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Self-administration of cocaine by humans: a laboratory perspective.

Laboratory research evaluating the behavioural and physiological effects of cocaine has produced important basic information relevant to the prediction and control of cocaine abuse. Adaptation for human subjects of laboratory procedures originally developed with non-humans has provided the methodology for assessing the relationship between cocaine-taking and the self-reported effects of cocaine. This laboratory model for evaluating drug-taking has been adapted to include all the routes of administration by which cocaine is abused. Data collected in cocaine choice/self-administration studies indicate that there is a generally good correlation between cocaine self-administration and its stimulant-like 'positive' effects. There are, however, areas in which these two measures clearly diverge, and drug self-administration procedures provide a sensitive measure of cocaine's effects when it is taken by the routes and in the patterns people use outside the laboratory. Combining these measures with other behavioural evaluations provides useful information for understanding cocaine use and abuse. In addition, and importantly, these laboratory procedures are useful tools in the development and assessment of treatment interventions which might be used effectively.

Choice Behavior↗

Resting energy metabolism of Goeldi's monkey (Callimico goeldii) is similar to that of other callitrichids.

The resting metabolic rates (RMRs) of six adult Goeldi's monkeys (Callimico goeldii) were measured using standard methods of open circuit respirometry during both the active (daytime) and inactive (nighttime) circadian phases for this species. One subject was measured both while she was pregnant and after she delivered a full-term, stillborn infant. Inactive-phase RMR within thermal neutrality (above 27.5 degrees C) averaged 288.5 +/- 30.8 ml O2/hr; active-phase RMR within thermal neutrality averaged 416.3 +/- 60.9 ml O2/hr. These values are 74.6% and 107.6%, respectively, of the mammalian expected for animals of this body mass. During the inactive phase, metabolic rate increased an estimated 4.3% for every degree decline in temperature below 27.5 degrees C. The RMR in Goeldi's monkey is similar quantitatively and qualitatively to those of other captive callitrichids that have been studied, with active-phase RMR being at or slightly above the mammalian expected, and inactive-phase RMR being significantly reduced. We propose that this circadian pattern of RMR is a consequence of small body size, and is not a specific metabolic adaptation within the Callitrichidae. Thus we predict that metabolic studies measuring both circadian phases in other small primates will also find this pattern of reduced RMR during the inactive phase. The inactive-phase RMR within thermal neutrality of the pregnant female was not different from that measured after the stillbirth, despite an almost 15% difference in body mass. During pregnancy, however, the female was more metabolically responsive to temperature below thermal neutrality, and had a lower upper critical temperature (i.e., was less tolerant of heat).

Animals↗

Proximate and ultimate causes of adoption in ring-billed gulls.

From 1987 to 1994, the annual frequency of adoption by breeding pairs at a Lake Erie ring-billed gull, Larus delawarensis, colony ranged from 3 to 37% (average 8%/year, N=7 years) and, on average, foster parents raised 0.5 fewer of their own chicks to fledging than pairs that did not adopt. The key evolutionary question is: why do some individuals apparently suffer the costs associated with a behaviour that appears to enhance the fitness of others? From 1992 to 1995, I investigated the proximate and ultimate causes of adoption in ring-billed gulls from the perspectives of both the foster parents and adopted chicks, and tested predictions that differentiated between various competing adaptive and nonadaptive hypotheses that have been proposed to explain it. While I was able to demonstrate a breeding cost, I failed to identify any benefits to foster parents. Thus, the adaptive hypotheses that rely on the foster parents benefiting were not supported (e.g. kin selection, reciprocal altruism, acquisition of parenting experience). From the foster parent's perspective, adoption was mediated through errors in parent-offspring recognition. Under natural conditions, most fostering pairs were tending small chicks (<6 days old) at the time of adoptions; in chick-transfer experiments, resident parents did not discriminate against foreign chicks until their own chicks were 7-9 days old. Chicks (N=25) that subsequently abandoned their natal nests were lighter, and grew at a slower rate, than chicks that survived to fledging in their home broods. Thus, departing chicks were at a survival disadvantage in their home broods. Chicks that gained acceptance into foreign broods where they were older/larger than the resident chicks realized high survival at the expense of their foster siblings and parents. Based upon individual growth rates and the corresponding survival probabilities, disadvantaged chicks approximately doubled their survival chances through foster care. Why has selection not eliminated adoption? I argue that adoption is an evolutionary arms race between the two principle actor groups; disadvantaged chicks, which benefit through foster care, and host parents, which avoid providing foster care (e.g. infanticide). In ring-billed gulls, selection has failed to eliminate adoption because the long-term reproductive cost (estimated at 4%, this study) of an occasional adoption is probably offset by the relatively higher costs associated with stricter kin discrimination mechanisms (e.g. parental infanticide). (c) 1998 The Association for the Study of Animal Behaviour.

