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PubMedDate not supplied

Vaccine- and hepatitis B immune globulin-induced escape mutations of hepatitis B virus surface antigen.

Hepatitis B virus surface antigen (HBsAg) vaccination has been shown to be effective in preventing hepatitis B virus (HBV) infection. The protection is based on the induction of anti-HBs antibodies against a major cluster of antigenic epitopes of HBsAg, defined as the 'a' determinant region of small HBsAg. Prophylaxis of recurrent HBV infection in patients who have undergone liver transplantation for hepatitis B-related end-stage liver disease is achieved by the administration of hepatitis B immune globulins (HBIg) derived from HBsAg-vaccinated subjects. The anti-HBs-mediated immune pressure on HBV, however, seems to go along with the emergence and/or selection of immune escape HBV mutants that enable viral persistence in spite of adequate antibody titers. These HBsAg escape mutants harbor single or double point mutations that may significantly alter the immunological characteristics of HBsAg. Most escape mutations that influence HBsAg recognition by anti-HBs antibodies are located in the second 'a' determinant loop. Notably, HBsAg with an arginine replacement for glycine at amino acid 145 is considered the quintessential immune escape mutant because it has been isolated consistently in clinical samples of HBIg-treated individuals and vaccinated infants of chronically infected mothers. Direct binding studies with monoclonal antibodies demonstrated a more dramatic impact of this mutation on anti-HBs antibody recognition, compared with other point mutations in this antigenic domain. The clinical and epidemiological significance of these emerging HBsAg mutants will be a matter of research for years to come, especially as data available so far document that these mutants are viable and infectious strains. Strategies for vaccination programs and posttransplantation prophylaxis of recurrent hepatitis need to be developed that may prevent immune escape mutant HBV from spreading and to prevent these strains from becoming dominant during the next decennia.

Hepatitis B↗
PubMed1991

Effects of PAF antagonists on renal vascular escape and tachyphylaxis in perfused rabbit kidney.

Renal vascular escape is a physiological phenomenon of adaptation that occurs in vascular smooth muscle. It has been described in many preparations subjected to electrical stimulation or treated with vasoactive agents, such as noreprinephrine, angiotensin and vasopressin. We have recently demonstrated that a naturally occurring ginkgolide (BN 52021), which is a PAF antagonist, was able to block norepinephrine-induced escape in perfused rabbit kidney. In the present work other PAF antagonists, such as the ginkgolides BN 52022 and BN 52024, and the synthetic compounds 48740 RP and WEB 2086, were tested. Their effects on renal vascular escape, perfusion pressure and tachyphylaxis were evaluated. They all were shown to block the escape. Among the ginkgolides, BN 52024 is generally recognized as one of the weaker PAF antagonists. However, in spite of this, BN 52024 was able to significantly and simultaneously block renal vascular escape and tachyphylaxis in perfused rabbit kidney infused with norepinephrine.

Animals↗
PubMed2003

Survival, growth, and escape from herbivory are determined by habitat and herbivore species for three Australian woodland plants.

To understand how plant communities are structured by herbivory it is essential to investigate the roles of different herbivores and the responses of a variety of plant species in different habitats. We examined the effects of mammalian herbivores on survival and growth of transplanted seedlings of two native trees (Eucalyptus albensand Callitris glaucophylla), and one native grass (Themeda australis) in white box ( E. albens) woodlands in eastern Australia over 3 years. Herbivores were manipulated using four fencing treatments that successively excluded livestock, macropods, and rabbits from woodland and grassland (cleared pasture). Survival was highest in the absence of mammalian herbivores and in woodlands, and patterns differed among plant species. Survival of T. australis was low, especially in grasslands, and mortality by overgrowth was common in ungrazed treatments. All plant species were taller in fenced plots, and differences between treatments were greater in grassland. Rabbits and livestock had the greatest influence on C. glaucophylla, while T. australis and E. albens were most affected by livestock and macropods. We used field data to parameterize stage-classified matrix models to predict escape from herbivory (escape height >100 cm) for tree species. Reduced herbivory increased the proportion of individuals reaching escape height after 15 years. Rate of escape was greater in grassland, and this faster growth appeared to counteract much of the negative impact of herbivores. While T. australis was unable to escape herbivory, larger, ungrazed individuals were more likely to flower and therefore contribute to the maintenance of the population. Our results show that habitat and herbivore species strongly influence the effect of herbivory on vegetation.

