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[Is brain surgery on primates in basic research morally acceptable?]

In the contemporary controversy about the legitimacy of vivisection a few basic assumptions are shared by nearly all participants of the discussion. (I) Pure Research in the service of medicine is of great value for humankind. It contributes to prolonging human life and the alleviation and prevention of human suffering. (II) Brain surgery for the sole purpose of pure research is morally unacceptable in the case of any human being. (III) Primates are sensitive beings which lead a rich social life and are endowed with remarkable intellectual capacities. (IV) Primates have a moral standing, possibly to a lesser degree compared with human beings, certain acts are therefore an injustice toward them. The controversy then is about the question whether premise (I) outweighs (IV), i.e. whether the benefit of the pure research is from a moral point of view more important than the suffering of innocent primates. I shall present four arguments against such a conclusion. 1) According to premise (I) brain surgery on human beings for the sole purpose of pure research is morally unacceptable. Since this prohibition is meant to include all human beings it cannot rest on the exclusive human possession of reason because e.g. some mentally handicapped human beings lack this faculty. All other properties which may be named as basis for the ascription of a moral status which forbids brain surgery for pure research, are possessed also by some animals, especially primates; therefore it is impossible to deny them the same moral status. 2) Brain surgery on primates is confronted with an insoluble dilemma: If the characteristics of the primate brain are very similar to that of human beings, the scientific benefit is obvious, but the procedure appears to be morally unacceptable exactly because of this similarity. If, on the other hand, the characteristics differ significantly, brain surgery may seem legitimate but the scientific benefit becomes doubtful at best. 3) We could quite easily save hundreds of human lives if e.g. speed limits would be reduced (say) by half. Most of us, however, are unwilling to accept such a loss of quality of life in order to save a certain number of human lives. Since we are no prepared to pay this comparatively modest price, we have, in my eyes, no moral right to impose considerable pain and suffering on a primate to save human lives. 4) Pure research in the service of human medicine is from a moral point of view of great importance. Since most of the work in this area is done or financed by private corporations and not by state institutions, from a economical point of view the aim consists in making profit. Since the latter aspect has gained more and more weight in the last years the moral worth of pure research cannot rule out any other moral concern.

Journal Article↗

Assessment of stimulus preference and reinforcer value with profoundly retarded individuals.

We evaluated a procedure for identifying potential reinforcers with profoundly retarded individuals. In Experiment 1, six persons were repeatedly exposed to 16 stimuli, and approach behaviors to each stimulus were used to identify preferred and nonpreferred stimuli. In Experiment 2, we examined the reinforcing properties of preferred and nonpreferred stimuli by delivering them contingently on the occurrence of arbitrarily selected responses. Results revealed that the preferred stimulus conditions typically produced higher rates of responding than did either the baseline or the nonpreferred stimulus conditions, suggesting that the procedure can be used to assess reinforcer value for individuals with limited behavioral repertoires.

Adolescent↗

Biocommodity Engineering.

