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PubMed1994

Kinetic and mutational analysis of human immunodeficiency virus type 1 reverse transcriptase inhibition by inophyllums, a novel class of non-nucleoside inhibitors.

Inophyllums are novel non-nucleoside inhibitors of human immunodeficiency virus (HIV) type 1 reverse transcriptase identified through an enzyme screening program and isolated from the plant Calophyllum inophyllum. The kinetics of reverse transcriptase inhibition by inophyllum B were characterized using recombinant purified enzyme, a heteropolymeric RNA template, and a scintillation proximity assay. Preincubation of inhibitor with the enzyme-template-primer complex for 11 min was required for maximal inhibition of reverse transcriptase to occur, suggesting that inophyllum B had a slow on-rate and that template-primer must bind to reverse transcriptase prior to inhibitor binding. Inhibition of reverse transcriptase by inophyllums was shown to be reversible. When thymidine triphosphate was the variable substrate, inophyllum B inhibited reverse transcriptase noncompetitively with a Ki of 42 nM. Enzyme inhibition with respect to template-primer was uncompetitive with a Ki of 26 nM. Reverse transcriptase enzymes containing point mutations in which tyrosine 181 was changed to either cysteine or isoleucine exhibited marginal resistance to inophyllums but were resistant to (+)-(5S)-4,5,6,7-tetrahydro-9-chloro-5-methyl-6- (3-methyl-2-butenyl)-imidazo[4,5,1-j,k][1,4]benzodiazepin-2-(1H)-t hione (TIBO R82913). A mutant enzyme in which tyrosine 188 was changed to leucine was cross-resistant to both inophyllum B and TIBO R82913, as was HIV type 2 reverse transcriptase. These studies suggest that inophyllum B and TIBO R82913 bind to distinct but overlapping sites. Inhibition of avian myeloblastosis virus reverse transcriptase and Moloney murine leukemia virus reverse transcriptase by inophyllum B was detectible, suggesting that these inhibitors may be more promiscuous than other previously described non-nucleoside inhibitors. Inophyllums were active against HIV type 1 in cell culture with IC50 values of approximately 1.5 microM. These studies imply that the inophyllums have a novel mechanism of interaction with reverse transcriptase and as such could conceivably play a role in combination therapy.

Antiviral Agents↗

PubMed1998

Establishment of a functional human immunodeficiency virus type 1 (HIV-1) reverse transcription complex involves the cytoskeleton.

After interaction of human immunodeficiency virus type 1 (HIV-1) virions with cell surface receptors, a series of poorly characterized events results in establishment of a viral reverse transcription complex in the host cell cytoplasm. This process is coordinated in such a way that reverse transcription is initiated shortly after formation of the viral reverse transcription complex. However, the mechanism through which virus entry and initiation of reverse transcription are coordinated and how these events are compartmentalized in the infected cell are not known. In this study, we demonstrate that viral reverse transcription complexes associate rapidly with the host cell cytoskeleton during HIV-1 infection and that reverse transcription occurs almost entirely in the cytoskeletal compartment. Interruption of actin polymerization before virus infection reduced association of viral reverse transcription complexes with the cytoskeleton. In addition, efficient reverse transcription was dependent on intact actin microfilaments. The localization of reverse transcription to actin microfilaments was mediated by the interaction of a reverse transcription complex component (gag MA) with actin but not vimentin (intermediate filaments) or tubulin (microtubules). In addition, fusion, but not endocytosis-mediated HIV-1 infectivity, was impaired when actin depolymerizing agents were added to target cells before infection but not when added after infection. These results point to a previously unsuspected role for the host cell cytoskeleton in HIV-1 entry and suggest that components of the cytoskeleton promote establishment of the reverse transcription complex in the host cell and also the process of reverse transcription within this complex.

Cell Line↗

PubMed1995

Reverse T3 does not reliably differentiate hypothyroid sick syndrome from euthyroid sick syndrome.