Adaptation, Physiological↗
PubMed2000

Therapeutic implications of escape from angiotensin-converting enzyme inhibition in patients with chronic heart failure.

The level of inhibition of the angiotensin-converting enzyme (ACE) provided by standard doses of ACE inhibitors may only be partial during long-term treatment in patients with severe chronic heart failure (CHF). Partial ACE inhibition with time is often referred to as escape from ACE inhibition and labeled ACE escape. Several lines of evidence suggest that ACE escape occurs in patients with severe CHF. Plasma levels of angiotensin II rise above initial values during long-term ACE inhibition, and the effects of ACE inhibitors on cardiac remodeling and lowering of sympathetic nervous system activity attenuate after 1 year of treatment. Moreover, angiotensin II type I receptor blockade (ARB) produces clinical and hemodynamic benefits in patients with CHF who are already receiving ACE inhibitors. The therapeutic implications of ACE escape include evaluation of higher- than-standard doses of ACE inhibitors and routine addition of ARB to ACE inhibition in patients with severe CHF. Data are reviewed to demonstrate that ACE escape reflects inadequate ACE dosage rather than a decrease in ACE inhibition occurring with time.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1983

The escape of molecular hydrogen and the synthesis of organic nitriles in planetary atmospheres.

What is the influence of hydrogen escape from the atmosphere of small planetary bodies on the synthesis of organic molecules in that atmosphere? To answer this question, laboratory experiments have been performed to study the evolution of different reducing model atmospheres submitted to electrical discharges, with and without the simulation of H2 escape. A study of mixtures of nitrogen and methane shows a very strong effect of H2 escape on the formation of organic nitriles, the only nitrogen containing organics detected in the gas phase. These are HCN, CH (triple bond) C-CN, (CN)2, CH2=CH-CN, CH3CN and CH3CH2CN. The yield of synthesis of most of these compounds is noticeably increased, up to several orders of magnitude, when hydrogen escape is simulated. The escape of H2 from the atmosphere of the primitive Earth may have played a crucial role in the formation of reactive organic molecules such as CH (triple bond) C-CN or (CN)2, which can be considered as important prebiotic precursors. These experimental results may also explain extant data concerning the nature and relative abundance of organics present in the atmosphere of Titan, a planetary satellite which may be an ideal model within our solar system for the study of organic cosmochemistry and exobiology.

Atmosphere↗
PubMed1984

On the mechanism of 'escape' from desensitization of the cyclic AMP response to TSH in cultured human thyroid cells.

Studies were conducted to examine the mechanism by which 'escape' from TSH desensitization of the cyclic AMP response to TSH (Endocrinology 109, 1156, 1981) occurs in confluent cultured thyroid cells. At confluence, cell replication and DNA synthesis are suppressed. An attempt was therefore made to reproduce escape in sparse thyroid cell monolayers using inhibitors of DNA synthesis. The concurrent presence of TSH and mitomycin C (5 micrograms/ml) did not influence the induction of desensitization to TSH after 6 h of stimulation, but cAMP levels then rebounded by 24 h; that is, mitomycin C reproduced escape in sparse cells. Hydroxyurea (10 mM) did not reproduce escape in sparse cells. Adenylate cyclase activity was unaltered in plasma membranes prepared from sparse thyroid cells treated with mitomycin C for 24 h. These data suggest that 'escape' from TSH desensitization is related to events occurring during the cell cycle associated with DNA synthesis, and is caused by an alteration in adenylate cyclase substrate or co-factor availability rather than in enzyme activity itself.

1-Methyl-3-isobutylxanthine↗
PubMed2005

Boundaries between chromosomal domains of X inactivation and escape bind CTCF and lack CpG methylation during early development.

