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PubMed2001

Recombinant measles viruses expressing altered hemagglutinin (H) genes: functional separation of mutations determining H antibody escape from neurovirulence.

Measles virus (MV) strain CAM/RB, which was adapted to growth in the brain of newborn rodents, is highly neurovirulent. It has been reported earlier that experimentally selected virus variants escaping from the monoclonal antibodies (MAbs) Nc32 and L77 to hemagglutinin (H) preserved their neurovirulence, whereas mutants escaping MAbs K71 and K29 were found to be strongly attenuated (U. G. Liebert et al., J. Virol. 68:1486-1493, 1994). To investigate the molecular basis of these findings, we have generated a panel of recombinant MVs expressing the H protein from CAM/RB and introduced the amino acid substitutions thought to be responsible for antibody escape and/or neurovirulence. Using these recombinant viruses, we identified the amino acid changes conferring escape from the MAbs L77 (377R-->Q and 378M-->K), Nc32 (388G-->S), K71 (492E-->K and 550S-->P), and K29 (535E-->G). When the corresponding recombinant viruses were tested in brains of newborn rodents, we found that the mutations mediating antibody escape did not confer differential neurovirulence. In contrast, however, replacement of two different amino acids, at positions 195G-->R and 200S-->N, which had been described for the escape mutant set, caused the change in neurovirulence. Thus, antibody escape and neurovirulence appear not to be associated with the same structural alterations of the MV H protein.

Animals↗

PubMed2002

Translocation after synthesis of a four-nucleotide RNA commits RNA polymerase II to promoter escape.

Transcription is a complex process, the regulation of which is crucial for cellular and organismic growth and development. Deciphering the molecular mechanisms that define transcription is essential to understanding the regulation of RNA synthesis. Here we describe the molecular mechanism of escape commitment, a critical step in early RNA polymerase II transcription. During escape commitment ternary transcribing complexes become stable and committed to proceeding forward through promoter escape and the remainder of the transcription reaction. We found that the point in the transcription reaction at which escape commitment occurs depends on the length of the transcript RNA (4 nucleotides [nt]) as opposed to the position of the active site of the polymerase with respect to promoter DNA elements. We found that single-stranded nucleic acids can inhibit escape commitment, and we identified oligonucleotides that are potent inhibitors of this specific step. These inhibitors bind RNA polymerase II with low nanomolar affinity and sequence specificity, and they block both promoter-dependent and promoter-independent transcription, the latter occurring in the absence of general transcription factors. We demonstrate that escape commitment involves translocation of the RNA polymerase II active site between synthesis of the third and fourth phosphodiester bonds. We propose that a conformational change in ternary transcription complexes occurs during translocation after synthesis of a 4-nt RNA to render complexes escape committed.

Base Sequence↗

PubMed1991

Norepinephrine release during autoregulatory escape: effects of alpha 2-receptor blockade.

The partial recovery that intestinal blood flow undergoes during continued sympathetic nerve stimulation is termed autoregulatory escape. This study tested two hypotheses that might explain escape: 1) diminishing norepinephrine (NE) release during sustained stimulation and 2) an alpha 2-receptor-mediated competition between local and neural control mechanisms. The rates of NE release before and during stimulation of the perivascular sympathetic nerves were determined by measuring blood flow in isolated loops of canine small intestine and assaying the concentrations of NE in arterial and venous blood. The presence of functional alpha 2-receptors was demonstrated by clonidine injections, and the effects of alpha 2-receptor blockade were studied during yohimbine infusions. The time course of NE release was inconsistent with a cause-effect relationship; NE release was greatest during the phase when resistance had already escaped. Deliberately altering NE release by changing the stimulus duration did not affect escape. The study demonstrated 1) that diminished NE release during continued sympathetic stimulation does not occur and cannot account for escape, 2) that resistance vessels in the canine intestinal circulation possess functional alpha 2-receptors which are responsible for part of the vasoconstriction caused by sympathetic stimulation, 3) that blockade of presynaptic alpha 2-receptors significantly enhanced NE release during the initial 30-s period but not during the escape phase, and 4) that alpha 2-receptor blockade enhances autoregulatory escape. Altogether these findings indicate that the postsynaptic alpha 2-receptors on intestinal resistance vessels deserve further investigation as the possible site at which local and neural mechanisms compete to influence vascular resistance.

Adrenergic alpha-Agonists↗

PubMed2002

Synergistic effects of nitric oxide and prostaglandins on renal escape from vasopressin-induced antidiuresis.

