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PubMed1976

Loss of carrier-determined tolerance in vitro with loss of receptor blockade.

Experiments were done to determine whether carrier-determined tolerance is reversible and whether the loss of tolerance is accompanied by the loss of receptor blockade. Spleen cells from mice made tolerant with DNP-isologous IgG remained tolerant when transferred to irradiated syngeneic mice. If these same tolerant spleen cells were incubated for 24 hr or more before transfer the tolerance was lost. Autoradiology was done on the tolerant cells with either 125I anti-DNP or 125DNP-KLH, before and after incubation in vitro. When the cells were tolerant the number of DNP ABC was decreased whereas cells having DNP on their surface were increased. When the cells lost tolerance after in vitro incubation, the hapten-bearing cells were no longer present although the number of cells free DNP receptors increased to normal. These data suggest that in carrier determined tolerance the reactivation of tolerant lymphocytes may involve reversible receptor blockade.

Animals↗
PubMed1976

Studies on tolerance development to single doses of morphine in mice.

Single-dose tolerance to the antinociceptive effect of morphine can be demonstrated using an adequate initial priming dose of morphine and allowing an interval of 48 to 72 hours for its development. The threshold dose necessary to produce tolerance was found to be about 3 to 4 times greater than that for producing analgesia but higher doses of morphine did not enhance further tolerance development. Evidence of tolerance was indicated by the fact that when the antinociceptive response to morphine was assessed by the hot-plate and the tail-flick procedures, a shift in the dose-response curve of morphine to the right occurred after an adequate single priming dose of morphine. Cross-tolerance was evidenced by a decrease in analgetic response to methadone 3 days after a single priming dose of morphine and a decrease in morphine response after a single dose of methadone. The development of single-dose tolerance was inhibited by cycloheximide. Single-dose tolerance was also blocked by 5,6-dihydroxytryptamine and perhaps enhanced by L-tryptophan. Cyclic 3',5'-adensine monophosphate did not affect single-dose tolerance development significantly although the direction was in favor of augmentation. Morphine uptake by the brain was not modified by the development of single-dose tolerance. Physical dependence, as measured by naloxone-precipitated withdrawal jumping, was not observed when single-dose analgetic tolerance was maximal. The results suggest that single-dose tolerance to morphine involves the synthesis of some macromolecule and support previous findings in this laboratroy involving an association with serotonin.

5,6-Dihydroxytryptamine↗
PubMed1989

Nitroglycerin-induced tolerance affects multiple sites in the organic nitrate bioconversion cascade.

The effect of nitroglycerin (NTG)-induced tolerance on the spasmolytic effects of a series of vasodilators was determined to establish potential sites of tolerance. Concentration-effect curves to vasodilators were completed concurrently in U46619-contracted bovine isolated coronary artery rings pre-exposed to 100 microM NTG for 10 min (NTG-tolerant rings) and in control rings not pre-exposed to NTG. Compared to control rings, NTG-tolerant rings were markedly less responsive (P less than .01, n = 8-10) to the spasmolytic actions of NTG, isosorbide dinitrate, sodium nitroprusside (SNP) and 3-morpholinosydonimine (SIN-1), whereas the spasmolytic actions of S-nitroso-N-acetylpenicillamine and nitric oxide were only marginally attenuated in NTG-tolerant rings. On the other hand, no significant difference in the relaxant responses of NTG-tolerant and control coronary artery rings were observed to either the endothelium-dependent vasodilator, A23187 or the guanylate cyclase-independent vasodilator, theophylline. In additional cross-tolerance studies, relaxations to the organic nitrate vasodilator, NTG were significantly more attenuated (P less than .05, n = 5) by tolerance induced by NTG, than by either SNP or SIN-1, whereas the actions of the non-nitrate vasodilators, SNP and SIN-1 were attenuated more by SNP-and SIN-1-induced tolerance than by NTG-induced tolerance (P less than .05, n = 5). We conclude that, in this isolated coronary artery preparation, NTG-induced tolerance affects at least two major sites in the cascade of events between the initial site of NTG action and guanylate cyclase activation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Characterization of cytotoxic cells in mice rendered neonatally tolerant of MHC alloantigens: evidence for repertoire modification.