To assess the efficacy of reverse T3 in differentiating between the hypothyroid and euthyroid state in the setting of illness, all reverse T3 determinations obtained over a 4-year period in a University teaching hospital were analyzed in the context of concurrent thyroid function tests, bilirubin, albumin, creatinine, subsequent treatment, and follow-up. Based on T4 (or free T4 index) and TSH, the thyroidal state of the patient and the appropriateness of the reverse T3 determination were assigned. A total of 262 reverse T3 determinations were made in 246 patients. There is an inverse linear relationship between the log TSH and the reverse T3. Patients with hypothyroidism plus illness may have a normal reverse T3 and patients with euthyroidism may have a low reverse T3. Reverse T3 is linearly related to bilirubin up to a bilirubin of approximately 171 microM (10 mg/dL). Sixty percent of the reverse T3 determinations were obtained for seemingly inappropriate indications. In association with a low free T4 index/T4, an unmeasurable reverse T3 did not lead to institution of thyroid hormone treatment in over 52% of cases. Although reverse T3 may be elevated in the setting of nonthyroidal illness, it is not reliable in distinguishing between the hypothyroid sick patient and the euthyroid sick patient. This is probably because of drug and disease effects on thyroid hormone metabolism as well as the presence of sufficient T4 substrate for conversion to reverse T3 in many hypothyroid sick patients.

Adolescent↗

PubMed1998

Deactivation and conformational changes of cutinase in reverse micelles

Deactivation data and fluorescence intensity changes were used to probe functional and structural stability of cutinase in reverse micelles. A fast deactivation of cutinase in anionic (AOT) reverse micelles occurs due to a reversible denaturation process. The deactivation and denaturation of cutinase is slower in small cationic (CTAB/1-hexanol) reverse micelles and does not occur when the size of the cationic reverse micellar water-pool is larger than cutinase. In both systems, activity loss and denaturation are coupled processes showing the same trend with time. Denaturation is probably caused by the interaction between the enzyme and the surfactant interface of the reversed micelle. When the size of the empty reversed micelle water-pool is smaller than cutinase (at W0 5, with W0 being the water:surfactant concentration ratio) a three-state model describes denaturation and deactivation with an intermediate conformational state existing on the path from native to denaturated cutinase. This intermediate was clearly detected by an increase in activity and shows only minor conformational changes relative to the native state. At W0 20, the size of the empty water-pool was larger than cutinase and the data was well described by a two-state model for both anionic and cationic reverse micelles. For AOT reverse micelles at W0 20, the intermediate state became a transient state and the deactivation and denaturation were described by a two-state model in which only native and denaturated cutinase were present. For CTAB/1-hexanol reverse micelles at W0 20, the native cutinase was in equilibrium with an intermediate state, which did not suffer denaturation. 1-Hexanol showed a stabilizing effect on cutinase in reverse micelles, contributing to the higher stabilities observed in the cationic CTAB/1-hexanol reverse micelles. Copyright 1998 John Wiley & Sons, Inc.

Journal Article↗

PubMed1989

Human chorionic gonadotropin (hCG) induces gonad reversal in a protogynous fish, the bluehead wrasse, Thalassoma bifasciatum (Teleostei, Labridae).

Female to male successive hermaphroditism (protogyny) is common in several groups of marine fish. Thalassoma bifasciatum, the bluehead wrasse (Labridae), found in the reefs of the Caribbean normally undergoes sex reversal after receiving behavioral cues. This report deals with the successful use of human chorionic gonadotropin (hCG) in inducing gonad reversal in this species. Eighty percent (n = 40) of the treated fish showed signs of reversal in 1-6 weeks; only 11% (n = 54) of the control (nontreated) group showed signs of reversal during the same period. The number of fish undergoing reversal increased with the length of the treatment period, 55% after 1 week, 100% after 6 weeks. A bluehead color pattern, typical of the terminal male phase, also appeared more frequently in the longer treated groups. To determine the efficacy of hCG in inducing gonad reversal, morphological criteria for reversal had to be established. For the majority of treated fish, the presence of both spermatogenic cysts and degenerating oocytes was sufficient to label these gonads unambiguously as undergoing reversal. However, at the extremes of this process, i.e., onset (early) and endpoint (late) stages, ambiguity could arise in identifying a gonad as undergoing reversal, and, therefore, key criteria were established for these stages. In our hands, the most consistent and reliable criterion for the early stage reversal was appearance of male germ line cells, clusters of "spermatogonial-like" cells. For the late stage, recognizable remnants of late-state oocytes had to be present. Some details of the histological changes that occur during early, middle, and late stages of reversal are also described. It is suggested that these results with hCG shed new light on the endocrine control of gonad reversal in T. bifasciatum.

Animals↗

PubMed1996

A [+18RGD] protamine variant for nontoxic and effective reversal of conventional heparin and low-molecular-weight heparin anticoagulation.