Recent results from our laboratories indicate that renal escape from AVP-induced antidiuresis is accompanied by marked downregulation of kidney aquaporin-2 (AQP2) and AVP V2 receptors. The present studies evaluated the effect of nitric oxide (NO) and PG synthesis blockade on escape from antidiuresis. dDAVP-infused rats were water loaded (WL) for 5 days. l-NAME, an NO synthesis inhibitor, or diclofenac, a cyclooxygenase inhibitor, was infused subcutaneously beginning 1 day before WL. As early as 2 days after WL, urine volume increased and urine osmolality decreased, indicating the onset of escape. Endogenous NO synthesis, measured as urinary NO2 + NO3 excretion, was significantly increased in the WL group compared with the non-WL controls during all 5 days of WL. l-NAME (20 mg. kg(-1). day(-1)) markedly decreased urine volume on days 4 and 5 of WL, indicating inhibition of the escape phenomenon. Kidney AQP2 protein was significantly increased by this dose of l-NAME as well. A lower dose of l-NAME (10 mg. kg(-1). day(-1)) or diclofenac (2.5 mg. kg(-1). day(-1)) did not significantly affect the escape phenomenon by itself, but the combination of l-NAME and diclofenac showed a marked inhibitory effect on the escape phenomenon, which was also accompanied by a significant increase in kidney AQP2 expression. These results therefore suggest that renal NO and PG both play important roles in escape from AVP-induced antidiuresis by acting synergistically to downregulate kidney AQP2 expression.

Animals↗

PubMed2003

Regulation of NHE3, NKCC2, and NCC abundance in kidney during aldosterone escape phenomenon: role of NO.

Escape from aldosterone-induced renal NaCl retention is an important homeostatic mechanism in pathophysiological states in which plasma aldosterone levels are inappropriately elevated, e.g., in primary aldosteronism. Our previous studies demonstrated that the escape process occurs largely as a result of a marked suppression of the abundance of the thiazide-sensitive Na-Cl cotransporter (NCC) of the distal convoluted tubule but have also demonstrated a paradoxical increase in the protein abundance of the apical Na/H exchanger of the proximal tubule (NHE3). In the present study, we confirmed the increase in NHE3 and also showed that a similar increase in NHE3 protein abundance occurs in escape from ANG II-mediated NaCl retention. To investigate the potential role of nitric oxide (NO) in the observed upregulation of NHE3, we repeated the aldosterone escape experiment with a superimposed infusion of a NO synthase inhibitor, NG-nitro-l-arginine methyl ester (l-NAME). l-NAME infusion abolished the increase in NHE3 protein abundance. Furthermore, in a different experiment, NO synthase inhibition uncovered an associated decrease in the abundance of the Na-K-2Cl cotransporter (NKCC2) of the thick ascending limb, not seen with simple aldosterone escape. However, NO synthase inhibition did not block the decrease in NCC abundance normally seen with aldosterone escape. Furthermore, l-NAME infusion in aldosterone-treated rats markedly decreased both NHE3 and NKCC2 protein abundance, without changes in the corresponding mRNA levels. We conclude that NHE3 and NKCC2 protein abundances in kidney are positively regulated by NO and that the increase in NHE3 abundance seen in the aldosterone escape phenomenon is NO dependent.

Aldosterone↗

PubMed1999

The relationship between building design and escapes from secure units.

The research presented is a survey of all of the identified forensic psychiatry Medium Secure Units (MSUs) within Great Britain. The study examined the numbers and nature of all escapes from these units over a 42-month period. The research focused on the relationship between the building design of the units and the nature of patient escapes. The results showed that overall numbers of patient escapes from the units was low. The average number of escapes was 3.14 per unit over the three-and-a-half-year time-span of the survey. However, the recent increases in bed numbers in medium secure units had been paralleled by a larger percentage rise in escapes. Most escapes from the units occurred from three main areas. These were the perimeter fence, the roof, and internal and external windows. The implications of the methods of escape and their relationship to the building design of MSUs were discussed and recommendations made for future building designs.

England↗

PubMedDate not supplied

Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy.