Escape from X inactivation results in expression of genes embedded within inactive chromatin, suggesting the existence of boundary elements between domains. We report that the 5' end of Jarid1c, a mouse escape gene adjacent to an inactivated gene, binds CTCF, displays high levels of histone H3 acetylation, and functions as a CTCF-dependent chromatin insulator. CpG island methylation at Jarid1c was very low during development and virtually absent at the CTCF sites, signifying that CTCF may influence DNA methylation and chromatin modifications. CTCF binding sites were also present at the 5' end of two other escape genes, mouse Eif2s3x and human EIF2S3, each adjacent to an inactivated gene, but not at genes embedded within large escape domains. Thus, CTCF was specifically bound to transition regions, suggesting a role in maintaining both X inactivation and escape domains. Furthermore, the evolution of X chromosome domains appears to be associated with repositioning of chromatin boundary elements.

Acetylation↗
PubMed2004

Effects of relief space and escape holes on pressure characteristics of maxillary edentulous impressions.

STATEMENT OF PROBLEM: The selective pressure technique has been recommended for making impressions of maxillary edentulous residual ridges. Although various methods for making impressions have been reported, a definitive procedure has not been clearly elucidated. PURPOSE: This in vitro study evaluated changes in impression pressure produced by different types of relief space and escape holes in the impression tray for making an impression of a simulated maxillary edentulous arch. MATERIAL AND METHODS: Silicone impression material (Exadenture) and a maxillary edentulous acrylic cast were used. A miniature pressure sensor was embedded at the mid-palatal suture (point-P) and at the left first molar area on the edentulous ridge (point-R). Three types of tray relief were used: no spacer (NS), a 0.36-mm-thick sheet of wax (SS), or a 1.40-mm-thick base plate wax (BS). Four types of escape holes were made: no hole (NH), or escape holes of 0.5, 1.0, or 2.0 mm in diameter (05H, 10H, and 20H, respectively) in the area opposing point-P. Twelve trays were formed using these relief space and escape hole combinations. The cast and tray were attached to a rheometer for applying a continuous isotonic force of 5.0 kgf and compressive speed of 120 mm/min. Impressions were made and measurement of pressure (kPa) began immediately prior to compression and continued until the materials had polymerized for 2 minutes, with a sampling time of 5 Hz. Measurements were performed 5 times for each tray. The data were analyzed using 3-way analysis of variance and the Bonferroni test (alpha=.05). RESULTS: At initial pressure, the data obtained at point-P showed significantly higher values for NSNH, NS05H, SSNH, and SS05H (range: 22.29 +/- 1.58 kPa to 29.96 +/- 1.41 kPa) than those at point-R (range: 18.61 +/- 1.12 kPa to 22.71 +/- 2.11 kPa). At end pressure, the data obtained from NSNH at point P showed a significantly higher value (25.36 +/- 1.69 kPa) than that of point-R (15.36 +/- 0.99 kPa) (P<.001), whereas data from NS10H and NS20H at point-P showed a significantly lower value (6.32 +/- 0.84 kPa and 4.50 +/- 0.42 kPa) than at point-R (15.50 +/- 0.49 kPa and 14.98 +/- 0.88 kPa) (P<.001). The data obtained from SS05H, SS10H, and NS20H at point-P showed significantly lower values (range: 3.72 +/- 0.44 kPa to 9.10 +/- 0.26 kPa) than those at point-R (range: 13.40 +/- 1.31 kPa to 14.40 +/- 0.98 kPa). Moreover, the data obtained from BSNH, BS05H, BS10H, and BS20H at point-P showed significantly lower values (range: 3.24 +/- 1.96 kPa to 10.20 +/- 1.84 kPa) than those of point-R (range: 11.69 +/- 1.01 kPa to 14.04 +/- 2.08 kPa). CONCLUSION: For making impressions of an edentulous maxilla, the data suggest that a tray with an escape hole 1.0 mm or larger or a spacer thickness of base plate wax (1.40 mm) be used.