A common prediction of clonal deletion/inactivation hypotheses is that cells with high avidity for tolerogen are preferentially eliminated, with low avidity cells being most likely to escape the tolerance induction mechanism. Thus it would be expected that the tolerogen-specific cells in tolerant mice would have a different repertoire than those in normal mice. To find evidence in favor of this prediction, neonatal B10.A mice were rendered tolerant to B10 by the injection of 15 X 10(6) (B10.A X B10)F1 spleen and bone marrow cells, and tolerance was assessed by the acceptance of B10 skin grafts for greater than 50 days. Mice rendered tolerant in this manner contain severely reduced (to less than 10% of normal) but detectable numbers of tolerogen-specific cytotoxic cell precursors that can be activated in the presence, but not absence, of exogenous interleukin 2. Spleen cells from the tolerant animals were compared with those of normal B10.A mice with respect to the expression of differentiation markers on the surface of B10-specific cytotoxic cells and their precursors, and the relative strength of the anti-B10 response toward Kb and Db as a measure of the repertoire of the cytotoxic cell populations. The T cell nature of the tolerogen-specific cytotoxic cells in both normal and tolerant mice was confirmed by their susceptibility to lysis by anti-Thy-1 or Lyt-2 antibody and complement. More importantly, cold target inhibition experiments showed that cytotoxic T cells from tolerant mice were inhibited to a greater degree by B10.A(2R) (KkDb) cold targets than B10.A(5R) (KbDd), suggesting that the response was preferentially directed at the D end of H-2, in direct contrast to normal B10.A spleen cells, which show a preferential response against Kb. Measurement of the frequency of anti-Kb and anti-Db cytotoxic T cell precursors in the spleens of normal and tolerant mice confirmed the differential specificities seen in the cold target experiments. The data suggest that neonatal tolerance induction results in repertoire modification of the anti-tolerogen response rather than a uniform decrease in anti-tolerogen reactivity. Possible mechanisms to explain the alteration in the repertoire of tolerant mice are discussed.

Animals↗
PubMed1977

Cellular basis of persistent tolerance induced by an aggregate free heterologous immunoglobulin.

Attempts were made to break the tolerance of lymph node B cells to deaggregated human gamma globulin. Using allotype-congenic mice, lymph node cells from virgin or tolerant (5 mg) CBA/Igb donors were transferred tonormal CBA/Iga recipients and the proportion of responding donor B cells estimated 1 and 13 days later. The response of the non-tolerant virgin cells diminished with time but was still detectable at 13 days whereas the response of the tolerant cells was tenfold lower than normal cells at day 1 and was not detectable at 13 days. This functional deletion of tolerant cells was not reversed by enzymatic stripping of the immuno-globulin receptors before transfer, nor by removing T cells-which might have had a suppressor action. In other experiments Igb mice were thymectomized or left as controls at various times before tolerance induction. Lymph node cells from these mice were transferred, together with non-tolerant Iga cells, to irradiated recipients. The cell from tolerant thymectomized donors strongly suppressed the response of non-tolerant cells, whereas the tolerant control cells showed no suppressor activity. It is considered that B-cell tolerance can be maintained by something other than receptor blockade, or active suppression-although the latter can arise in some circumstances.

Animals↗
PubMed1986

Tolerance defects in New Zealand Black and New Zealand Black X New Zealand White F1 mice.