Continuous angiotensin-converting enzyme (ACE) inhibitor therapy does not necessarily produce significant decreases in plasma aldosterone levels (aldosterone escape). We examined the role of aldosterone escape in 75 essential hypertensive patients treated with an ACE inhibitor (enalapril maleate [34 patients], imidapril hydrochloride [24 patients] or trandolapril [17 patients]) for 40 weeks. With treatment, blood pressure decreased and plasma renin activity increased, while plasma aldosterone concentrations did not change. Aldosterone escape was observed in 38 of the 75 patients and in 17 of 37 patients with left ventricular hypertrophy before treatment. Left ventricular mass index did not change in patients with aldosterone escape but decreased significantly in patients without aldosterone escape. The present study demonstrated a high incidence of aldosterone escape in patients with essential hypertension despite the use of ACE inhibitors. The results also suggest that aldosterone escape may reverse the beneficial effects of an ACE inhibitor on left ventricular hypertrophy.

Aged↗

PubMed1987

Atrial natriuretic peptide during mineralocorticoid escape in the human.

The relationship between plasma atrial natriuretic peptide (ANP) and mineralocorticoid escape was examined in six normal men (age, 20-32 yr) treated with 0.4 mg/day fludrocortisone acetate for 9-14 days. Urinary sodium excretion decreased from 162 +/- 15 (SEM) meq/24 h before to 97 +/- 10 meq/24 h during fludrocortisone acetate administration (P less than 0.05). Despite continued fludrocortisone acetate administration, sodium excretion subsequently returned to baseline (escape). Plasma ANP increased from 33 +/- 6 pg/ml (control) to 55 +/- 14 pg/ml on the first day of escape (P less than 0.05). Escape was associated with a decrease in PRA from 0.90 +/- 0.22 (control) to 0.26 +/- 0.08 ng/ml X h (escape, P less than 0.05). The escape phenomenon was not associated with a significant change in mean arterial pressure or glomerular filtration rate. This study demonstrates that mineralocorticoid escape is temporally related to a significant increase in circulating ANP.

Adult↗

PubMed1999

Kidney aquaporin-2 expression during escape from antidiuresis is not related to plasma or tissue osmolality.

Recent results indicate that renal escape from vasopressin-induced antidiuresis is accompanied by a marked downregulation of whole kidney aquaporin-2 (AQP-2) protein and mRNA expression. However, in those studies, the escaped animals were also markedly hypo-osmolar compared to controls as a result of water loading during antidiuresis. The present studies evaluated whether systemic or local osmolality contributes to the downregulation of AQP-2 expression in this model. In the first study, two groups of 1-deamino-[8-D-arginine]-vasopressin (dDAVP)-infused rats were water-loaded; after establishment of escape, one group was then water-restricted for 4 d to reverse the escape, whereas the other group continued daily water loading. Whole kidney AQP-2 protein was measured by Western blotting, and inner medulla AQP-2 mRNA was determined by Northern blotting. Results were compared to dDAVP-infused rats fed solid chow. After 4 d of water restriction, urine volume decreased to the same level as in the rats on solid chow; however, plasma sodium concentrations and plasma osmolality remained low. Despite maintenance of significant hypo-osmolality, rats in which escape was subsequently reversed by water restriction reestablished high dDAVP-stimulated kidney levels of AQP-2 after 4 d of water restriction. In the second study, AQP-2 expression was evaluated in different regions of kidneys from water-loaded rats undergoing escape from antidiuresis. Despite markedly different interstitial osmolalities, significant downregulation of AQP-2 expression compared to dDAVP-infused control rats was seen in the inner medulla, outer medulla, and cortex. Thus, neither systemic nor interstitial osmolality appears to appreciably be correlated with downregulation of kidney AQP-2 expression during escape from antidiuresis. These results therefore suggest that additional vasopressin- and osmolality-independent factors, likely related to the effects of extracellular fluid volume expansion, also regulate kidney AQP-2 expression in rats.

Analysis of Variance↗

PubMed1969

The effects of escape conditioning and shock intensity on responding during inescapable shock.

Eight albino rats, conditioned to press a lever to escape shock, continued to lever press during short inescapable shocks presented subsequently. The rate of this behavior was found to be higher for higher shock intensities regardless of the order in which shock values were presented. Relative to the immediately preceding escape rate, responding during inescapable shock was higher following conditioning at higher fixed-ratio escape requirements. Four subjects not conditioned to escape shock pressed the lever very infrequently during inescapable shock and showed little change with changes in shock intensity. The escape conditioning effects suggest that responding during inescapable shock is superstitious escape behavior. The effects of shock intensity on this behavior appear to be similar to reported effects of shock intensity on escape behavior.

Journal Article↗

PubMed1974

Free-operant escape-avoidance of noise by rats.