Journal Article↗

Estimation and use of protein backbone angle probabilities.

A procedure is described for estimating the probabilities for the backbone phi-psi angles of a protein molecule from the data base of known protein structures. The procedure is basically an adaptation of a published secondary structure prediction scheme, applied to the phi-psi angle bins rather than to the secondary types. The phi-psi angle probabilities estimated this way include all effects of local sequence and are "context sensitive" in that the probabilities for a given residue type depend on its position along the sequence. These probabilities can be used to predict the three-dimensional structure of short polypeptides that are stabilized mainly by local interactions only and to predict the protein folding initiation sites, with moderate to good success rates in each case. They are also potentially useful for efficient sampling in a Monte Carlo scheme of protein tertiary structure prediction methods.

Amino Acid Sequence↗

Does perception of biological motion rely on specific brain regions?

Perception of biological motions plays a major adaptive role in identifying, interpreting, and predicting the actions of others. It may therefore be hypothesized that the perception of biological motions is subserved by a specific neural network. Here we used fMRI to verify this hypothesis. In a group of 10 healthy volunteers, we explored the hemodynamic responses to seven types of visual motion displays: drifting random dots, random dot cube, random dot cube with masking elements, upright point-light walker, inverted point-light walker, upright point-light walker display with masking elements, and inverted point-light walker display with masking elements. A gradient in activation was observed in the occipitotemporal junction. The responses to rigid motion were localized posteriorly to those responses elicited by nonrigid motions. Our results demonstrate that in addition to the posterior portion of superior temporal sulcus, the left intraparietal cortex is involved in the perception of nonrigid biological motions.

Adult↗

A role for computer simulation in solving the riddles of autoreceptor-mediated regulation of GABA release.

The autoreceptor-mediated control of GABA release was simulated on a personal computer using commercially available software (STELLA/ITHINK). The experimental data to be matched were taken from previous publications. A basic model was able to fairly accurately reproduce frequency dependencies of GABA release in the presence and absence of uptake inhibition as well as concentration-response curves for changes in release produced by the agonist, (-)-baclofen, or by relatively low concentrations of the antagonists, phaclofen and CGP 35348. Obvious mismatch was observed at high concentrations of a potent antagonist, at a stimulation frequency of 2 Hz. Whereas the experimental data indicate a 3-fold increase in release as compared to controls, simulation predicts a 7-fold increase. By adaptation of the model, simulation data were obtained indicating that this mismatch was not due to (a) the autoreceptor occurring as two subtypes with different affinities for antagonists, (b) the occurrence of an agonist and antagonist state of the autoreceptor, with the latter prevailing at low synaptic concentrations of endogenous GABA, and (c) overruling of uptake inhibition by markedly elevated synaptic GABA concentrations. On the other hand, a simple restriction of the amount of transmitter able to be released per time unit produced much better matching data. A refined model assuming a restricted replacement capacity for exocytotically emptied synaptic vesicles at their docking sites gave similar results. As a consequence, we shall attempt to address this possibility experimentally. Simulation can never prove a case in the positive sense. It can, however, help to exclude ill-matching solutions of a problem and to prioritize among possible ones, which then must be experimentally addressed. We found simulation with this user-friendly software extraordinarily useful, also and not least because it necessitates and stimulates very intense dealing with a subject.