The susceptibility of autoimmune NZB and (NZB X NZW)F1 mice to the induction of tolerance by monomeric BSA was compared with several normal mouse strains. Unresponsiveness in T and B lymphocyte compartments was probed by challenging with DNP8BSA and measuring anti-DNP and anti-BSA antibodies separately. Tolerance induced by monomeric BSA was carrier specific, and there was no evidence of epitope-specific suppression. Normal NZW, NFS, and B10.D2 mice were easily rendered tolerant with monomeric BSA and did not produce anti-DNP or anti-BSA antibodies after challenge with DNP8BSA. By contrast, the lack of anti-DNP antibody response in similarly treated NZB mice was dependent on the dose of monomeric BSA, indicating that the helper T cells were partially resistant to tolerance induction. NZB mice treated with a high dose of monomeric BSA produced anti-BSA, but not anti-DNP, antibodies after immunization. Thus, the anti-carrier B cells in NZB mice may have been primed by monomeric BSA. The presence of the xid gene on the NZB background rendered the mice susceptible to induction of tolerance, suggesting that the tolerance defect in NZB mice involves the B cell compartment. This abnormal antibody response was a dominant trait: (NZB X NFS)F1 and (NZB X B10.D2)F1 mice had the same characteristics as NZB mice. These F1 hybrids do not develop autoimmune disease, indicating that resistance to experimental tolerance induction expressed at a B cell level may not be sufficient for disease development. In contrast to NZB and other NZB F1 hybrids, (NZB X NZW)F1 hybrids treated with monomeric BSA and challenged with DNP8BSA responded to both DNP and BSA. The contribution of a B cell defect to the tolerance abnormality of (NZB X NZW)F1 mice was examined by analyzing the effect of the xid gene on the progeny of (NZB.xid X NZW)F1 mice. Unlike the effect of the xid gene on NZB mice, both phenotypically normal heterozygous female and phenotypically xid hemizygous male mice produced anti-DNP and anti-BSA antibodies after tolerance induction and immunization, demonstrating that a major helper T cell abnormality was present in (NZB X NZW)F1 mice. The (NZW X B10.D2)F1 hybrid was rendered tolerant by this procedure, indicating that the helper T cell defect (NZB X NZW)F1 mice may have resulted from gene complementation with the NZB mice contributing partial resistance of T helper cells to tolerance induction.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1976

Specific, transient suppression of the immune response by HGG tolerant spleen cells. II. Effector cells and target cells.

In a previous report, it was shown that spleen cells from mice made tolerant to human gamma-globulin (HGG)5 could specifically inhibit the immune response of normal spleen cells after adoptive transfer to lethally irradiated recipients. However, that report also showed that the suppressive activity was only transiently associated with tolerant spleen cell populations. It was concluded from those experiments that while suppressive activity could be demonstrated in tolerant spleen cells under certain conditions, such activity was not obligatory for the maintainance of the tolerant state. The experiments presented here were performed to determine the nature of the effector cell(s) and the target cell(s) involved in this system of suppression of the immune response. Treatment of cells from tolerant animals with anti-thymocyte serum and complement to remove thymus-derived (T) cells completely abrogated suppresive activity. Removal of adherent cells from tolerant spleen cells by passage over glass wool columns resulted in partial loss of the suppression. The inhibitory activity of the suppressor cells was resistant to 900 R irradiation regardless of whether the tolerant spleen cells were irradiated before or after adoptive transfer. The cellular target(s) for the supprssor cells was examined by using lipopolysaccharide (LPS) as an alternative source of helper activity for the response to HGG. LPS, injected at the time of the initial antigenic challenge of mice that had been reconstituted with tolerant and normal spleen cells, prevented the expression of suppression against bone marrow-derived (B) cells. However, when LPS was presented only at the time of secondary antigenic challenge, it was unable to overcome suppression of the immune response of reconstituted recipients. Thus, LPS could produce a state where the B cells were resistant to suppression, but LPS could not rescue the responsiveness of B cells once the cells in the reconstituted recipient had been suppressed. In addition, the immune response to both the hapten dinitrophenol (DNP) and the carrier (HGG) were suppressed when recipients of tolerant and normal spleen cells were challenged with DNP6HGG. This indicates that T helper cells are also a target for suppression. The results presented in this paper are discussed in relation to a possible mechanism of suppression which proposes that suppressive activity represents the induction of tolerance in immunologically competent cells by HCG which is closely associated with the tolerant spleen cells.