A series of experiments was conducted to establish free-operant escape-avoidance responding in rats using noise as the stimulus. Naive rats did not acquire a bar-press response on an escape-avoidance of noise schedule. Similarly, free-operant responding established using escape-avoidance of shock was not maintained when noise was substituted for shock. Noise stimuli of 110 dB did maintain responding, but at a lower level than during training, when the noise stimuli had first been paired with shock. Noise stimuli of 97 dB and 87 dB were not effective under those same conditions. Additional rats were trained on a free-operant escape-avoidance schedule of shock and then exposed to a delayed conditioning procedure in which noise was the conditioned stimulus and shock was the unconditioned stimulus. When these subjects were then tested with noise alone, two of the three subjects conditioned and tested with 105-dB noise displayed escape-avoidance of noise, but none of the rats conditioned and tested at 97 dB displayed escape-avoidance of noise. The results suggest that free-operant escape-avoidance of noise can be demonstrated; however, only higher intensity noise stimuli that have been paired with shock are effective.

Journal Article↗

PubMed2005

HIV-1 viral escape in infancy followed by emergence of a variant-specific CTL response.

Mutational escape from the CTL response represents a major driving force for viral diversification in HIV-1-infected adults, but escape during infancy has not been described previously. We studied the immune response of perinatally infected children to an epitope (B57-TW10) that is targeted early during acute HIV-1 infection in adults expressing HLA-B57 and rapidly mutates under this selection pressure. Viral sequencing revealed the universal presence of escape mutations within TW10 among B57- and B5801-positive children. Mutations in TW10 and other B57-restricted epitopes arose early following perinatal infection of B57-positive children born to B57-negative mothers. Surprisingly, the majority of B57/5801-positive children exhibited a robust response to the TW10 escape variant while recognizing the wild-type epitope weakly or not at all. These data demonstrate that children, even during the first years of life, are able to mount functional immune responses of sufficient potency to drive immune escape. Moreover, our data suggest that the consequences of immune escape may differ during infancy because most children mount a strong variant-specific immune response following escape, which is rarely seen in adults. Taken together, these findings indicate that the developing immune system of children may exhibit greater plasticity in responding to a continually evolving chronic viral infection.

Acquired Immunodeficiency Syndrome↗

PubMed1998

[Clinical relapse of rheumatoid arthritis (escape phenomenon) during low-dose methotrexate therapy].

OBJECTIVE: To clarify the incidence and background of clinical relapse (escape phenomenon) during low-dose methotrexate therapy for rheumatoid arthritis. METHODS: Seventy one patients with rheumatoid arthritis (RA) were analyzed. They were started on therapy with methotrexate (MTX) between April 1, 1991 and May 30, 1995. Among them, 60 patients showed clinical improvement within 6 months after the start of the therapy and were subjected to the analysis for clinical relapse (escape phenomenon). RESULTS: Twelve patients showed an initial improvement followed by a relapse with increased serum CRP and number of painful joints despite the MTX therapy was continued. Two types of the relapses were seen; (1) early, escape (relapse after an initial brief improvement) in 7 patients, and (2) late escape (relapse after a long-term improvement with MTX therapy) in 5 patients. The early escape was seen at 9.0 +/- 0.7 months after the start of therapy while the late escape was seen at 23.3 +/- 4.8 months. Patients with both types of escape phenomenon had the longer duration of the disease and more advanced stage. There was no relationship between clinical relapse and age, baseline RA activity, MTX dose, or concurrent use of corticosteroids and other disease modifying anti-rheumatic drugs. The efficacy of MTX for RA was restored by increasing dose of MTX in 11 patients. CONCLUSION: These results suggest that clinical relapse is not rare in RA patients during low-dose methotrexate therapy, but could be improved by increasing dose.

Antirheumatic Agents↗

PubMed2001

Descending influences on escape behavior and motor pattern in the cockroach.

The escape behavior of the cockroach is a ballistic behavior with well characterized kinematics. The circuitry known to control the behavior lies in the thoracic ganglia, abdominal ganglia, and abdominal nerve cord. Some evidence suggests inputs may occur from the brain or suboesophageal ganglion. We tested this notion by decapitating cockroaches, removing all descending inputs, and evoking escape responses. The decapitated cockroaches exhibited directionally appropriate escape turns. However, there was a front-to-back gradient of change: the front legs moved little if at all, the middle legs moved in the proper direction but with reduced excursion, and the rear legs moved normally. The same pattern was seen when only inputs from the brain were removed, the suboesophageal ganglion remaining intact and connected to the thoracic ganglia. Electromyogram (EMG) analysis showed that the loss of or reduction in excursion was accompanied by a loss of or reduction in fast motor neuron activity. The loss of fast motor neuron activity was also observed in a reduced preparation in which descending neural signals were reversibly blocked via an isotonic sucrose solution superfusing the neck connectives, indicating that the changes seen were not due to trauma. Our data demonstrate that while the thoracic circuitry is sufficient to produce directional escape, lesion or blockage of the connective affects the excitability of components of the escape circuitry. Because of the rapidity of the escape response, such effects are likely due to the elimination of tonic descending inputs.