The application of biotechnology to the production of commodity products (fuels, chemicals, and materials) offering benefits in terms of sustainable resource supply and environmental quality is an emergent area of intellectual endeavor and industrial practice with great promise. Such "biocommodity engineering" is distinct from biotechnology motivated by health care at multiple levels, including economic driving forces, the importance of feedstocks and cost-motivated process engineering, and the scale of application. Plant biomass represents both the dominant foreseeable source of feedstocks for biotechnological processes as well as the only foreseeable sustainable source of organic fuels, chemicals, and materials. A variety of forms of biomass, notably many cellulosic feedstocks, are potentially available at a large scale and are cost-competitive with low-cost petroleum whether considered on a mass or energy basis, and in terms of price defined on a purchase or net basis for both current and projected mature technology, and on a transfer basis for mature technology. Thus the central, and we believe surmountable, impediment to more widespread application of biocommodity engineering is the general absence of low-cost processing technology. Technological and research challenges associated with converting plant biomass into commodity products are considered relative to overcoming the recalcitrance of cellulosic biomass (converting cellulosic biomass into reactive intermediates) and product diversification (converting reactive intermediates into useful products). Advances are needed in pretreatment technology to make cellulosic materials accessible to enzymatic hydrolysis, with increased attention to the fundamental chemistry operative in pretreatment processes likely to accelerate progress. Important biotechnological challenges related to the utilization of cellulosic biomass include developing cellulase enzymes and microorganisms to produce them, fermentation of xylose and other nonglucose sugars, and "consolidated bioprocessing" in which cellulase production, cellulose hydrolysis, and fermentation of soluble carbohydrates to desired products occur in a single process step. With respect to product diversification, a distinction is made between replacement of a fossil resource-derived chemical with a biomass-derived chemical of identical composition and substitution of a biomass-derived chemical with equivalent functional characteristics but distinct composition. The substitution strategy involves larger transition issues but is seen as more promising in the long term. Metabolic engineering pursuant to the production of biocommodity products requires host organisms with properties such as the ability to use low-cost substrates, high product yield, competitive fitness, and robustness in industrial environments. In many cases, it is likely to be more successful to engineer a desired pathway into an organism having useful industrial properties rather than trying to engineer such often multi-gene properties into host organisms that do not have them naturally. Identification of host organisms with useful industrial properties and development of genetic systems for these organisms is a research challenge distinctive to biocommodity engineering. Chemical catalysis and separations technologies have important roles to play in downstream processing of biocommodity products and involve a distinctive set of challenges relative to petrochemical processing. At its current nascent state of development, the definition and advancement of the biocommodity field can benefit from integration at multiple levels. These include technical issues associated with integrating unit operations with each other, integrating production of individual products into a multi-product biorefinery, and integrating biorefineries into the broader resource, economic, and environmental systems in which they function. We anticipate that coproduction of multiple products, for example, production of fuels, chemicals, power, and/or feed, is likely to be essential for economic viability. Lifecycle analysis is necessary to verify the sustainability and environmental quality benefits of a particular biocommodity product or process. We see biocommodity engineering as a legitimate focus for graduate study, which is responsive to an established personnel demand in an industry that is expected to grow in the future. Graduate study in biocommodity engineering is supported by a distinctive blend of intellectual elements, including biotechnology, process engineering, and resource and environmental systems.

Journal Article↗

On the cause of mental retardation in Down syndrome: extrapolation from full and segmental trisomy 16 mouse models.

Down syndrome (DS, trisomy 21, Ts21) is the most common known cause of mental retardation. In vivo structural brain imaging in young DS adults, and post-mortem studies, indicate a normal brain size after correction for height, and the absence of neuropathology. Functional imaging with positron emission tomography (PET) shows normal brain glucose metabolism, but fewer significant correlations between metabolic rates in different brain regions than in controls, suggesting reduced functional connections between brain circuit elements. Cultured neurons from Ts21 fetuses and from fetuses of an animal model for DS, the trisomy 16 (Ts16) mouse, do not differ from controls with regard to passive electrical membrane properties, including resting potential and membrane resistance. On the other hand, the trisomic neurons demonstrate abnormal active electrical and biochemical properties (duration of action potential and its rates of depolarization and repolarization, altered kinetics of active Na(+), Ca(2+) and K(+) currents, altered membrane densities of Na(+) and Ca(2+) channels). Another animal model, the adult segmental trisomy 16 mouse (Ts65Dn), demonstrates reduced long-term potentiation and increased long-term depression (models for learning and memory related to synaptic plasticity) in the CA1 region of the hippocampus. Evidence suggests that the abnormalities in the trisomy mouse models are related to defective signal transduction pathways involving the phosphoinositide cycle, protein kinase A and protein kinase C. The phenotypes of DS and its mouse models do not involve abnormal gene products due to mutations or deletions, but result from altered expression of genes on human chromosome 21 or mouse chromosome 16, respectively. To the extent that the defects in signal transduction and in active electrical properties, including synaptic plasticity, that are found in the Ts16 and Ts65Dn mouse models, are found in the brain of DS subjects, we postulate that mental retardation in DS results from such abnormalities. Changes in timing and synaptic interaction between neurons during development can lead to less than optimal functioning of neural circuitry and signaling then and in later life.