Protamine sulfate reversal of heparin anticoagulation causes adverse side effects. Additionally, protamine sulfate is relatively ineffective at reversing factor Xa inhibition caused by low-molecular weight heparin (LMWH, Enoxaparin). Previously, a +18 compound partially reversed heparin and LMWH with minimal toxicity. In the present study, a new +18 protamine-like variant, [+18RGD], with an added RGD sequence [acetyl-EA(R2A2R2A)4R2GRGDSPA-amide], was compared to a previously developed compound, [+18BE,Acetyl-EAA-(K2A2K2A)4K2-Amide] and standard protamine [Prot +21] regarding the reversal of conventional unfractionated heparin (Hep) and LMWH. These three agents were given at 1 mg per 100 IU activity of Hep or LMWH rapidly over 10 sec. Hemodynamic toxicity was based on maximum declines in blood pressure, heart rate, cardiac output, and oxygen consumption over the first 5 min after reversal (calculated as a total toxicity score, TTS). The more negative the TTS, the more toxic the agent. Degrees of toxicity (TTS) of [+18RGD], [+18BE],and[Prot +21] for reversal of Hep were -1.19, -2.00, and -7.32, respectively; and for reversal of LMWH they were -2.85, -3.98,and -6.17, respectively. These differences were significant for Hep (P < 0.01) and approached significance for LMWH (P = 0.07). Maximum hemodynamic perturbations paralleled the TTS pattern. [+18RGD] provided equal reversal efficacy to [Prot +21] for Hep, with a statistically significant (P < 0.05) lessening of platelet count declines (Plt 27, -46, and -55%, respectively). [+18RGD] improved reversal efficacy for LMWH, at 3, 10, and 30 min following its administration. At 3 min, antifactor Xa reversal was 72, 40, and 30%, respectively, for [+18RGD], [+18BE], and [Prot +21]; [+18RGD] effects were significantly better (P < 0.01). [+18RGD] reversed both Hep and LMWH anticoagulation with minimal toxicity. Such a compound should decrease clinical complications attending the use of standard protamine for reversal of conventional heparin or LMWH anticoagulation.

Amino Acid Sequence↗

PubMed1997

Femoropopliteal bypass: in situ or reversed vein grafts? Ten-year results of a randomized prospective study.

One hundred femoropopliteal bypass procedures performed in 91 patients between October 1980 and January 1985 were randomly divided into two statistically comparable groups including 50 in situ vein grafts and 50 reversed vein grafts. The indication for bypass was chronic critical ischemia in 97% of cases. The lower anastomosis was made on the distal popliteal artery in 75% of cases. Follow-up ranged from 10 years (for the last patient included) to 14 years. Three patients have been lost to follow-up. Median survival was 54 months in the in situ graft group and 76.5 months in the reversed graft group. Actuarial survival at 10 years was 30.8% in the in situ graft group and 29.5% in the reversed graft group. Actuarial limb salvage at 10 years was 73.5% in the in situ graft group and 74.4% in the reversed graft group. Graft occlusion was observed in 10 cases during the perioperative period (six in the in situ graft group and four in the reversed graft group) and in 19 cases during the late postoperative period (12 in the in situ graft group and seven in the reversed graft group). Reoperation during follow-up was required in 13 cases in the in situ graft group (11 patients) and in nine cases in the reversed graft group (five patients). Discounting residual arteriovenous fistulas (FAV) (five ligations in four patients), the incidence of lesions involving the bypass and anastomoses threatening graft patency was 6% in the in situ graft group and 8% in the reversed graft group. Actuarial primary patency at 10 years was 41.7% in the in situ graft group and 64.5% in the reversed graft group (p < 0.05). Actuarial secondary patency at 10 years was 64.8% in the in situ graft group and 70.2% in the reversed graft group (NS). As a function of vein diameter, actuarial secondary patency at 10 years in the in situ graft group was 37.5% for bypasses using veins with a diameter of 4 mm or less and 80.6% for bypasses using veins larger than 4 mm (p < 0.05). In the reversed graft group the patency rate was 71.2% for bypasses using veins with a diameter of 4 mm or less and 65.5% for bypasses using veins larger than 4 mm. In addition to requiring a training period the in situ technique raises the problem of valve removal especially for small diameter veins. The absence of these disadvantages makes the reversed technique the procedure of choice for femoropopliteal bypass.