Acrylic Resins↗
PubMed2006

Waiting times for the appearance of cytotoxic T-lymphocyte escape mutants in chronic HIV-1 infection.

The failure of HIV-1 to escape at some cytotoxic T-lymphocyte (CTL) epitopes has generally been explained in terms of viral fitness costs or ineffective or attenuated CTL responses. Relatively little attention has been paid to the evolutionary time required for escape mutants to be detected. This time is significantly affected by selection, mutation rates, the presence of other advantageous mutations, and the effective population size of HIV-1 in vivo (typically estimated to be approximately 10(3) in chronically infected patients, though one study has estimated it to be approximately 10(5)). Here, we use a forward simulator with experimentally estimated HIV-1 parameters to show that these delays can be substantial. For an effective population size of 10(3), even highly advantageous mutants (s = 0.5) may not be detected for a couple of years in chronically infected patients, while moderately advantageous escape mutants (s = 0.1) may not be detected for up to 10 years. Even with an effective population size of 10(5), a moderately advantageous escape mutant (s = 0.1) may not be detected in the population within 2 years if it has to compete with other selectively advantageous mutants. Stochastic evolutionary forces, therefore, in addition to viral fitness costs and ineffective or attenuated CTL responses, must be taken into account when assessing the selection of CTL escape mutations.

HIV Infections↗
PubMed2004

Influenza H5 virus escape mutants: immune protection and antibody production in mice.

Avian H5N1 influenza A viruses are considered to be of high pandemic potential as they are able to cross the avian-human species barrier and cause disease in humans. In the present study we assessed the impact of amino acid substitutions in the hemagglutinin (HA) of antigenic escape mutants of influenza A/Mallard/Pennsylvania/10218/84 (H5N2) (Mld/PA/84-MA) virus on the level of neutralizing antibodies and the ability to protect mice against challenge with the wild type H5 influenza virus. beta-Propiolactone-inactivated vaccines prepared from eight different H5 escape mutants could be separated into two groups based on levels of protection. One group of escape mutants [m46(7), m46(7)-24B9, m46(7)-55, and m46(7)-55-24B9] was characterized by providing high levels of protection (90.0-95.4% survival) to mice against subsequent challenge with 5 LD(50) of wild type Mld/PA/84-MA virus. The other group of escape mutants [m176/26, m55(2), m55(2)-24B9, and m24B9-176/26] provided moderate level of protection (57.1-66.6% survival) in mice. Analysis of the amino acid substitutions in the HA revealed that two amino acid changes in antigenic site B of the HA molecule (D(126)-->N and K(152)-->N) were associated for decreases in the levels of antibody and the immune protection afforded by vaccination with these H5 virus escape mutants. The phenotypic effects of mutations in HA gene of H5 virus may be of importance to appraise the extent and direction of H5 influenza viruses antigenic evolution.

Amino Acid Substitution↗
PubMed1983

Effect of local lidocaine anesthesia on ventricular escape intervals during permanent pacemaker implantation in patients with complete heart block.

Transient asystole is often noted during the course of permanent pacemaker implantation in patients with complete heart block. Since subcutaneous lidocaine is frequently used as the local anesthetic agent for permanent pacemaker implantation, the effect of this drug on ventricular escape intervals was studied. Ventricular escape intervals after transient cessation of pacing were studied in 9 patients with complete heart block before and 10, 30, and 45 minutes after subcutaneous lidocaine administration for permanent pacemaker implantation. The total lidocaine dose ranged from 170 to 400 mg (1.9 to 9.5 mg/kg of body weight). Therapeutic blood levels were achieved in 7 patients. The mean ventricular escape interval before lidocaine was 1.83 +/- 0.32 seconds, which increased to 2.58 +/- 1.35, 2.96 +/- 1.06, and 2.68 +/- 1.27 seconds at 10, 30, and 45 minutes after lidocaine (p less than 0.02). The mean maximal escape interval before lidocaine was 2.06 +/- 0.30 seconds, which increased to 3.80 +/- 1.44 seconds (p less than 0.01), a mean increase of 84%. The percent increase in maximal escape interval was related directly to the peak lidocaine level achieved. After lidocaine administration, 5 patients had asystole greater than 4 seconds and 1 required resumption of pacing. Thus, subcutaneous lidocaine contributes to the occurrence of asystole seen during permanent pacemaker implantation. It is advisable to limit the amount of lidocaine administered during permanent pacemaker implantation to the minimum necessary to achieve adequate local anesthesia. Strong consideration should be given to the use of a temporary pacemaker in patients with complete heart block during permanent pacemaker implantation even in the absence of previous asystole.