Animals↗

PubMed1989

Strain-specific effects of antidepressants on escape deficits induced by inescapable shock.

The effects of several antidepressants (desmethylimipramine, amitriptyline and bupropion) on escape deficits induced by inescapable shock were assessed in four strains of mice. The extent of the escape interference engendered by inescapable shock varied across strains of mice. These deficits of escape performance were differentially affected by the drug treatments across strains. Repeated administration of desmethylimipramine eliminated the escape interference in A/J, but did not affect the performance in Balb/cByJ, C57BL/6J or CD-1 mice. Bupropion, in contrast, had a modest effect only in CD-1 mice. Unlike these compounds, the 5-HT reuptake blocker, amitriptyline, was found to influence escape performance irrespective of whether the drug was acutely or chronically applied. It is suggested that (a) the relative contributions of various mechanisms subserving the escape interference may vary across strains of mice, hence accounting for the strain-specific effects of the drug treatments, and (b) various antidepressants influence performance by affecting different components of the behavioral output, some of which may be apparent after acute treatment while others are expressed only after repeated treatment with the compound.

Amitriptyline↗

PubMed1999

Effects of serotonergic and opioidergic drugs on escape behaviors and social status of male crickets.

We examined the effects of selective serotonin depletion and opioid ligands on social rank and related escape behavior of the cricket Gryllus bimaculatus. Establishment of social rank in a pair of males affected their escape reactions. Losers showed a lower and dominants a higher percentage of jumps in response to tactile cercal stimulation than before a fight. The serotonin-depleting drug alpha-methyltryptophan (AMTP) caused an activation of the escape reactivity in socially naive crickets. AMTP-treated animals also showed a lower ability to become dominants. With an initial 51.6+/- 3.6% of wins in the AMTP group, the percentage decreased to 26+/-1.6% on day 5 after injection. The opiate receptor antagonist naloxone affected fight and escape similarly as AMTP. In contrast to naloxone, the opioid agonist [d-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin decreased escape responsiveness to cercal stimulation in naive and subordinate crickets. We suggest that serotonergic and opioid systems are involved in the dominance induced depression of escape behavior.

Animals↗

PubMed1982

Effect of medial hypothalamic stimulation inducing both escape and approach on unit activity in rat mesencephalon.

The activity of central gray (CG) neurons was previously shown to be affected by medial hypothalamic (MH) stimulation, and the discharge rate alterations were found to be often closely correlated with the vigor of the stimulation-induced escape responses. Since MH stimulation induces not only escape responses but also approach responses, this allowed a further investigation of the degree of specificity of the correlation between stimulation-induced neuronal activity and escape responses. Out of 129 CG units studied (in 39 rats), 26 clearly responded to the MH stimulation. When the stimulation parameters were varied, the mean discharge rate alterations of 9 units located in the dorsal part of the mesencephalic CG proved to be closely correlated exclusively with the alterations that affected the stimulation-induced escape responses. Furthermore, the variation of the most frequent interspike interval (modal ISI) proved to be closely correlated with the variation of the escape response in 3 instances in which the mean discharge rate showed no such correlation. In a few instances (2 units located much more ventrally, the spike rate alterations were closely correlated only with the alterations that affected the approach responses. It is suggested that neuronal activity in the dorsal part of the CG is rather specifically implicated in the generation of MH stimulation-induced aversive effects and escape responses.

Animals↗

PubMed1993

Strain-dependent escape deficit in two rat models of learned helplessness.

The shuttle box escape deficit produced by prior inescapable shock (IS) or by escapable shock (ES) was investigated in Koltushi high- (KHA) and low-avoidance (KLA) rat strains, genetically selected on the basis of divergent acquisition of a conditioned avoidance response in a two-way shuttle box. IS enhanced escape failures only in KHA rats. In contrast, ES produce escape deficit only in KLA rats. These data suggest that the learned helplessness interpretation of escape deficit might be relevant only when IS is administered to KHA rats. In the case of KLA rats exposed to ES, escape deficit represents a coping behavior.

Animals↗