Aged↗

PubMed2006

Neural correlates of response reversal: considering acquisition.

Previous work on response reversal has typically used a single pair of stimuli that serially reverse. This conflation of acquisition and reversal processes has prevented an examination of the functional role of neural systems implicated in response reversal during acquisition despite the relevance of such data in evaluating accounts of response reversal. In the current study, participants encountered 16 independent reversing stimulus pairs in the context of a probabilistic response reversal paradigm. Functional regions of interest identified as involved in response reversal through a contrast used in the previous literature (punished errors made in the reversal phase versus rewarded correct responses), were interrogated across conditions. Consistent with suggestions that middle frontal cortex codes reward, this region showed significantly greater responses to rewarded rather than punished trials irrespective of accuracy or learning phase (acquisition or reversal). Consistent with the suggestion that this coding of the expectation of reinforcement is acquired via input from the amygdala, we observed significant positive connectivity between activity within the amygdala and a region of rostral anterior cingulate cortex highly proximal to this region of middle frontal/mesial prefrontal cortex. In contrast, inferior frontal cortex, anterior cingulate cortex and caudate showed greater responses to punished errors than to the rewarded correct responses. These three regions also showed significant activation to rewarded errors during acquisition, in contrast to positions suggesting that inferior frontal cortex represents punishment or suppresses previously rewarded responses. Moreover, a connectivity analysis with an anterior cingulate cortex seed revealed highly significant positive connectivity among them. The implications of these data for recent accounts of response reversal and of response reversal impairments in specific neuropsychiatric populations are discussed.

Adult↗

PubMed2003

Cutinase-AOT interactions in reverse micelles: the effect of 1-hexanol.

Cutinase encapsulated in dioctyl sulfosuccinate reverse micelles displays very low stability, undergoing fast denaturation due to an anchoring at the micellar interface. The denaturation process and the structure of the reverse micelle were characterized using biophysical techniques. The kinetics of denaturation observed from fluorescence match the increase of the hydrodynamic radius of reverse micelles. Denaturation in reverse micelles is mainly the unfolding of the three-dimensional structure since the decrease in the circular dichroism ellipticity in the far-UV range is very small. The process is accompanied by an increase in the steady-state anisotropy, as opposed to what happens for denaturation in aqueous solution. Since 1-hexanol used as co-surfactant in dioctyl sulfosuccinate reverse micelles slows or even prevents cutinase denaturation, its effect on cutinase conformation and on the size of reverse micelles was analyzed. When 1-hexanol is present, cutinase is encapsulated in a large reverse micelle, as deduced from dynamic light scattering. The large reverse micelle filled with cutinase was built from the fusion of reverse micelles according to a pseudo-unimolecular process ranging in time from a few minutes to 2h depending on the reverse micellar concentration. This slow equilibrium driven by the encapsulated cutinase has not been reported previously. The encapsulation of cutinase in dioctyl sulfosuccinate reverse micelles establishes a completely new equilibrium characterized by a bimodal population of empty and filled reverse micelles, whose characteristics depend greatly on the interfacial characteristics, that is, on the absence or presence of 1-hexanol.

Anisotropy↗

PubMed2003

Monoamines stimulate sex reversal in the saddleback wrasse.

Monoamine neurotransmitters (norepinephrine, dopamine, and serotonin) play an important role in reproduction and sexual behavior throughout the vertebrates. They are the first endogenous chemical signals in the regulation of the hypothalamo-pituitary-gonadal (HPG) axis. In teleosts with behavioral sex determination, much is known about behavioral cues that induce sex reversal. The cues are social, processed via the visual system and depend on the ratio of females to males in the population. The mechanisms by which these external behavioral cues are converted to an internal chemical regulatory process are largely unknown. The protogynous Hawaiian saddleback wrasse, Thalassoma duperrey, was used to investigate the biological pathway mediating the conversion of a social cue into neuroendocrine events regulating sex reversal. Because monoamines play an important role in the regulation of the HPG axis, they were selected as likely candidates for such a conversion. To determine if monoamines could affect sex reversal, drugs affecting monoamines were used in an attempt to either induce sex reversal under non-permissive conditions, or prevent sex reversal under permissive conditions. Increasing norepinephrine or blocking dopamine or serotonin lead to sex reversal in experimental animals under non-permissive conditions. Increasing serotonin blocked sex reversal under permissive conditions, while blocking dopamine or norepinephrine retarded the process. The results presented here demonstrate that monoamines contribute significantly to the control sex reversal. Norepinephrine stimulates initiation and completion of gonadal sex of reversal as well as color change perhaps directly via its effects on the HPG axis. Dopamine exercises inhibitory action on the initiation of sex reversal while 5-HT inhibits both initiation and completion of sex reversal. The serotonergic system appears to be an integral part of the pathway mediating the conversion of a social cue into a neuroendocrine event. The complex organization of neurochemical events controlling the psychosocial, physiological, and anatomical events that constitute reversal of sexual identity includes monoamine neurotransmitters.