Animals↗
PubMed1995

CD4+ T cells anergized by high dose feeding establish oral tolerance to antibody responses when transferred in SCID and nude mice.

The cellular mechanism for oral tolerance in specific Ab response was investigated by cell-transfer experiments, using severe combined immunodeficiency (SCID) and BALB/c nu/nu mice. High dose feeding with bovine alpha s1-casein, a major allergen in milk, to BALB/c mice induced Ag-specific oral tolerance to the specific Ab response. This state of oral tolerance was successfully transferred to SCID mice with splenocytes from orally tolerant BALB/c mice. In SCID mice that were transferred with tolerant T cells and normal B cells before being immunized with alpha s1-casein, oral tolerance to the Ab responses was generated. In addition, only the T cells established the tolerant state in nude mice. A decreased proliferative response of the splenic T cells from BALB/c mice against alpha s1-casein was also shown, indicating that the decreased Ab responses were attributed to the unresponsiveness of the splenic T cells. Next, the tolerant splenic T cells were further separated into CD4+ T cells and CD8+ T cells, remixed with normal cells, and then transferred to nude mice, which revealed that the tolerant state in the nude mice was principally generated by the CD4+ T cells. When tolerant CD4+ T cells were cotransferred with normal CD4+ T cells to nude mice, there was no significant reduction in the specific Ab responses. These results demonstrate that splenic CD4+ T cells anergized by high dose feeding established oral tolerance to the Ab responses when transferred to SCID and nude mice.

Administration, Oral↗
PubMed1994

Acute and chronic opioid tolerance: a pharmacological review.

Opioid tolerance is a significant clinical phenomenon. Patients may develop opioid tolerance within several hours even after a single bolus of opioid. Animal studies have revealed that there were two kinds of opioid tolerance, namely acute opioid tolerance and chronic opioid tolerance. Acute opioid tolerance may develop within 4 hours after a single bolus of fentanyl or morphine, and 1 hour after a single injection of alfentanil. Chronic opioid tolerance may develop with an incubation period of 8-10 days and last for a long period. The characteristics of acute opioid tolerance may differ from those of chronic opioid tolerance. The mechanisms underlying acute and chronic opioid tolerance are not well studied and need to be further explored. However, in the future, the combined administration of delta opioid receptor antagonists or opioid agonist-antagonists along with opioid agonist (such as morphine) may not only provide less opioid tolerance but also maintain adequate analgesia in clinical practice.

Animals↗
PubMed1993

Changes in glucose tolerance among elderly Finnish men during a five-year follow-up: the Finnish cohorts of the Seven Countries Study.

UNLABELLED: It was the purpose of this study to report the natural history of glucose tolerance during a five-year follow-up among elderly Finnish men, and to evaluate the role of age and body-mass index in explaining the variation in glucose tolerance both cross-sectionally and longitudinally. In the survivors of the Finnish cohorts of the Seven-Countries Study, aged 65 to 84 years at baseline, a two-hour oral glucose-tolerance test was performed according to current WHO criteria. Subjects with fasting blood glucose > 10 mmol/l were directly classified as having diabetes at baseline.-- FINDINGS: At baseline, of the 637 men 216 had normal and 234 had impaired glucose tolerance, 187 were diabetic. At follow-up, 172 men had died; 38 (18%) of the subjects with normal glucose tolerance at baseline had either impaired glucose tolerance or diabetes; 17 (7%) of the men with initially impaired glucose tolerance had developed diabetes, and 79 (34%) were normalized. 25 (13%) and 22 (12%) of the initially diabetic subjects had reverted to impaired or normal glucose tolerance, respectively. The age was able to explain 1-2% of variation in blood glucose level in cross-sectional but not in longitudinal comparison. Body-mass index was an important predictor of abnormal glucose tolerance in previously normally responding men. By contrast, obesity did not contribute to the development of diabetes among men with impaired glucose tolerance.-- PRINCIPAL CONCLUSIONS: The incidence of impaired glucose tolerance was high in these elderly Finnish men as compared with studies in middle-aged Caucasoid subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1993