Animals↗

Haemodynamic and hormonal changes during acute and chronic diuretic treatment in essential hypertension.

The short- and long-term effects of diuretic treatment with chlorthalidone 50 mg/day on haemodynamic and hormonal parameters in patients with essential hypertension (WHO grade I) were investigated. After three days of treatment, all patients showed a rise in plasma renin activity (PRA), plasma aldosterone (PA), urinary norepinephrine excretion (UNE) and heart rate (HR), and a decrease in body weight (BW) and extracellular volume (ECV) and blood volume (BV); the change in blood pressure (BP) was variable. The changes in BP were correlated with those in BV. After three months of therapy, the signs of volume depletion tended to fade, but the lower ECV persisted. In contrast to the 4-day study, after three months the change in BP correlated inversely with changes in ECV and renin dependency (saralasin response), and positively with PRA and changes in UNE. It is concluded that the BP response to diuretic treatment is determined by the adaptation with time of the haemodynamic reactions to the volume-depleted state. Whether this adaptation will take place cannot be predicted from the control values of the parameters studied, or from acute changes observed during the first days of treatment.

Adolescent↗

Robust and self-tuning blood flow control during extracorporeal circulation in the presence of system parameter uncertainties.

Three different discrete controllers were designed and tuned to be used in conjunction with a rotary blood pump during cardiopulmonary heart-lung support. The controllers were designed to operate in both steady and pulsatile modes. The system and methods were tested in a circulatory haemodynamic simulator. To guarantee stable control of the non-linear circulatory system in the presence of patient parameter uncertainties, a proportional plus integral (PI) and an H infinity controller were robustly tuned, using a non-linear time-varying model. (H infinity refers to the Hardy space, the set of bounded functions, analytic in the right half plane. The H infinity controller is the solution to the H infinity norm optimisation problem.) A self-tuning general predictive controller (GPC), together with an adaptive Kalman filter (KF) estimator, was compared with the two robustly tuned controllers. The closed-loop blood flow control circuit was set up in simulation routines first. The blood flow controllers were validated in a circulatory hydrodynamic simulator (MOCK) combined with a rotary blood pump. Parameters of the system simulator were changed continuously, and the controllers were tested over a wide range of different operating points. Disturbances in the form of discontinuous additive parameter uncertainties were applied. The closed-loop systems remained robustly stable. The robustly tuned H infinity controller showed the best control performance, in contrast to the GPC controller, which was near instability in regions of strongly varying non-linear system gain. Compared with the H infinity controller, the PI controller showed slightly worse behaviour, but the closed-loop response was acceptable, even in regions of strongly varying non-linear system gain and during pulsatile perfusion. The rotary blood pump could provide stationary and pulsatile perfusion under control conditions. Controlled variables were hereby mean blood flow, pulsatility index and heart rate. All three controllers were developed for an arterial mean flow of 0-6 l min(-1) and a heart rate of up to 70 beats per minute. Pulsatile closed-loop perfusion could provide up to 30 mmHg pressure variation in the simulated ascending aorta at a mean flow of 3 l min(-1).

Aorta↗

Adaptation, plant evolution, and the fossil record.

