Supporting affect regulation in children with multiple disabilities during psychotherapy: a multiple case design study of therapeutic attachment.

In a controlled multiple case design study, the development of a therapeutic relationship and its role in affect regulation were studied in 6 children with visual disabilities, severe intellectual disabilities, severe challenging behavior, and prolonged social deprivation. In the 1st phase, children had sessions with an experimental therapist stimulating therapeutic attachment, alternating with a control therapist providing positive personal attention only. In the 2nd phase, both therapists applied behavior therapy. Clients sought more proximity to the experimental therapist compared with the control therapist. Psychophysiological arousal (respiratory sinus arrhythmia and pre-ejection period) was lower when the experimental therapist applied behavior modification than when the control therapist did. Despite prolonged social deprivation, the attachment behavioral system appeared responsive to stimulation. The effects on affect regulation may explain the synergy between psychotherapy based on interpersonal and behavior modification approaches.

The absorption, metabolism, and excretion of the novel neuromodulator RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-) in humans.

RWJ-333369 (1,2-ethanediol, [1-2-chlorophenyl]-, 2-carbamate, [S]-; CAS Registry Number 194085-75-1) is a novel neuromodulator in clinical development for the treatment of epilepsy. To study the disposition of RWJ-333369, eight healthy male subjects received a single oral dose of 500 mg of (14)C-RWJ-333369. Urine, feces, and plasma were collected for analysis for up to 1 week after dosing. Radioactivity was mainly excreted in urine (93.8 +/- 6.6%) and much less in feces (2.5 +/- 1.6%). RWJ-333369 was extensively metabolized in humans, since only low amounts of parent drug were excreted in urine (1.7% on average) and feces (trace amounts). The major biotransformation pathways were direct O-glucuronidation (44% of the dose), and hydrolysis of the carbamate ester followed by oxidation to 2-chloromandelic acid, which was subsequently metabolized in parallel to 2-chlorophenyl glycine and 2-chlorobenzoic acid (mean percentage of the dose for the three acids together was 36%). Other routes were chiral inversion followed by O-glucuronidation (11%), and aromatic hydroxylation in combination with sulfate conjugation (5%). In plasma, unchanged drug accounted for 76.5% of the total radioactivity, with the R-enantiomer and the O-glucuronide of the parent drug as the only measurable plasma metabolites. With the use of very sensitive liquid chromatography-tandem mass spectrometry techniques, only traces of aromatic (pre)mercapturic acid conjugates were detected in urine (each <0.3% of the dose), suggesting a low potential for reactive metabolite formation. In conclusion, the disposition of RWJ-333369 in humans is characterized by virtually complete absorption, extensive metabolism, and unchanged drug as the only significant circulating species.

Visual impairments in people with severe and profound multiple disabilities: an inventory of visual functioning.

BACKGROUND: The prevalence of visual impairments in people with severe and profound multiple disabilities (SPMD) is the subject of considerable debate and is difficult to assess. METHODS: In a typical Dutch care organization, all clients with SPMD (n = 76) participated in the study and specific instruments adapted to these clients (requiring a minimum of cooperation) were used to measure visual acuity, the visual field, binocular vision, contrast sensitivity, refractive errors and visual functioning behaviour. RESULTS: We found an unexpected 92% of clients with SPMD to have visual impairments. Previously, only 30% were known to have visual problems. None of the persons observed had normal visual acuity. Subnormal visual acuity was the best result. The severity of the visual impairment was related to the severity of the intellectual disability. In addition to the problem of acuity, impairments in the visual field, impaired contrast sensibility and impaired binocular functioning were found, as well as impaired visual attention, fixation and following. In 22% of the clients observed, refractive errors were found and glasses were advised. CONCLUSIONS: Consequences for caregiving and for modifications of the environment were discussed.

Perspectives on quality of life of people with intellectual disabilities: the interpretation of discrepancies between clients and caregivers.