Adaptation, Physiological↗

PubMed1999

Factors predicting atracurium reversal time.

BACKGROUND: To identify individual factors and combination of factors predictive of reversal time (defined as time from neostigmine administration to train-of-four (TOF) ratio 0.70) from atracurium-induced neuromuscular block, the present study tested the following variables as possible predictors of reversal time: 1) degree of block at the time of antagonism as quantified by first response to TOF or double-burst stimulation (DBS); 2) time from last supplemental dose of atracurium to administration of neostigmine (pre-reversal time); and 3) time from administration of initial atracurium dose to T1 (the magnitude of the first twitch in TOF) recovered to 10% (duration of action of the initial dose of atracurium). METHODS: The study population comprised 83 female patients, ASA physical status 1 or 2, anaesthetized with fentanyl, thiopental, halothane and nitrous oxide. Initial and supplemental doses of atracurium were 0.5 mg x kg(-1) and 0.15 mg x kg(-1), respectively. Evoked responses to TOF or DBS were recorded mechanomyographically. Neuromuscular block was antagonized with neostigmine, 0.07 mg x kg(-1), at varying time intervals (6-50 min) after the final atracurium dose. RESULTS: Multiple linear regression analyses testing T1, D1 (the magnitude of the first twitch in DBS), pre-reversal time and duration of action of the initial dose of atracurium, demonstrated that with superficial block, T1 >15%, T1 is the only significant predictor for reversal time. With moderate block, 0< T1 < or =15%, both T1 and duration of action of the initial atracurium dose are significant predictors for reversal time. With profound block, T1=0, duration of action of the initial dose and pre-reversal time are significant predictors for reversal time. CONCLUSION: 1) T1 is a more important predictor for reversal time from atracurium-induced neuromuscular block than D1; 2) predictors differ with the degree of block: with T1 > 15%, T1 is the only significant predictor; with 0< T1 < or =15%, the duration of action of the initial dose and T1 are predictors for reversal time; with T1=0, the duration of action of the initial dose and pre-reversal time predict reversal time.

Adult↗

PubMed1976

Reversal of the physiological effects of monocular deprivation in the kitten's visual cortex.

1. Twenty-three kittens were monocularly deprived of vision until the age of 4, 5, 6 or 7 weeks. Their deprived eyes were then opened, and their experienced eyes shut for a further 3-63 days. After this time physiological recordings were made in the visual cortex, area 17. Three control kittens, monocularly deprived for various periods, showed that at the time of reverse-suturing, few neurones could be influenced at all from the deprived eye. 2. Following reverse-suturing, the initially deprived eye regained control of cortical neurones. This switch of cortical ocular dominance was most rapid following reverse-suturing at the age of 4 weeks. Delaying the age of reverse-suturing reduced the rate and then the extent of the cortical ocular dominance changes. 3. The cortex of reverse-sutured kittens is divided into regions of cells dominated by one eye or the other. The relative sizes of these ocular dominance columns changed during reversed deprivation. The columns devoted to the initially deprived eye were very small in animals reverse-sutured for brief periods, but in animals that underwent longer periods of reversed deprivation, the columns driven by that eye were larger, while those devoted to the initially open eye were smaller. 4. Clear progressions of orientation columns across the cortex were apparent in many of the kittens, but, in contrast to the situation in normal or strabismic kittens, these sequences were disrupted at the borders of eye dominance columns: the cortical representations of orientation and ocular dominance were not independent. 5. Binocular units in these kittens were rather rare, but those that could be found often had dissimilar receptive field properties in the two eyes. Commonly, a cell would have a normal orientation selective receptive field in one eye, and an immature, unselective receptive field in the other. Cells that had orientation selective receptive fields in both eyes often had greatly differing orientation preferences in the two eyes, occasionally by nearly 90 degrees. 6. During the reversal of deprivation effects, the proportion of receptive fields exhibiting mature properties declined in the initially experienced eye, while the proportion increased in the initially deprived eye. Similarly, the average band width of orientation tuning of receptive fields in the initially deprived eye decreased, while that of receptive fields in the initially experienced eye increased. 7. One kitten was reverse-sutured twice, to demonstrate that cortical ocular dominance may be reversed a second time, even after one reversal of ocular dominance. 8. It is suggested that the sensitive period for cortical binocular development consists of two phases. In the first phase, all cortical neurones may be modified by experience, but the rate at which they may be modified decreases with age. In the second phase, an increasing number of cortical neurones becomes fixed in their properties, while those that remain modifiable are as modifiable as they were at the end of the first phase. 9...