The importance of adaptation in determining patterns of evolution has become an important focus of debate in evolutionary biology. As it pertains to paleobotany, the issue is whether or not adaptive evolution mediated by natural selection is sufficient to explain the stratigraphic distributions of taxa and character states observed in the plant fossil record. One means of addressing this question is the functional evaluation of stratigraphic series of plant organs set in the context of paleoenvironmental change and temporal patterns of floral composition within environments. For certain organ systems, quantitative estimates of biophysical performance can be made on the basis of structures preserved in the fossil record. Performance estimates for plants separated in time or space can be compared directly. Implicit in different hypotheses of the forces that shape the evolutionary record (e.g. adaptation, mass extinction, rapid environmental change, chance) are predictions about stratigraphic and paleoenvironmental trends in the efficacy of functional performance. Existing data suggest that following the evolution of a significant structural innovation, adaptation for improved functional performance can be a major determinant of evolutionary changes in plants; however, there are structural and development limits to functional improvement, and once these are reached, the structure in question may no longer figure strongly in selection until and unless a new innovation evolves. The Silurian-Devonian paleobotanical record is consistent with the hypothesis that the succession of lowland floodplain dominants preserved in the fossil record of this interval was determined principally by the repeated evolution of new taxa that rose to ecological importance because of competitive advantages conferred by improved biophysical performance. This does not seem to be equally true for Carboniferous-Jurassic dominants of swamp and lowland floodplain environments. In these cases, environmental disruption appears to have been a major factor in shaping the fossil record. This does not mean that continuing adaptation was not important during this interval, but it may indicate that adaptive evolution was strongest in environments other than those best represented in the paleobotanical record.

Adaptation, Biological↗

Early detection of relapse after bone marrow transplantation in patients with chronic myelogenous leukaemia.

In patients with chronic myelogenous leukaemia (CML) treated by allogeneic bone marrow transplantation (BMT), detection of residual leukaemic cells carrying the characteristic bcr/abl rearrangement by highly sensitive techniques, such as qualitative polymerase chain reaction (PCR), is of limited value in predicting disease progression. We have therefore adapted the PCR for quantitative assessment of bcr/abl rearranged cells and applied this technique to the monitoring of residual disease in 28 CML patients during up to 106 months of follow-up after BMT. In 5 patients, quantitative PCR revealed increasing amounts of the pathological bcr/abl message, indicating the presence of a proliferating neoplastic clone, and all 5 had a subsequent relapse of disease. By contrast, the remaining 23 patients have been in maintenance-free complete remission for up to 106 months post-BMT. The monitoring by quantitative PCR of residual leukaemic cells during the post-transplant course of CML patients may allow early detection of relapse and provide a rationale for the timely initiation of treatment.

Bone Marrow Transplantation↗

Bias in spatial memory: a categorical endorsement.

Two experiments investigated how angular estimates reflect bias as a function of response mode, geometric plane of variation, number of implicit categories, memory load and intervening task conditions. In Experiment 1, participants made motor and verbal estimates of incline and azimuth from memory. Estimates in both response modes showed signs of bias predicted by a single-category adaptation of Huttenlocher et al. [Huttenlocher, J., Hedges, L. V., & Duncan, S. (1991). Categories and particulars: Prototype effects in estimating spatial location. Psychological Review, 98, 352-376] category-adjustment model. In Experiment 2, participants made motor estimates of azimuth from memory under a variety of conditions. Stimuli in this experiment were distributed along two contiguous spatial categories. Although increasing levels of cognitive load did not produce a graded effect, participants' estimates were biased and were well described by a multiple-category adaptation of the category-adjustment model. Results from both studies supported an implicit region-based model of bias in spatial memory. These findings were discussed with respect to accounts of spatial memory that propose multiple systems or formats for coding.

Adolescent↗

Specific comorbidity risk adjustment was a better predictor of 5-year acute myocardial infarction mortality than general methods.

OBJECTIVE: To compare methods of risk adjustment in a population of individuals with acute myocardial infarction (AMI), in order to assist clinicians in assessing patient prognosis. STUDY DESIGN AND SETTING: A historical inception cohort design was established, with follow-up of or=66 years who had an AMI in 1994 or 1995 were selected (n = 4,874). The three risk-adjustment methods were the Ontario AMI prediction rule (OAMIPR), the D'Hoore adaptation of the Charlson Index, and the total number of distinct comorbidities. Logistic regression models were built including each of the adjustment methods, age, sex, socioeconomic status, previous AMI, and cardiac procedures at time of AMI. RESULTS: The OAMIPR had the highest C-statistic and R(2). CONCLUSION: Clinicians are advised to consider the specific comorbidities that are present, not merely their number, and those that emerge over time, not merely those present at the time of the infarct.