Large discrepancies have sometimes been found between the quality of life (QOL) experienced by clients with intellectual disabilities and their QOL as described by their caregivers. Olsen and Schober (Soc Indi Res 1993; 28: 173-193) may have provided a framework useful to conceptualize such discrepancies. They suggested that lack of concordance between objective circumstances (i.e. poverty) and perceived QOL must not be treated as measurement noise, but as a source of information. They speculated on the psychological processes that underly and explain this lack of concordance; particularly processes that try to deal with the stress induced by cognitive dissonance and learned helplessness. In this study low to moderate agreement was found between caregivers judgement of QOL of individual clients and clients' own perception of QOL. In some areas and for some clients the discrepancies indicated dissonance (caregivers are satisfied, clients are not) and in other areas and for other clients adaptation (clients are satisfied, caregivers are not). There were systematic differences between clients falling in these groups with respect to their personal characteristics and with respect to factual conditions of care. These outcomes are interpreted with respect to Olson and Schober's contentions regarding the psychological processes that underly a person's experience of QOL. The Olson and Schober framework appears to be a fruitful way to combine different sources of information regarding QOL.

Synthesis and biodistribution of [(11)C]R116301, a promising PET ligand for central NK(1) receptors.

N1-(2,6-Dimethylphenyl)-2-(4-{(2R,4S)-2-benzyl-1-[3,5-di(trifluoromethyl)[carbonyl-(11)C]benzoyl]hexahydro-4-pyridinyl}piperazino)acetamide ([(11)C]R116301) was prepared and evaluated as a potential positron emission tomography (PET) ligand for investigation of central neurokinin(1) (NK(1)) receptors. 1-Bromo-3,5-di(trifluoromethyl)benzene was converted in three steps into 3,5-di(trifluoromethyl)[carbonyl-(11)C]benzoyl chloride, which was reacted with N1-(2,6-dimethylphenyl)-2-{4-[(2R,4S)-2-benzylhexahydro-4-pyridinyl]piperazino}acetamide providing [(11)C]R116301 in 45-57% decay-corrected radiochemical yield. The total synthesis time, from end of bombardment (EOB) to the formulated product, was 35 min. Specific activity (SA) was 82-172 GBq/micromol (n=10) at the end of synthesis. N1-([4-(3)H]-2,6-Dimethylphenyl)-2-(4-{(2R,4S)-2-benzyl-1-[3,5-di(trifluoromethyl)benzoyl]hexahydro-4-pyridinyl}piperazino)acetamide ([(3)H]R116301) was also synthesized (SA: 467 GBq/mmol). The B(max) for [(3)H]R116301 measured in vitro on Chinese hamster ovary cell membranes stably transfected with the human NK(1) receptor was 19.10+/-1.02 pmol/mg protein with an apparent dissociation constant of 0.08+/-0.01 nM. Ex vivo, in vivo and in vitro autoradiography studies with [(3)H]R116301 in gerbils demonstrated a preferential accumulation of the radioactivity in the striatum, olfactory tubercule, olfactory bulb and locus coeruleus. In vivo, the biodistribution of [(11)C]R116301 in gerbils revealed that the highest initial uptake is in the lung, followed by the liver and kidney. In the brain, maximum accumulation was found in the olfactory tubercules (1.10+/-0.08 injected dose (ID)/g 20 min post injection (p.i.)) and the nucleus accumbens (1.00+/-0.12ID/g 10 min p.i.). Tissue/cerebellum concentration ratios for striatum and nucleus accumbens increased with time due to rapid uptake followed by a slow wash out (1.29 and 1.64, respectively, 30 min p.i.). A tissue to cerebellum ratio of 1.33 and 1.62 was also observed for olfactory bulb and olfactory tubercules, respectively (20 min p.i.). In summary, [(11)C]R116301 appears to be a promising radioligand suitable for the visualization of NK(1) receptors in vivo using PET.

Understanding challenging behaviour in people with severe and profound intellectual disability: a stress-attachment model.