Attenuation and reversal of morphine tolerance by the competitive N-methyl-D-aspartate receptor antagonist, LY274614.

The ability of a competitive (LY274614; (+-)-6-phosphonomethyl-decahydroisoquinolin-3-carboxylic acid) and a noncompetitive (MK801; [(+)-5 methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen maleate) N-methyl-D-aspartate receptor antagonist to modulate the development of tolerance to morphine's antinociceptive (analgesic) effects was assessed by using hot-plate latency in rats. Concurrent treatment with LY274614 or MK801 by continuous s.c. infusion significantly attenuated the development of morphine tolerance produced by twice daily injections of morphine (10 mg/kg s.c.). This attenuation of morphine tolerance by LY274614 was dose-dependent, 12 or 24 mg/kg/24 hr s.c. infusion). Additionally, animals tested 1 week after the discontinuation of all drug treatments were observed to retain their analgesic sensitivity to morphine, whereas control animals remained relatively tolerant. These results suggest that LY274614 and MK801 do not alter the expression of tolerance but actually modify the development of morphine tolerance. Morphine-tolerant animals infused with LY274614 for 7 days regained their analgesic sensitivity to morphine. Furthermore, LY274614 also reversed the development of tolerance and restored morphine sensitivity in tolerant animals that continued to receive morphine. The demonstration that LY274614 can prevent and reverse the development of morphine tolerance without reducing the analgesic response suggests that the adaptive system involved in the development and maintenance of tolerance requires a functional N-methyl-D-aspartate receptor. LY274614 lacks the phencyclidine-like side effects seen with MK801, and this may favor the clinical development of this competitive N-methyl-D-aspartate receptor antagonist as an adjunct for patients receiving chronic opioids for pain management.

Animals↗
PubMed1995

Vasorelaxing effect of S-nitrosocaptopril on dog coronary arteries: no cross-tolerance with nitroglycerin.

S-Nitrosocaptopril (S-NO-Cap) produced dose-dependent relaxation in isolated dog coronary arteries. This relaxation consisted of two parts: an initial phasic relaxation and a subsequent sustained relaxation. Relaxation was potentiated by superoxide dismutase but was suppressed by pyrogallol, methylene blue or oxyhemoglobin. The relaxant responses of coronary artery to vasoactive agents were reexamined after the development of nitrate tolerance induced by a 1-hr treatment with 4.4 x 10(-4) M nitroglycerin (NTG). NTG tolerance was verified by a 40-fold increase in the EC50 values. The relaxant response to nitroprusside was only marginally suppressed in NTG-tolerant arteries. NTG-tolerant arteries were not tolerant to nitric oxide (NO) or 8-bromo-cyclic guanosine monophosphate (cGMP) and did not show a significant change in the concentration-response curves. Similarly, the concentration-response curves for S-NO-Cap in NTG-tolerant coronary arteries were not significantly different from those in nontolerant coronary arteries. Captopril (5 x 10(-4) M) did not enhance the vasodilative effect of NTG or reverse NTG tolerance. The NTG-induced increase in cGMP was abolished after NTG tolerance was established. On the other hand, the S-NO-Cap-induced increase in cGMP was unaffected by NTG tolerance. In conclusion, these findings indicate that (1) S-NO-Cap is an NO-like substance, (2) an impaired formation of NO or S-nitrosothiol is responsible for the formation of NTG tolerance and (3) S-NO-Cap, which does not show cross-tolerance with NTG, may serve as a therapeutic alternative to current nitrovasodilators.

