and undiagnosed Type 2 diabetes mellitus in primary hyperparathyroidism.

AIMS: To evaluate the frequency of impaired glucose tolerance (IGT)and undiagnosed diabetes mellitus together with the indices of insulin resistance (IR) in primary hyperparathyroidism (pHPT). METHODS: Out of 105 consecutive pHPT patients (F/M 78/27, asymptomatic/symptomatic 68/37, age (mean +/- s.d.) 60.7 +/- 12.7 years,body mass index 25.2 +/- 3.8 kg/m2, ionized calcium (iCa) 1.49 +/- 0.16 mmol/l,parathormone 200.4 +/- 233.9 pg/ml),59 without known diabetes mellitus and controls (n = 60) underwent an oral glucose tolerance test (OGTT, 75 g os). As indices of IR, homeostasis model assessment (HOMAIR)or OGTT data (insulin sensitivity index composite (ISI comp)) were evaluated. RESULTS: In pHPT the prevalence of IGT (mean, 95% confidence intervals (CI), 40.7%, 27.8-53.6) was higher than in controls (25.0%, 13.7-36.3, P < 0.03). Similarly,the prevalence of undiagnosed diabetes mellitus was higher in pHPT(15.3%, 5.8-24.7) than in controls (5.0%, 0-10.7, P < 0.05). Moreover,the prevalence of IGT and undiagnosed diabetes was higher in pHPT than that previously reported in the general population of Northern Italy(8.5% and 3.2%, respectively). The indices showed that insulin resistance was higher in pHPT than in controls: HOMAIR (median, 95% CI,2.6, 2.5-3.9 vs. 1.7, 1.6-2.5, respectively; P < 0.003); ISI comp (3.5, 3.4-4.6 vs. 5.1, 4.9-7.2, respectively; P < 0.002). CONCLUSIONS: Our data in a large and modern day pHPT series, with a preponderance of asymptomatic patients, confirm increased insulin resistance and pre-valence of IGT and undiagnosed diabetes.

Aged↗
PubMed1970

Tolerance to opioid narcotics, II. Cellular tolerance to levorphanol in mouse brain.

Mice were made tolerant to a large dose of levorphanol, a congener of morphine. Then (3)H-levorphanol was given. The concentration of free, unchanged levorphanol in the brain water (ultrafiltrate) was found to be much higher than required to produce pharmacologic effects in nontolerant animals. The result indicates that tolerance arises from a diminished sensitivity to the drug at cellular or subcellular sites of drug action in the brain.

Animals↗
PubMed1973

Allograft tolerance: presumptive evidence that serum factors from tolerant animals that block lymphocyte-mediated immunity in vitro are soluble antigen-antibody complexes.

Serum factors present in rats rendered operationally tolerant to skin allografts by inoculation of allogeneic bone-marrow cells as newborns inhibit or "block" the cytotoxic effect of immune lymphocytes in vitro. These blocking factors were specifically removed from tolerant serum by absorption with allogeneic cells and later eluted from the absorbing cells in glycine buffer (pH 3.1). Blocking activity of the eluted material was resolved into fractions of low and higher molecular weight, which may be soluble histocompatibility antigen and specific alloantibody, respectively. Both antigen and antigen-antibody complexes may block in vitro, depending upon the assay used.

Animals↗
PubMed1989

Liver function in protein-energy malnutrition measured by cinnamic acid tolerance and benzoic acid tolerance: effect of carnitine supplementation.

1. Rats fed on a protein-depleted diet for 8 weeks were repleted for 5 weeks on high-protein (HP), high-protein + 20 g DL-carnitine/kg (HP + C), or low-protein + 20 g DL-carnitine/kg (LP + C) diets. At 4 and 8 weeks of depletion, and 1 and 5 weeks of repletion, rats from each treatment group were given a benzoic acid tolerance test (BATT) or a cinnamic acid tolerance test (CATT) as a measure of liver function. 2. BATT and CATT measured the molar percentage of a test dose (1 mmol/kg body-weight) of benzoic acid or cinnamic acid excreted in the urine as hippuric acid within 24 h. Liver weight, liver lipid levels, and carnitine concentration in plasma and liver were also measured following liver-function testing. 3. BATT and CATT were severely impaired in protein-depleted rats, but returned rapidly to control levels following protein refeeding. Correlations of BATT and CATT with liver lipid concentration were high (r -0.49 and -0.62 respectively), and both tests show promise as clinical tests for liver function in protein-energy malnutrition. 4. Carnitine supplementation was required to return liver carnitine concentration of protein-depleted rats to control levels during repletion, but was not associated with accelerated reduction in liver fat concentration in protein-repleted rats.

Animals↗
PubMed1990

Induction of anti-allo-class I H-2 tolerance by inactivation of CD8+ helper T cells, and reversal of tolerance through introduction of third-party helper T cells.