Aged↗
PubMed1996

Manifest and concealed AV nodal reentry in Wenckebach type of AV conduction with AV junctional escape rhythm.

An electrocardiogram was obtained that was characterized by sinus rhythm with progressive prolongation of the PR interval not followed by a blocked sinus impulse. After a critically long PR interval, the QRS complex was followed by a premature P' wave, representing an echo beat, a manifest reentry in the atrioventricular (AV) node. The pause, occasioned by the premature P' wave, was at times interrupted by an AV junctional escape beat, occurring with an escape interval of 1.21-1.24 seconds. On other occasions, however, the escape beat did not manifest on schedule, even though the pause was markedly longer than the escape cycle. This suggested that the manifest reentry was followed by a further concealed reentry, resulting in inapparent discharge of the AV junctional escape pacemaker, whose firing was postponed, thereby allowing the sinus impulse to capture the ventricles.

Aged↗
PubMed2001

Escape deficits induced by inescapable shock and metabolic stress are reversed by adenosine receptor antagonists.

We examined the relationship between metabolic stress, brain adenosine regulation, and the learned helplessness effect in four experiments in rats. Glucoprivation and metabolic inhibition were induced by treating previously restrained (nonshocked) rats with 2-deoxy-D-glucose (2DG) shortly before escape testing. Experiment 1 demonstrated that 2-deoxy-D-glucose impairs escape performance in a dose-dependent manner. Experiment 2 showed that 2-deoxy-D-glucose and shock induced escape deficits are completely reversed by peripheral administration of the adenosine receptor antagonist caffeine. This result indicates that both inescapable shock and 2-deoxy-D-glucose result in compensatory adenosine regulation which, in turn, mediates the behavioral impairment. Experiment 3 determined that 8-[p-sulfophenyl]-theophylline, a peripheral adenosine receptor antagonist, fails to reverse the escape deficit resulting from metabolic stress, whereas centrally acting theophylline does. Experiment 4 showed that the behavioral impairments from both 2-deoxy-D-glucose and inescapable shock are reversed by intracranial ventricular (icv) caffeine treatment. The results of Experiments 3 and 4 indicate that the enhanced adenosine regulation and the ensuing performance deficit resulting from 2-deoxy-D-glucose treatment occurred in the central nervous system. These data are discussed in terms of the metabolic demands of neuronal over-activation during escape testing in inescapably shocked rats and the loss of normal behavioral function due to compensatory adenosine regulation in the brain.

Adenosine Triphosphate↗
PubMed2003

Partial reinforcement across trials impairs escape performance but spares place learning in the water maze.

We studied the effects of partial reinforcement on escape performance and place learning in the water maze. Rats given 50% reinforcement across trials (i.e. the escape platform was present only on odd trials) were compared to controls given 100% reinforcement (platform present on all trials). Control groups either received 8 or 4 trials per day, which was equal to either the total number of trials (100%-8) or reinforced escapes (100%-4) of the 50% group. Analysis of escape performance (latency) revealed that the 50% group was impaired relative to the 100%-8 group, but not the 100%-4 group, during the first 5 days of acquisition. The 50% group was impaired relative to both control groups on days 6-10 of overtraining. However, analyses of within-trial behavior (target annulus preference and thigmotaxis) on nonreinforced trials suggest that the 50% group did learn the location of the hidden platform (place information), in addition to a wall-based thigmotactic response. By dividing the 60s nonreinforced trials into three 20-s time bins, we were able to detect a significant preference for the target annulus early in the trial (bin 1 of trial 40 and bins 1-2 of trial 80). Further, there was a significant increase in time spent in the periphery of the pool, near the wall, in the last time bin of trial 40. Because the platform was in the middle zone, this behavior competed with a place response. We conclude that across-trial partial reinforcement procedures may promote response competition and mask evidence of place learning in addition to weakening escape performance late in training.