Animals↗
PubMed1997

Different mechanisms mediate development and expression of tolerance and dependence for peripheral mu-opioid antinociception in rat.

The mu-opioid [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO) exerts a peripheral antinociceptive effect against prostaglandin E2 (PGE2)-induced mechanical hyperalgesia in the hindpaw of the rat. Tolerance and dependence develop to this effect. We have shown previously that tolerance and dependence can be dissociated and are mediated by different second messenger systems. In the present study, we evaluated whether the same or different second messenger systems mediate the development of this peripheral opioid tolerance or dependence compared with the expression of the loss of antinociceptive effect or rebound opioid antagonist hyperalgesia (i. e., expression of tolerance and dependence). DAMGO-induced tolerance was prevented by pretreatment with the nitric oxide synthase inhibitor NG-methyl-L-arginine (NMLA) but not by the protein kinase C (PKC) inhibitor chelerythrine, the adenylyl cyclase inhibitor 2',5'-dideoxyadenosine (ddA), or the calcium chelators 3,4,5-trimethoxybenzoic acid 8-(diethylamino)-octyl ester (TMB-8) and 2-[(2-bis-[carboxymethyl]amino-5-methylphenoxy)-methyl]-6-methoxy-8-bis [carboxymethyl]aminoquinoline (Quin-2). Once established, however, expression of DAMGO tolerance was acutely reversed by TMB-8 or Quin-2 but not by chelerythrine or NMLA. In contrast, naloxone-precipitated hyperalgesia in DAMGO-tolerant paws, a measure of dependence, was blocked by pretreatment with chelerythrine but not by NMLA, ddA, TMB-8, or Quin-2. Naloxone-precipitated hyperalgesia in DAMGO-tolerant paws was acutely reversed by chelerythrine, ddA, TMB-8, or Quin-2 but not by NMLA. Taken together, these results provide the first evidence that different mechanisms mediate the development and expression of both tolerance and dependence to the peripheral antinociceptive effect of DAMGO. However, although the development of tolerance and dependence are entirely separable, the expression of tolerance and dependence shares common calcium-dependent mechanisms.

Analgesics↗
PubMed1999

Endotoxin tolerance in rats: expression of TNF-alpha, IL-6, IL-10, VCAM-1 AND HSP 70 in lung and liver during endotoxin shock.

Endotoxin can induce a state of tolerance against its own pathological effects, commonly referred to as endotoxin tolerance. This phenomenon has been found to be associated with reduced serum levels of cytokines such as TNF-alpha, IL-1, IL-6 and IL-10. In the present study the expression of TNF-alpha, IL-6, IL-10, the adhesion molecule VCAM-1 and the heat shock protein 70 was determined in vivo in lung and liver of LPS-tolerant and naive rats by means of semiquantitative RT-PCR after i.v. LPS injection. TNFalpha, IL-6, IL-10, HSP 70 and VCAM-1 were induced in lung and liver after LPS injection. In liver and lung of endotoxin-tolerant rats TNF-alpha and IL-6 were induced to a lower degree after LPS treatment when compared to non-tolerant controls. The LPS-induced IL-10 expression was also slightly attenuated in the lung of tolerant rats, but in the liver no differences between tolerant and non-tolerant animals were observed. HSP 70 and VCAM-1 were expressed after systemic LPS treatment in liver and lung. The degree of induction, however, was the same in tolerant and untreated controls. The presented data show that endotoxin tolerance is reflected by a reduced cytokine expression in lung and liver in vivo. On the other hand, levels of expression of the adhesion molecule VCAM-1 and the stress protein HSP 70 do not appear to be changed by endotoxin tolerance.