Age Factors↗

PubMed1999

Effect of seminal oxidative stress on fertility after vasectomy reversal.

OBJECTIVE: To evaluate seminal oxidative stress in men after vasectomy reversal and to determine whether seminal oxidative stress could predict fertility after vasectomy reversal. DESIGN: Measurement of seminal reactive oxygen species (ROS) and total antioxidant capacity (TAC) in normal donors, men who were fertile after vasectomy reversal, and men who were infertile after vasectomy reversal. SETTING: A male infertility clinic of a tertiary care center. PATIENT(S): Thirty men who underwent vasectomy reversal and 17 normal donors. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Semen characteristics, seminal ROS, and TAC were measured with chemiluminescence assays in samples from donors and reversal patients. RESULT(S): Mean adjusted seminal ROS (log [ROS+1]) was higher in infertile reversal patients (2.38+/-0.25) than in normal donors (1.30+/-0.14). Seminal ROS was also higher in all (fertile and infertile reversal combined) reversal patients than in donors. Total antioxidant capacity did not differ between groups. The ROS-TAC score, a composite index of seminal oxidative stress, was a significant predictor of fertility. A ROS-TAC score of 45 or greater had a positive predictive value of 73% in predicting fertility. CONCLUSION(S): Seminal oxidative stress is associated with vasectomy reversal. The ROS-TAC score is a possible predictor of infertility after vasectomy reversal.

Adult↗

PubMed1983

Multiple-unit activity of the prefrontal cortex and mediodorsal thalamic nucleus during reversal learning of discriminative avoidance behavior in rabbits.

Multiple-unit activity of the prefrontal cortex (PFC) and the mediodorsal (MD) thalamic nucleus was recorded during reversal training following differential conditioning of a locomotory (wheel rotation) avoidance response in rabbits. The positive and negative conditional stimuli (CS+ and CS-) were pure tones and the unconditional stimulus (UCS) was footshock. A major objective was to compare the activity in the PFC and MD nucleus with that in the neighboring cingulate cortical and anteroventral (AV) thalamic system, studied previously. During the first session of reversal training the rostral-sulcal subfield of the PFC manifested significant discriminative activity appropriate to the original habit, i.e., a greater discharge to the original CS+ than to the original CS-. The difference between the CS+ and CS- elicited discharges diminished as reversal learning progressed, but discriminative activity appropriate to the reversal problem did not develop. The medial subdivision of the MD nucleus which is interconnected reciprocally with the rostral-sulcal PFC subfield did not manifest discriminative activity during reversal training (nor had it done so during original learning). The caudal subfield of the PFC (which had shown rapidly developing acquisition of the discriminative discharges followed by diminution of the discriminative discharges during original training) manifested an original discriminative effect in the initial session of reversal training followed by the reverse discriminative discharge in the criterial session. The lateral subdivision of the MD nucleus which is interconnected reciprocally with the caudal PFC subfield, also manifested the original discriminative effect in the initial session of reversal training, followed by the reverse discriminative effect during the subsequent (precriterial and criterial) sessions. Thus, as in the AV nucleus, the lateral MD subdivision showed earlier and more robust development of discriminative activity appropriate to the reversal problem, than its cortical counterpart. The present results also suggested that cerebral cortical areas such as the caudal PFC, which transfer discriminative activity to their respective thalamic nuclei during discriminative acquisition, are subsequently more likely to manifest the reverse discriminative activity, than are cortical areas such as the rostral-sulcal subfields of the PFC, which do not transfer their discriminative activity.