BACKGROUND: Advances in our knowledge of attachment, stress and coping may foster new explanations for the development of challenging behaviour in people with intellectual disability (ID). METHOD: Research on stress and coping among people with ID was reviewed initially, and then studies on the security of the attachment relationships of people with ID with their caregivers were analysed. RESULTS: There is evidence that people with ID are more vulnerable to stress and use less effective coping strategies. Furthermore, the body of studies on attachment indicates that people with ID are at risk for developing insecure, especially disorganized attachment. There is evidence from other populations that the combination of stress, and insecure or disorganized attachment may put people at risk for developing behaviour problems. CONCLUSION: A stress-attachment model of the development of challenging behaviour among people with ID shows promise as an explanatory framework. The uncovering of these developmental mechanisms may be particularly useful for the prevention of behavioural problems.

The quality of life of people with mental retardation: in search of an adequate approach.

There is a lack of instruments that measure the quality of life of people with mental retardation. These types of instruments could be used in order to give an indication of the quality of care they receive. At the moment we are developing an instrument that measures quality of life. Our first task is to find an adequate definition of 'quality of life'. In this article an attempt is made to define this term as it relates to people with mental retardation. Starting from literature in the field of disabilities, reflections in the social sciences and philosophical analysis, a combined approach is adopted, according to which quality of life consists of specific objective and subjective factors.

Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of alpha-anilinophenylacetamide derivatives targeted at HIV-1 reverse transcriptase.

In vitro evaluation of a large chemical library of pharmacologically acceptable prototype compounds in a high-capacity, cellular-based screening system has led to the discovery of another family of human immunodeficiency virus type 1 (HIV-1) inhibitors. Through optimization of a lead compound, several alpha-anilinophenylacetamide (alpha-APA) derivatives have been identified that inhibit the replication of several HIV-1 strains (IIIB/LAI, RF, NDK, MN, HE) in a variety of host cell types at concentrations that are 10,000- to 100,000-fold lower than their cytotoxic concentrations. The IC50 of the alpha-APA derivative R 89439 for HIV-1 cytopathicity in MT-4 cells was 13 nM. The median 90% inhibitory concentration (IC90) in a variety of host cells was 50-100 nM. Although these alpha-APA derivatives are active against a tetrahydroimidazo [4,5,1-jk][1,4]benzodiazepin-2(1H)-thione-(TIBO)-resistant HIV-1 strain, they do not inhibit replication of HIV-2 (strains ROD and EHO) or simian immunodeficiency virus (strains Mac251, mndGB1, and agm3). An HIV-1 strain containing the Tyr181-->Cys mutation in the reverse transcriptase region displayed reduced sensitivity. alpha-APA derivative R 89439 inhibited virion and recombinant reverse transcriptase of HIV-1 but did not inhibit that of HIV-2. Reverse transcriptase inhibition depended upon the template/primer used. The relatively uncomplicated synthesis of R 89439, its potent anti-HIV-1 activity, and its favorable pharmacokinetic profile make R 89439 a good candidate for clinical studies.

In vitro labeling of serotonin-S2 receptors: synthesis and binding characteristics of [3H]-7-aminoketanserin.

[3H]-7-Aminoketanserin (7-amino-3-[2-[4-(2-tritio-4-fluorobenzoyl)-1- piperidinyl]ethyl]-2,4-(1H,3H)-quinazolinedione), an amino derivative of the selective serotonin-S2 antagonist ketanserin, was synthesized and tested for in vitro labeling of serotonin-S2 receptors. The compound showed a very high affinity for both membrane-bound and detergent-solubilized serotonin-S2 receptors with KD values of 0.35 and 2.03 nM, respectively. At nanomolar concentrations, binding to serotonin-S1 sites was totally absent. Serotonin-S2 receptor binding was characterized by a slow dissociation and a very low nonspecific binding. In rat frontal cortex preparations, binding could be displaced by nanomolar concentrations of different serotonin antagonists and micromolar concentrations of serotonin agonists. Compounds with other pharmacological profiles were poorly or not active. Introduction of an amino function in this new radioligand led to a decreased lipophilicity. Therefore, besides being a valuable radioligand for routine binding studies, [3H]-7-aminoketanserin will probably be a good ligand for labeling serotonin-S2 receptors on intact cells.