Animals↗

Self-restraint: a review of etiology and applications in mentally retarded adults with self-injury.

Self-restraint has been noted in studies of self-injurious behavior (SIB) in mentally retarded individuals. These studies have investigated self-restraint in the context of SIB, and as a result it has been difficult to isolate the function of self-restraint within this complex clinical situation. This article summarizes and critically analyzes the literature on self-restraint, particularly its identification, etiology, modification, and relationship to SIB. At present there is some empirical evidence to suggest that self-restraint is negatively reinforced by the termination or avoidance of SIB. Other studies have demonstrated that self-restraint can develop stimulus control properties for the absence of SIB. Finally, it has been suggested that self-restraint may function independently of SIB and be maintained by escape from demands or by conditioned reinforcement. Clinical concerns include the need for a functional analysis of self-restraint, the undesirable effects on SIB of reducing self-restraint, and the necessity of replacing self-restraint topographies with ones which do not interfere with daily activities.

Adult↗

In pursuit of knowledge.

This article is based on the proposition that to understand the nature of knowledge, and how best to acquire it, one must look first at how the brain abstracts knowledge from the information provided by sensory receptors. The nature of this biological process of knowledge acquisition is suggested by the necessary conditions for the occurrence of learning, and from consideration of these necessary conditions in terms of what is currently known about the properties and limitations of neural systems. This entails discussion of an important distinction that must be made between "perceptual" and "associative" learning and between the neural systems required to mediate these two kinds of learning. There is also discussion of the manner in which language can overcome the limitations of neurological systems to greatly extend the scope of associative learning. This leads on to discussion of the role of active efferent language systems and temporary memory in the mediation of thinking. Consideration of the main features of the biological process of knowledge acquisition confirms, and extends to perception, Hume's famous conclusion that knowledge derives from the similarity or temporal contiguity of recurring events. New insights are also obtained concerning the biological causes of bias in the knowledge acquisition process, concerning the intellectual process of theory generation, and concerning the role of theory in the conduct of empirical research. Finally, and most importantly, it can be concluded that all knowledge is theory and hence that the ultimate goal of science is the development of better theories.

History, 20th Century↗

Predictors for attacks on people after deinstitutionalization.

BACKGROUND: The deinstitutionalization movement is presently spreading in Europe, but studies evaluating the effects of deinstitutionalization on behaviour disturbances among people with intellectual disability (ID) are inconclusive. The prevalence of aggressive behaviour among people with ID is high in both institutions and in community. Aggression and attacks on people are a significant problem for people with ID in both institutions and society. In the present paper, the authors focus on individuals who started attacking people after deinstitutionalization. METHOD: The authors studied individual and environmental characteristics before and after deinstitutionalization to look for individual and environmental predictors for the development of aggression with the hope that some could be possible intervention points for preventive action. In an institution for people with ID, all who did not attack people before deinstitutionalization were included. The individuals who started attacking others after deinstitutionalization (n = 22) were the study group (group A) and those who did not (n = 42) comprised the control group (group B). The population was examined before and after deinstitutionalization. As far as possible the same methods were used at both occasions. The covariates included individual ones, such as mental health, behaviour disturbances and behaviour deficits, and environmental ones, such as caretaker education, caretaker:patient ratio, housing and leisure activities. Psychiatric disorders were identified in 1987 and 1995 with the Psychopathology Instrument for Mentally Retarded Adults (PIMRA), which was filled in by the caretakers. RESULTS: Group A showed significantly more self-injurious behaviour (SIB) than group B in 1987. The sum of behaviour disturbances shown in the past year, attacks on property, SIB and other disruptive behaviours were also significantly higher in group A than in group B. The soundness scores on the PIMRA for the people in group A were lower than for the people in group B. Group A contained significantly fewer people without behavioural problems in the past year. The authors could not find any differences on other individual characteristics such as aetiologies of ID and behaviour deficits in 1987. The caretakers' evaluations of the clients need for help, based on behaviour disturbances and mental health problems, were significantly higher in group A. The people in this study differed in age, gender and degree of ID from those in most other studies on ID and challenging behaviour. CONCLUSION: The individual predictors for starting to attack others after deinstitutionalization were SIB, a slight load of other behaviour problems and a low soundness score on the PIMRA. The only environmental predictor was the caretakers' evaluation of the subjects' need for help caused by behaviour problems and mental illness. The authors could not identify possible preventive intervention points, neither individual or environmental, and therefore, further studies are needed.