Animals↗
PubMed1997

Nitrate tolerance, rebound, and their clinical relevance in stable angina pectoris, unstable angina, and heart failure.

Vascular tolerance develops rapidly in isolated vascular strips exposed to millimolar concentrations of nitroglycerin. Several mechanisms, including depletion of sulfhydryl groups, reduced biotransformation of nitrates to NO or nitrosothiols, oxygen free radical injury, and downregulation of a membrane-bound enzyme or a nitrate receptor, have been proposed, but the exact mechanism responsible for in-vitro tolerance remains unknown. In-vivo tolerance of the beneficial effects of nitrates on hemodynamics, myocardial ischemia, and exercise performance develops rapidly. It has been suggested, but remains to be proven, that development of venous tolerance and not arterial tolerance is responsible for the attenuation of nitrate effects during long-term nitrate therapy. Several mechanisms, including neurohormonal activation, depletion of sulfhdryl groups, and the shift of fluid from the extravascular to intravascular compartment have been implicated. However, the use of agents to counteract these mechanisms (ACE inhibitors, sulfhydryl donors, diuretics) has produced conflicting results. Thus, at present the mechanism responsible for in vivo tolerance to nitrates remains unknown. Both in vitro and in vivo vascular tolerance to nitrates can be prevented or minimized by providing nitrate-free or low-nitrate intervals. However, during nitrate-free periods, rebound phenomena (rest angina in patients with ischemic heart disease or a deterioration in exercise performance prior to the renewal of the morning dose in patients with stable angina) remain a clinical concern. When treating patients with stable angina pectoris, it must be recognized that none of the nitrate preparations or formulations can provide round-the-clock antianginal or antiischemic prophylaxis. In these patients, beneficial antianginal and antiischemic effects of nitrates for 10-14 hours during the daytime can be maintained by using formulations and dosing regimens that avoid or minimize the development of tolerance (standard formulation of isosorbide-5-mononitrate, 20 mg in the morning and 7 hours later; slow-release formulation of isosorbide-5-mononitrate, 120-240 mg once a day; or nitroglycerin patch delivering 0.6 nitroglycerin per hour for 10-12 hours each day). Only the patch on and off treatment is associated with nitrate rebound. Although intermittent nitrate therapy is not associated with the development of tolerance, this strategy cannot be recommended for treating unstable angina because rebound angina during nitrate-free periods complicates clinical decision making. In the acute phase of unstable angina, continuous treatment with intravenous nitroglycerin is recommended because it permits rapid up- or down-titration. Tolerance towards antianginal and antiischemic effects does develop in a substantial number of patients with 24 hours, but this can be overridden by dose escalation and restoration of the therapeutic effectiveness of nitroglycerin. Tolerance towards the beneficial effects of nitrates on hemodynamics and on exercise performance also develops rapidly during continuous or long-term nitrate therapy, and for these reasons nitrates are not used as first-line therapy to treat chronic heart failure. In combination with hydralazine, high-dose isosorbide dinitrate (30-40 mg four times a day) improves survival, but this combination therapy is inferior to ACE inhibitors.

Angina Pectoris↗
PubMed2002

Identification of AFLP and microsatellite markers linked with an aluminium tolerance gene in barley ( Hordeum vulgare L.).