Animals↗

PubMed1982

Cingulate cortical and anterior thalamic neuronal correlates of the overtraining reversal effect in rabbits.

Multiple-unit activity of the cingulate cortex and the anteroventral (AV) nucleus of the thalamus in rabbits was recorded during reversal training, following differential conditioning of a locomotory (wheel rotation) avoidance response. The CS+ and CS- were pure tones (1 or 8 kHz) and the UCS was a footshock delivered through the grid floor of the wheel. One group of the rabbits received original training to a criterion followed immediately by reversal training. A second group received training to criterion followed by additional training sessions (overtraining), prior to reversal training. The results indicated that the overtraining reversal effect (ORE) occurred. That is, the overtrained subjects acquired the reverse discrimination in significantly fewer sessions than the non-overtrained subjects. The overall (non-discriminative) neuronal reactivity in all cingulate cortical laminae was reduced by overtraining, whereas the overall reactivity of the AV thalamus was enhanced. In addition, the non-overtrained subjects manifested a discriminative neuronal response appropriate to the original task (i.e. a greater response to the CS- than to the CS+ for reversal training), throughout the precriterial sessions of reversal training. This persistent 'original habit effect' occurred only at brief latencies (20-30 msec) after CS onset, and only in the deep cortical laminae (V-VI). The neuronal activity of the superficial laminae (I-IV) in non-overtrained subjects underwent a transition, in parallel with the behavior, from a discriminative response appropriate to the original task to one appropriate to the reversal task. No significant training-related changes were seen at any cortical depth in the overtrained subjects. Presentation of non-contingent footshocks during two sessions of reversal training following criterion re-enhanced the overall reactivity and the brief-latency discriminative neuronal response appropriate to the original task, which had undergone decline during reversal training, in the deep cortical laminae of the non-overtrained subjects. The enhanced overall reactivity and the discriminative activity in the superficial laminae of non-overtrained subjects had not declined during reversal training and were not altered by the non-contingent footshocks. The implications of these data are discussed in regard to the neural causation of the ORE.

Animals↗

PubMed1985

Reversal learning in senescent rats.

The ability of old (24 months) and young (3 months) male rats to reverse a previously acquired discrimination was compared in 5 experiments. The old rats did not need more trials to learn a position habit in a T-maze to obtain water reward, but required more trials to reverse the position habit. The old rats showed a similar deficit in a second, but not in subsequent reversals of the position habit. In a second experiment, old rats were slower in learning to operate one of two levers in an operant chamber to obtain food reward on a CRF schedule, but by the session prior to reaching criterion for acquisition they showed response rates similar to the young animals. When the rats were required to operate the alternative lever to obtain reward, the young rats emitted 70% of their responses during the first reversal session on the newly-correct lever, but the old rats only 35%. Nevertheless, the groups were similar in the number of sessions required to reach a criterion of 95% of responses on the correct lever. In 3 subsequent reversals, old and young rats did not differ nor were there differences in the number of responses in 4 extinction sessions in the rats which had received reversal training. In experiment 3 with old and young rats which had received only acquisition training, old rats emitted fewer responses than young animals during extinction. From these experiments it was hypothesized that the apparent difficulty of old rats in learning a reversal task was due to the low probability of their emitting spontaneously a novel or previously unrewarded response, and not to a difficulty in forming a new association. This hypothesis was tested in two further experiments in which rats were required to learn a brightness discrimination in a T-maze. Old and young rats which had learned and reversed position habits in the T-maze in experiment 1, did not differ in either acquisition or reversal of the brightness discrimination, suggesting that old rats do not differ from young animals in reversal tasks when the motor response requirements for the task are already within the animals' behavioural repertoire. Consistent with this hypothesis, naive old rats were slower than young rats in acquiring a similar brightness discrimination but did not differ in the reversal task.

Aging↗

PubMed1990

Differential inhibitory effects of various flavonoids on the activities of reverse transcriptase and cellular DNA and RNA polymerases.