Animals↗
PubMed1997

Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS.

The precise role played by HIV-specific cytotoxic T lymphocytes (CTL) in HIV infection remains controversial. Despite strong CTL responses being generated during the asymptomatic phase, the virus persists and AIDS ultimately develops. It has been argued that the virus is so variable, and the virus turnover so great that escape from CTL recognition would occur continually, but so far there is limited evidence for CTL escape. The opposing argument is that evidence for CTL escape is present but hard to find because multiple anti-HIV immune responses are acting simultaneously during the asymptomatic phase of infection. We describe six donors who make a strong CTL response to an immunodominant HLA-B27-restricted epitope. In the two donors who progressed to AIDS, CTL escape to fixation by the same mutation was observed, but only after 9-12 years of epitope stability. CTL escape may play an important role in the pathogenesis of HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed2004

HIV evolution: CTL escape mutation and reversion after transmission.

Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.

Adult↗
PubMed2000

Role for endogenous endothelin in the regulation of plasma volume and albumin escape during endotoxin shock in conscious rats.

To explore the role of endogenous endothelin (ET) in the regulation of vascular functions, we studied the effects endothelin receptor blockade on blood pressure, plasma volume and albumin escape during endotoxin shock in conscious, chronically catheterized rats. Red blood cell volume and plasma volume were determined by using chromium-51-tagged erythrocytes and iodine-125-labelled albumin, respectively. Intravenous injection of lipopolysaccharide (LPS, 10 mg kg(-1)) resulted in hypotension, haemoconcentration, and increased total-body albumin escape, which is reflected by a 30% reduction in plasma volume. Plasma ET-1 concentrations increased 2.1 fold and 5.4 fold at 30 and 120 min post-LPS, respectively. LPS-induced losses in plasma volume and albumin escape were significantly attenuated by pretreatment of animals with the dual ET(A)/ET(B) receptor antagonist bosentan (17.4 micromol kg(-1), i.v. 15 min prior to LPS) or the ET(A) receptor antagonist FR 139317 (3.8 micromol kg(-1), i.v.) during both the immediate and delayed phases of endotoxin shock. The inhibitory actions of bosentan and FR 139317 were similar. Both antagonists augmented the hypotensive action of LPS. Administration of bosentan or FR 139317 70 min after injection of LPS also attenuated further losses in plasma volume and increases in total body and organ albumin escape rates with the exception of the lung and kidney. These results indicate a role for endogenous endothelin in mediating losses in plasma volume and albumin escape elicited by LPS predominantly through activation of ET(A) receptors, and suggest that by attenuating these events, ET(A) or dual ET(A)/ET(B) receptor blockers may be useful agents in the therapy of septic shock.

Animals↗
PubMed2001

Functional characterization of Fas ligand on tumor cells escaping active specific immunotherapy.

Mice transgenic for the rat HER-2/neu oncogene (rNeu-TG) developed spontaneous breast tumors that can escape a rNeu-specific immune response induced by active specific immunotherapy (ASI). The ability of these escape tumors to grow appeared to be due to upregulation of the Fas ligand (Fas-L) molecule. In an effort to develop tools for the better elucidation of the role of Fas-L and other regulatory mechanisms in tumor escape, we established cell lines derived from escape tumors. These tumor cell lines retained MHC class I, rNeu and Fas-L expression in vitro and formed tumors in vaccinated mice. Tumor growth was accompanied by permanent Fas-L expression in vivo, both in vaccinated and control vaccinated mice, indicating that these cells have acquired constitutive Fas-L expression. Moreover, these cells induced target cell apoptosis in vitro. Thus, these cells represent a unique tool to elucidate the importance of Fas-L expressed by tumors that escaped efficient systemic immune responses.

3T3 Cells↗