Barley is the most sensitive among the cereals to aluminium (Al) stress and breeding for more tolerant cultivars is a priority. To enhance selection efficiency for Al tolerance in barley, PCR-based AFLP and microsatellite markers linked to a locus conferring tolerance to aluminium were identified. The study used F(2) progeny derived from a single cross between Yambla (moderately tolerant of Al) and WB229 (tolerant of Al) and developed hydroponic pulse-recovery screening methods to assess tolerance of phenotypes based on root growth. The segregation ratios of tolerant and sensitive genotypes and F(3) progeny testing suggest that a single major gene controlled Al tolerance ( Alt). In order to determine the chromosomal location of the Alt gene, we used the AFLP technique coupled with bulk segregant analysis. We evaluated tolerant and sensitive bulks using 30 combinations of EcoRI/ MseI primers, and 12 of these permitted differentiation of the sensitive and tolerant bulks. More than 1,000 amplified fragments were obtained, and 98 polymorphic bands were scored. AFLP analysis of wheat-barley chromosome addition lines indicated that the Alt gene was located on barley chromosome 4H. Four chromosome 4H-specific microsatellite markers (Bmac310, Bmag353, HVM68 and HVMCABG) were tightly linked to Alt. The large allelic variation detected with microsatellite marker Bmag353 allowed us to implement this marker for routine marker-assisted selection for Al tolerance, and 396 plants could be screened on a single gel.

Journal Article↗
PubMed2002

Tolerance of early diet textures as indicators of recovery from dysphagia after stroke.

We undertook this 12-month retrospective cohort study, of 186 teaching hospital inpatients, to determine how tolerance of differing diet textures after a stroke predicts recovery from dysphagia. Outcome measures were insertion of a percutaneous endoscopic gastrostomy (PEG) tube and/or ability to tolerate a normal diet 28 days after the stroke. Likelihood ratios for needing a PEG were highest for intolerance of pureed food. People who tolerated grade 1 fluids (300-600 cP) or thinner, or who tolerated a modified soft diet or better, 7 days after the stroke did not need a PEG. Half (13/26) the people who could not tolerate grade 3 thickened fluids (10,000-12,000 cP) and 52% (13/25) of people who could not tolerate a puree diet 14 days after the stroke needed a PEG. No one who was intolerant of grade 2 thickened fluids (4000-7000 cP) 7 or 14 days after the stroke could tolerate a normal diet and fluids by day 28. If people were tolerating grade 3 thickened fluids at day 7, the proportion tolerating a normal diet at day 28 was 36%. We present similar data for tolerance of differing fluids and diets at each of the measured time points. We suggest a PEG should be considered in people unable to tolerate grade 3 thickened fluids or a puree diet 14 days after their stroke. However, even in these groups, half will recover sufficiently to manage oral feeding.

Adult↗
PubMed1992

Copper tolerance and copper accumulation of herbaceous plants colonizing inactive California copper mines.

Herbaceous plant species colonizing four copper mine waste sites in northern California were investigated for copper tolerance and copper accumulation. Copper tolerance was found in plant species colonizing soils with high concentrations of soil copper. Seven of the eight plant species tested were found at more than one copper mine. The mines are geographically isolated, which makes dispersal of seeds from one mine to another unlikely. Tolerance has probably evolved independently at each site. The nontolerant field control population of Vulpia microstachya displays significantly higher tolerance to copper at all copper concentration levels tested than the nontolerant Vulpia myrous population, and the degree of copper tolerance attained by V. microstachya at the two copper mines was much greater than that found in V. myrous. It suggests that even in these two closely related species, the innate tolerance in their nontolerant populations may reflect their potential for evolution of copper tolerance and their ability to initially colonize copper mine waste sites. The shoot tissue of the copper mine plants of Arenaria douglasii, Bromous mollis, and V. microstachya accumulated less copper than those plants of the same species from the field control sites when the two were grown in identical conditions in nutrient solution containing copper. The root tissue of these mine plants contain more copper than the roots of the nonmine plants. This result suggests that exclusion of copper from the shoots, in part by immobilization in the roots, may be a feature of copper tolerance. No difference in the tissue copper concentration was detected between tolerant and nontolerant plants of Lotus purshianus, Lupinus bicolor, and Trifolium pratense even though the root tissue had more copper than the leaves. It suggests that copper tolerance in these legume species is not due to a mechanism of differential capacity for copper accumulation in the roots. Different mechanisms of copper tolerance may have evolved among the plant species colonizing the northern California copper mine waste sites.

California↗