Age Factors↗

Dopamine and drug addiction: the nucleus accumbens shell connection.

Microdialysis studies in animals have shown that addictive drugs preferentially increase extracellular dopamine (DA) in the n. accumbens (NAc). Brain imaging studies, while extending these finding to humans, have shown a correlation between psychostimulant-induced increase of extracellular DA in the striatum and self-reported measures of liking and 'high' (euphoria). Although a correlate of drug reward independent from associative learning and performance is difficult to obtain in animals, conditioned taste avoidance (CTA) might meet these requirements. Addictive drugs induce CTA to saccharin most likely as a result of anticipatory contrast of saccharin over drug reward. Consistently with a role of DA in drug reward, D2 or combined D1/D2 receptor blockade abolishes cocaine, amphetamine and nicotine CTA. Intracranial self-administration studies with mixtures of D1 and D2 receptor agonists point to the NAc shell as the critical site of DA reward. NAc shell DA acting on D1 receptors is also involved in Pavlovian learning through pre-trial and post-trial consolidation mechanisms and in the utilization of spatial short-term memory for goal-directed behavior. Stimulation of NAc shell DA transmission by addictive drugs is shared by a natural reward like food but lacks its adaptive properties (habituation and inhibition by predictive stimuli). These peculiarities of drug-induced stimulation of DA transmission in the NAc shell result in striking differences in the impact of drug-conditioned stimuli on DA transmission. It is speculated that drug addiction results from the impact exerted on behavior by the abnormal DA stimulant properties acquired by drug-conditioned stimuli as a result of their association with addictive drugs.

Animals↗

Research perspectives for pre-screening alternatives to animal experimentation: on the relevance of cytotoxicity measurements, barrier passage determinations and high throughput screening in vitro to select potentially hazardous compounds in large sets of chemicals.

The MEIC study revealed a high predictivity of in vitro cytotoxicity data for human acute systemic toxicity. The idea, put forward by several authors, that compounds that show high cytotoxicity should not need further testing for confirmation but could be assumed toxic also in vivo provides a convenient concept for the selection of the most relevant compounds for further studies in large sets of chemicals, as in the REACH program. The automated techniques applied in high throughput screening (HTS) by the pharmaceutical and biotech industries to select hits in extensive compound collections represent an opportunity to significantly increase the capacity of cytotoxicity testing. Furthermore, it has been suggested that a combination of cytotoxicity data and some basic biokinetic information would greatly improve the accuracy in the extrapolation from in vitro to in vivo and thus make it possible to identify additional toxic compounds that might have escaped in the initial screen. Such information, which can be obtained in a medium throughput screening mode (MTS), includes biotransformation, absorption and some aspects of distribution. The measurement of the net flux of a compound over a cellular barrier, as the one formed in culture by human Caco-2 cells, gives useful, but limited, information on both gut absorption and blood-brain barrier penetration. The test procedures discussed here, as well as other supplementary in vitro tests, cannot always easily be described in terms of animal-based test replacements. In those instances, the necessary test validation cannot be carried out using animal reference data, and prediction models may have to be adapted to new ideas. Consequently, concepts of prospective validation to supplement the now well-established retrospective validation have to be developed.

Animal Testing Alternatives↗

Strong linkage disequilibrium between HLA-B*3913 and DRB1*0807 in Brazilians.