Adolescent↗

Time-series analysis of stereotyped movements: relationship of body-rocking to cardiac activity.

The pathological stereotypies frequently observed among severely mentally retarded and autistic persons are highly rhythmical in nature. Most attempts to quantify such behavior, however, have not analyzed stereotypy in terms of its cyclical properties. In the present paper we have detailed a method for electronically transducing stereotyped body-rocking and analyzing its frequency and amplitude characteristics with a standard polygraph and microprocessor. The relationship between stereotyped body-rocking and cardiac activity was also described using time-series analysis. The method described should provide a sensitive index of various experimental manipulations and treatment effects.

Adult↗

Lesch-Nyhan syndrome: altered kinetic properties of mutant enzyme.

Hypoxanthine-guanine phosphoribosyltransferase is virtually inactive in erythrocytes from patients with the classical Lesch-Nyhan syndrome. In one such patient, activity of this enzyme ranged from 8 to 34 percent of normal in erythrocytes when assayed with a very high concentration of magnesium 5-phosphoribosyl-1-pyrophosphate. In addition, the mutant enzyme exhibited sigmoidal kinetics with this substrate as well as an increased Michaelis constant for both guanine and hypoxanthine. These findings provide the first evidence for genetic heterogeneity within the group of patients with the Lesch-Nyhan syndrome.

Athetosis↗

The Aberrant Behaviour Checklist: a British replication and extension of its psychometric properties.

The Aberrant Behaviour Checklist was administered to 209 British mentally handicapped adults in two large residential facilities. This sample included a substantial proportion (45%) of non-ambulant people not included in previous studies. The five-factor solution originally reported by Aman et al. (1985a) was replicated using both four-point ratings and dichotomously recoded rating. For both methods of scoring, the five scales derived from Aman et al.'s original factor analysis remained highly internally consistent. Dichotomously coded ratings may offer the advantage over four-point ratings of retaining the same factor structure with better reliability.

Adult↗

Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome, West syndrome, and X-linked infantile spasms sharing the common features of generally intractable early seizures and mental retardation. Disease-causing mutations are distributed in both the catalytic domain and in the large COOH terminus. In this report, we examine the functional consequences of some Rett mutations of CDKL5 together with some synthetically designed derivatives useful to underline the functional domains of the protein. The mutated CDKL5 derivatives have been subjected to in vitro kinase assays and analyzed for phosphorylation of the TEY (Thr-Glu-Tyr) motif within the activation loop, their subcellular localization, and the capacity of CDKL5 to interact with itself. Whereas wild-type CDKL5 autophosphorylates and mediates the phosphorylation of the methyl-CpG-binding protein 2 (MeCP2) in vitro, Rett-mutated proteins show both impaired and increased catalytic activity suggesting that a tight regulation of CDKL5 is required for correct brain functions. Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif. Eventually, we show that the COOH terminus regulates CDKL5 properties; in particular, it negatively influences the catalytic activity and is required for its proper sub-nuclear localization. We propose a model in which CDKL5 phosphorylation is required for its entrance into the nucleus whereas a portion of the COOH-terminal domain is responsible for a stable residency in this cellular compartment probably through protein-protein interactions.

Animals↗

Relationships between sensory stimulation and stereotyped behaviour in severely mentally retarded and autistic children.

The reinforcing properties of four sensory stimuli (continuous and flashing light, vibration and sound) which were under the subject's control, were examined and the effect on stereotyped behaviour observed. The subjects were 24 severely retarded children in three diagnostic groups; Down's, Rubella and a group which included neither of these diagnoses. Duration of stimulation with continuous light was significantly lower than the other three stimuli, but there were no differential effects on stereotypy, nor diagnostic group differences.

Adolescent↗

Reliability of the assessment of dual diagnosis (ADD).