Four flavonoids, 5,6,7-trihydroxyflavone (baicalein), 3,3',4',5,7-pentahydroxyflavone (quercetin), 3,3',4',5,6,7-hexahydroxyflavone (quercetagetin) and 3,3',4',5,5',7-hexahydroxyflavone (myricetin), were found to be potent inhibitors of reverse transcriptases from Rauscher murine leukemia virus (RLV) and human immunodeficiency virus (HIV). Under the reaction conditions employed, any one of these flavonoids almost completely inhibited the activity of RLV reverse transcriptase at a concentration of 1 microgram/ml. HIV reverse transcriptase was inhibited by 100%, 100%, 90% and 70% in the presence of 2 micrograms/ml quercetin, myricetin, quercetagetin and baicalein, respectively. The mode of inhibition of these flavonoids was competitive (RLV reverse transcriptase) or partially competitive (HIV reverse transcriptase) with respect to the template.primer complex, (rA)n.(dT), and noncompetitive with respect to the triphosphate substrate, dTTP. The Ki values for RLV reverse transcriptase were found to be 0.37 microM and 0.08 microM for baicalein and quercetin, respectively and those for HIV reverse transcriptase were 2.52 microM, 0.52 microM, 0.46 microM and 0.08 microM for baicalein, quercetin, quercetagetin and myricetin, respectively. Comparative studies with other flavonoids (hydroxyflavones, dihydroxyflavones and polyhydroxyflavones and flavanones) carried out to clarify the structure/activity relationships, revealed that the presence of both the unsaturated double bond between positions 2 and 3 of the flavonoid pyrone ring, and the three hydroxyl groups introduced on positions 5, 6 and 7, (i.e. baicalein) were a prerequisite for the inhibition of reverse transcriptase activity. Removal of the 6-hydroxyl group of baicalein required the introduction of three additional hydroxyl groups at positions 3, 3' and 4' (quercetin), to afford a compound still capable of inhibiting the reverse transcriptase activity. Quercetagetin which contains the structures of both baicalein and quercetin, and myricetin which has the structure of quercetin with an additional hydroxyl group on the 5' position also proved strong inhibitors of reverse transcriptase activity. The inhibition by baicalein of reverse transcriptase is highly specific, whereas quercetin and quercetagetin were also strong inhibitors of DNA polymerase beta and DNA polymerase I, respectively. Myricetin was also a potent inhibitor of both DNA polymerase alpha and DNA polymerase I.

Animals↗

PubMed2003

Relevance of micrometastases detected by reverse transcriptase-polymerase chain reaction for melanoma recurrence: systematic review and meta-analysis.

CONTEXT: Cutaneous melanoma presents significant morbidity and mortality. Nowadays, about 90% of them are diagnosed by clinical examination and most are localized melanomas. Sentinel node biopsy has brought about a new and interesting approach towards localized cutaneous melanoma. The meaning of micrometastases in sentinel nodes diagnosed by the reverse transcriptase-polymerase chain reaction is not well established. OBJECTIVE: To define the real value of micrometastases diagnosed by the reverse transcriptases polymerase chain reaction in relation to melanoma recurrence. METHODS: Systematic literature review and meta-analysis. The Cochrane Library, Medline, Embase and Lilacs were the databases searched. We used the following key words: sentinel node and melanoma; sentinel node and reverse transcriptase-polymerase chain reaction; melanoma and reverse transcriptase-polymerase chain reaction. Cohort studies enrolling localized cutaneous melanoma patients who underwent sentinel node biopsy were selected. Sentinel node evaluations included hematoxylin and eosin, immunohistochemistry and reverse transcriptase-polymerase chain reaction. RESULTS: Out of the 1,542 studies evaluated, four were eligible. The four studies, when combined, were statistically homogeneous. The sample totaled 450 patients grouped as follows: 163 with a sentinel node negative to hematoxylin eosin and immunohistochemistry and positive to the reverse transcriptase-polymerase chain reaction; 192 with a sentinel node negative to hematoxylin eosin, immunohistochemistry and the reverse transcriptase-polymerse chain reaction and 95 patients with a sentinel node positive to hematoxylin eosin and/or immunohistochemistry. We analyzed the first two groups. The meta-analysis for the random model showed an increased effect from a positive reverse transcriptase-polymerase chain reaction on the recurrence rate. A similar result occurred in the meta-analysis for the fixed effect model. CONCLUSION: Patients with a positive reverse transcriptase-polymerase chain reaction had a greater recurrence rate than those with a negative reverse transcriptase-polymerase chain reaction. This suggests an important role for the reverse transcriptase-polymerase chain reaction in sentinel node examinations. In view of the small sample, a clinical trial could better evaluate this question.

Humans↗