The purpose of this research was to study the HLA-B39 distribution in 2560 healthy, unrelated, randomly selected individuals living in the southeastern region of Brazil (the states of Rio de Janeiro and São Paulo). Molecular methods were used to type HLA class I and II polymorphism: PCR-SSP, PCR-SSO, and PCR-SBT. HLA-B*39 was found in 7% (n = 182) of these individuals. HLA-B*3901, B*3906, and B*3913 were the most common alleles in this group (n = 57, 36, and 24, respectively). B*3913 was found associated with DRB1*0807 and DQB1*0402 in 16 of the 24 individuals and 13 of these were also associated with A*31012. This haplotype segregation was confirmed by family studies. Furthermore, in 5 of the 13 individuals carrying the A*31012, B*3913, DRB1*0807, and DQB1*0402 haplotype, HLA-DPB1*2701 was also present, suggesting that these alleles were found preferentially in cis association. DRB1-DPB1 linkage disequilibrium analysis was performed in 420 of the 2560 individuals and the association of DRB1*0807 with the uncommon DPB1*2701 was found to be highly significant (P <.0001). Because HLA-B*3913 and HLA-DRB1*0807 have been observed only in South American populations, it is possible that interlocus association has been selected to act on the same haplotype to collaborate in the class I and II restricted immune response to local pathogens and functional adaptation. Although numbers are small to predict which ethnic groups of the Brazilian population display this haplotype prevalently, it is possible to speculate that these data may have clinical application, such as in the selection of unrelated donors for bone marrow transplantation.

Brazil↗

Measurement of rate of expansion in the perception of radial motion.

Optic flow generated by rigid surface patches can be decomposed into a small number of elementary motion types. In these experiments, we show that the human visual system can evaluate expansion, one of these motion types, metrically. Moreover, we show that the discrimination of rates of expansion are spatially local. Because the estimation of the focus of expansion is somewhat imprecise, this locality sometimes produces predictable errors in the estimation of rate of expansion. One can make predictions like this with a model adapted from one previously developed for angular-velocity discrimination.

Discrimination, Psychological↗

Interplay of hydrophobic and electrostatic interactions in biopolymer chromatography. Effect of salts on the retention of proteins.

The effect of salt on the retention behavior of proteins in electrostatic and hydrophobic interaction chromatography is described by a three-parameter equation, log k' = A - B log ms + Cms, where k' is the retention factor and ms is the molality of the salt in the eluent. Parameter B, termed the electrostatic interaction parameter, depends on the characteristic charge of the protein and the salt counterion and governs the change of retention with the salt concentration in ion-exchange chromatography. According to the model the magnitude of the hydrophobic interaction parameter C is determined by the hydrophobic contact area upon protein binding at the stationary phase surface and the properties of the salt as measured by its molal surface tension increment. Retention data measured at different salt concentrations in the eluent on a variety of ion exchangers can be fitted to the above equation which yields U-shaped plots of log k' against log ms. The limiting slopes of the appropriate plots at sufficiently low and high salt concentrations can be used to evaluate the electrostatic and hydrophobic interaction parameters, respectively. The approach, which is based on a combination of established treatments of electrostatic and hydrophobic interactions offers a convenient framework for analyzing retention data in biopolymer high-performance liquid chromatography and for the characterization of stationary phases. Furthermore, it may facilitate some characterization of protein molecules on the basis of their retention behavior as a function of the concentration and nature of the salt in the eluent. In the treatment of electrostatic interactions use is made of the counterion condensation theory that is believed to make possible a more comprehensive analysis than the traditional stoichiometric ion-exchange model which assumes binding of the proteins by coulombic interactions at discrete sites. The treatment of hydrophobic interactions is based on an adaptation of the solvophobic theory which predicts that the hydrophobic portion of the free energy of binding is proportional to the hydrophobic contact area and the microthermodynamic surface tension of the aqueous salt solution. Despite its simplicity the theory was successful in explaining the observed effect of the nature and concentration of salt in the eluent, the pH and the effect of the density of fixed charges at the surface of the stationary phase in the absence of specific salt effects.

Biopolymers↗