The intravenous sensitization of C57BL/6 (B6) mice with class I H-2-disparate B6-C-H-2bm1 (bm1) spleen cells resulted in the abrogation of CD8+ T cell-mediated anti-bm1 (proliferative and interleukin 2-producing) T helper (Th) cell activities. In vitro stimulation of lymphoid cells from these mice with bm1 cells, however, generated a reduced, but appreciable, anti-bm1 cytotoxic T lymphocyte (CTL) response. Moreover, the anti-bm1 CTL response, upon stimulation with [bm1 x B6-C-H-2bm12 (bm12)]F1 spleen cells, was enhanced when compared with the response induced upon stimulation with bm1 cells. These in vitro results were reflected on in vivo graft rejection responses; bm1 skin grafts engrafted in the bm1-presensitized B6 mice exhibited prolonged survival, whereas (bm1 x bm12)F1 grafts placed collateral to bm1 grafts (dual engrafted mice) inhibited the tolerance to bm1. In the B6 mice 1-2 d after rejecting the bm1 grafts, anti-bm1 Th activities remained marginal, whereas potent anti-bm1 CTL responses were found to be generated from their spleen cells. Administration in vivo of anti-CD4 antibody into bm1-presensitized, dual graft-engrafted mice prolonged bm1 graft survival and interfered with enhanced induction of anti-bm1 CTL activity. These results indicate that anti-class I alloantigen (bm1) tolerance as induced by intravenous presensitization with the relevant antigens is not ascribed to the elimination of CD8+ CTL precursors, but to the specific inactivation of CD8+ Th cells, whose function can be bypassed by activating third-party Th cells.

Animals↗
PubMed1994

Dietary NaCl restriction deteriorates oral glucose tolerance in hypertensive patients with impairment of glucose tolerance.

This study investigated whether the change of glycemic response to oral glucose loading with an increase of dietary NaCl intake is different between salt-sensitive and salt-resistant groups, or whether it is related to glucose tolerance on a low NaCl diet independent of salt sensitivity. The plasma glucose and insulin response to 75 g oral glucose intake was assessed on low (34 mmol/day) and high (342 mmol/day) NaCl diets in 31 patients with essential hypertension, and the area under the curve for both variables (AUCglu and AUCins) was calculated. The data on the high NaCl diet were corrected for change in hematocrit. The percentage change in systolic, diastolic, and mean blood pressure between the two diets was defined as the salt sensitivity index (SSI) for systolic blood pressure (SSISBP), diastolic blood pressure (SSIDBP), and mean blood pressure (SSIMBP), respectively. The mean values of both AUCglu and AUCins decreased significantly with increase of NaCl intake; however, there was no significant correlation between SSI (SSISBP, SSIDBP, or SSIMBP) and the percentage changes in AUCglu and AUCins. Meanwhile, the percentage changes in AUCglu and AUCins significantly correlated with the respective values of AUCglu and AUCins on the low NaCl diet. These results suggest that extreme NaCl restriction may deteriorate glucose metabolism in hypertensive patients, especially in those with diabetes mellitus or impaired glucose tolerance.

Adult↗
PubMed1999

Expansion of neonatal tolerance to self in adult life: II. Tolerance preferentially spreads in an intramolecular manner.

Newborn rats exposed to a myelin basic protein determinant acquired long-lasting resistance to experimental autoimmune encephalomyelitis induced by another determinant only if both determinants are co-administered in adult life. We demonstrate here that during the course of disease both the anti-self response and the tolerant state spread in an intramolecular and not an intermolecular manner. Mechanisms involved in tolerance elicitation and expansion are then explored using an in vitro system in which indirect suppression could be measured.

Aging↗
PubMedDate not supplied

Microbiological tolerance in orthopaedic infections: delayed response of septic arthritis and osteomyelitis of the hip due to infection with tolerant Staphylococcus aureus.

A 14-year-old boy presented to another hospital with a clinical picture of septic arthritis. After aspiration of purulent material from the joint, empiric antibiotic treatment was initiated and an arthrotomy was performed. Antibiotic treatment was then modified to nafcillin according to microbiological sensitivity results of the isolated Staphylococcus aureus as determined by minimal inhibitory concentration testing. One week later purulent drainage recurred and open drainage had to be repeated; an abscess anterior to the joint was noted. Once again the infection failed to resolve, and the patient was transferred to our institution where a third arthrotomy had to be performed. The organism isolated at the first aspiration was reexamined and found to have a minimal bactericidal concentration to minimal inhibitory concentration ratio of 32, implying a tolerant organism. The antibiotic treatment was modified to an antibiotic not subject to the tolerance phenomenon, and the infection resolved without additional surgical intervention.

Adolescent↗
PubMed1986

Drug-induced in vitro tolerance to allogeneic antigens. I. Establishment of a tolerance induction system in a fully allogeneic murine combination.

C3H/HeSlc (H-2k) spleen cells were cultured with mitomycin C (MMC)-treated C57BL/6CrSlc (H-2b) spleen cells for 2 days and incubated with 5-fluorouracil (5-FU) for a further 9 hr. Thereafter, those C3H/He spleen cells were recultured with the same allogeneic cells for 5 days. Cell-mediated cytotoxicity (CMC) and mixed lymphocyte reaction (MLR) were profoundly suppressed, antigen-specifically, in such C3H/He spleen cells. In contrast, interleukin 2(IL-2) production was not impaired in the restimulating mixed lymphocyte culture (MLC) with C57BL/6. Moreover, an adequate amount of exogenous IL-2 added to the restimulating MLC did not lead to a restoration of the depressed CMC. Suppressor cell activity in the CMC assay was not detected in the C3H/He spleen cells exposed to such a tolerance induction. These results suggest that the unresponsiveness to alloantigens in CMC and MLR was induced through a clonal deletion mechanism, and there may exist a 5-FU-resistant--thus less-proliferative--cell population that can produce IL-2 even after the tolerance induction.

Animals↗