Emotional and behavioral problems are a major source of additional handicap for children, adolescents, and adults with mental retardation. To address these problems, clinicians need psychometrically sound instruments for assessing psychopathology in individuals with mental retardation. The initial psychometric properties of the Assessment for Dual Diagnosis (ADD), a new scale designed to screen for psychopathology in individuals with mild and moderate mental retardation, was examined. The authors conducted a preliminary evaluation of the interrater and test-retest reliability of the ADD. It was determined that the ADD had high stability across raters and high stability over time. In addition, good internal consistency was established with coefficient alpha. Potential uses for the scale and directions for future research are discussed.

Diagnosis, Dual (Psychiatry)↗

Psychometric properties of two measures of intrinsic motivation.

Howard's Maze Test and Maw and Maw's Which-to-Discuss Test were individually administered to 25 educable mentally retarded junior high school students. Although the internal consistency of both tests was acceptably high (.81 to .90, respectively), scores were essentially unrelated to a host of demographic and other types of variables. Moreover, the correlation between scores on the two instruments was only -.06. It was suggested that the tests might better be described as measures of diversive curiosity and specific curiosity, respectively, than as measures of intrinsic motivation.

Adolescent↗

Mental retardation and WAIS-R scatter analysis.

In an earlier article, the psychometric properties of Wechsler Adult Intelligence Scale-Revised (WAIS-R) subtest difference scores were explored using a sample with IQ < 80. Data were offered which allowed the practitioner to determine whether the difference between two subtests was statistically reliable. This article represents an extension of the earlier work. It presents a set of reliability estimates for the difference between a single WAIS-R subtest and the mean of all subtests, and permits the clinician to determine whether the difference obtained by a particular examinee is statistically significant.

Adult↗

Measurement of perceived competence in Dutch children with mild intellectual disabilities.

BACKGROUND: Little research has been conducted on the perceived competence of children with mild intellectual disabilities (MID). One of the reasons for the marked absence of research appears to be the lack of reliable and clearly valid measurement instruments for this particular group of children. In the present study, it was examined whether a pictorial scale originally designed to measure perceived competence in typically developing children could successfully be used with children with MID. METHODS: The pictorial scale was administered to a group of 106 children with MID. The construct validity, reliability and stability of the scale were investigated. RESULTS: The results of the exploratory factor analyses and the confirmatory factor analyses supported the conceptual framework proposed. The construct validity was also supported by the pattern of intercorrelations between the subscales. The scale had adequate internal consistency and the stability analyses showed sufficient stability across a 4-month period. CONCLUSIONS: The findings show the psychometric properties of the pictorial scale to justify its use with children with MID.

Child↗

Non-Gaussian behavior of the EEG in Down's syndrome suggests decreased neuronal connections.

Computer analyses of the electroencephalograms of normal children, and children with Down's syndrome who were mentally retarded, revealed differences in the distribution of amplitude between the two groups. Normal children, in the early postnatal period, generate EEG's which have a non-Gaussian distribution of amplitude that becomes increasingly Gaussian before one year of age and remains so throughout subsequent development. Conversely, the EEG's of children with Down's syndrome exhibit highly non-Gaussian properties at all ages studied. The EEG's of two mentally retarded autistic children did not show this property, so it is not merely a concomitant of mental retardation. The first-order Gaussian distribution may reflect the degree of inteneuronal coupling; since an increased number of connections on any neuron implies decreased functional dependence of that neuron on any other particular single neuron, the present evidence, which indicates stronger interneuronal coupling in mongoloids, suggests that Down's syndrome may be associated with incomplete postnatal development of interconnections between cortical neurons.

Autistic Disorder↗

[Spectral analytical study on the developmental properties of EEG in children: Generalized and localized components of EEG spectra in the normal and the mentally retarded children (author's transl)].

The purpose of the present study was to elucidate the developmental properties of EEG in the normal and the mentally retarded children through regional differences and regional regional interrelationships. The localized components appearing at 1 or 2 regions tended to show low coherences in relation to the occipital region. The generalized component, observed over all regions, indicated lower coherences in the theta component than in the alpha one. It may be inferred that the theta component shown in the developing children may be differenciated from the component around 10 Hz.

Adolescent↗