Role of fas ligand in uveal melanoma-induced liver damage.

BACKGROUND: Uveal melanoma, the most common adult intraocular malignancy, metastasizes preferentially to the liver. Areas of cell death surrounding uveal melanoma metastases were observed in the livers of mice. We hypothesized that uveal melanoma cells might express Fas ligand (FasL), facilitating FasL-mediated apoptosis of Fas-expressing hepatocytes. PURPOSE: To determine whether Fas ligand (FasL)-expressing human uveal melanoma cells induce apoptosis of human hepatocytes in vitro and in vivo. METHODS: Human uveal melanoma cell lines were assayed for FasL expression by flow cytometry and immunohistology. A human hepatocyte cell line was assayed for Fas expression by flow cytometry. Apoptosis of hepatocytes was detected by annexin V staining in vitro, and terminal deoxynucleotidyl transferase nick end labeling (TUNEL) in vivo. RESULTS: Human uveal melanoma cell lines expressed FasL, as determined by flow cytometry and immunohistology. Human hepatocytes were Fas-positive by flow cytometry. In vitro, annexin V staining revealed that human uveal melanoma cells induced apoptosis of human hepatocytes. TUNEL staining of liver metastases revealed apoptosis of murine hepatocytes in contact with metastatic human uveal melanoma cells. CONCLUSION: FasL-induced apoptosis of hepatocytes in contact with FasL-positive human uveal melanoma cells may contribute to hepatic failure during metastatic disease.

Human uveal melanoma cells produce macrophage migration-inhibitory factor to prevent lysis by NK cells.

Human uveal melanoma arises in an immune privileged ocular environment in which both adaptive and innate immune effector mechanisms are suppressed. Uveal melanoma is the most common intraocular tumor in adults and is derived from tissues in the eye that produce macrophage migration-inhibitory factor (MIF), a cytokine that has recently been demonstrated to produce immediate inhibition of NK cell-mediated lytic activity. Although NK cell-mediated lysis of uveal melanomas is inhibited in the eye, melanoma cells that disseminate from the eye are at risk for surveillance by NK cells. Moreover, uveal melanoma cells demonstrate a propensity to metastasize to the liver, an organ with one of the highest levels of NK activity in the body. Therefore, we speculated that uveal melanomas produced MIF as a means of escaping NK cell-mediated lysis. Accordingly, seven primary uveal melanoma cell lines and two cell lines derived from uveal melanoma metastases were examined for their production of MIF. MIF was detected in melanoma culture supernatants by both ELISA and the classical bioassay of macrophage migration inhibition. Melanoma-derived MIF inhibited NK cell-mediated lysis of YAC-1 and uveal melanoma cells. Cell lines derived from uveal melanoma metastases produced approximately twice as much biologically active MIF as cultures from primary uveal melanomas. Inhibition of NK cell-mediated killing by uveal melanoma-derived MIF was specifically inhibited in a dose-dependent manner by anti-MIF Ab. The results suggest that human uveal melanoma cells maintain a microenvironment of immune privilege by secreting active MIF that protects against NK cell-mediated killing.

A comparison of static and dynamic presentation procedures on discrimination learning of individuals with severe or moderate mental retardation.

A dynamic presentation of stimulus materials may be more effective than a static presentation. To test this hypothesis, we taught 16 individuals with moderate or severe mental retardation to identify two comparative discriminations (more, longer) by each of two different procedures. In the static, or traditional, presentation procedure the stimuli were positioned before a trial began and not manipulated by the experimenter during the trial. In the dynamic presentation procedure the individual watched the experimenter manipulate the relevant dimension of the stimuli during a series of trials. Both procedures were used in combination with a procedure that relied on fading and on many examples of both the correct and incorrect stimuli across trials. Data were presented in four phases: training, generalization, 1-week maintenance, and 1-month maintenance. No differences in percentage of unprompted correct responses were found between the two procedures in training, generalization, or any of the four maintenance tests. Discussion included possible reasons these results differed from those of prior studies as well as the need for further investigation of the dynamic presentation procedure used with more traditional teaching procedures that rely on extrastimulus prompts.

Behavioral assessment of feeding problems of individuals with severe disabilities.

As many as 80% of the individuals with severe or profound mental retardation exhibit feeding problems. Although behavioral interventions have been used to treat these problems, no assessment procedure for determining a functional relationship between a person's acceptance of food and the type and texture of that food has been reported. The purpose of this study was to test a behavioral assessment procedure for a feeding problem of limited intake. Five individuals with severe or profound mental retardation were fed 10 to 12 types of foods with one or more textures. Behavioral categories of acceptance, rejection, expulsion, and other negative behavior were recorded. Results indicated that each subject fit into one of four categories of feeding problems: (a) total refusal, (b) type selectivity, (c) texture selectivity, or (d) type and texture selectivity. Thus, although all 5 subjects exhibited limited intake, the food characteristics correlated with the problem were different for each individual. Results suggest that treatments for limited intake may be based on assessments that show the association of food type or texture to a person's rejection or expulsion of food.

Hypothesis-based interventions for tantrum behaviors of persons with developmental disabilities in school settings.

We conducted a functional assessment of problem behaviors of 2 students with developmental disabilities in their classroom environments. Results of the assessments showed that although there were more tantrums in demand than in no-demand conditions, the function of the behavior was to gain attention (positive reinforcement) rather than to avoid or escape demands (negative reinforcement); demand conditions apparently served a discriminative function for the availability of attention. Therefore, intervention was based on the positive reinforcement hypothesis, resulting in a substantial reduction of tantrums for both subjects.

The Task Demonstration Model: a concurrent model for teaching groups of students with severe disabilities.

This study investigated the use of the Task Demonstration Model (TDM) of group instruction for students with severe or moderate retardation. This model and the Standard Prompting Hierarchy (SPH) were tested against each other (and baseline) across three teachers and groups of students. Results on teacher variables showed that demands and praise were roughly equivalent for both procedures, but prompts were 12 times higher in SPH than in TDM. Data on student variables showed task engagement to be the same for SPH and TDM, percent correct to be 10% higher in TDM, but rate correct to be twice as much in TDM as in SPH.

A study of the homeostatic level of stereotypy and other motor movements of persons with mental handicaps.

Stereotypy is one of the most common behaviours demonstrated by persons with mental handicaps. As such, it has generated a number of theories concerning its origin or maintenance. One of these theories, the homeostatic one, suggests that some persons engage in stereotypies and other motor behaviours in order to maintain a relatively constant level of responding. If this was indeed true, the fact would have important implications for treatment, i.e. those persons who varied rates of both stereotypy and other movements but retained an overall level of motoric responding would seem to be those for whom procedures like the differential reinforcement of incompatible behaviour would be highly appropriate. The purpose of this paper was to determine whether some people do engage in constant levels of responding, and it did so by collecting data on stereotypy and other motor movements of 12 persons with retardation. Collected throughout the school day for 5 consecutive days on micro-computers, the data showed (1) that the stereotypic responding of four subjects was extraordinarily consistent, with the most deviant day's total being only 15 or 16% from the mean of the 5 days, (2) that other motor movements were inconsistent for all but one subject, but (3) that total movement (i.e. stereotypy plus other motor movements) was very high and was consistent for most subjects. The data were discussed in terms of assessing baselines for subjects for whom reinforcing adaptive motor movements would seem an appropriate means for reducing stereotypic responding.

An analysis of a group teaching procedure for persons with developmental disabilities.

This study evaluated whether a concurrent group teaching procedure, in which all students respond simultaneously, could be used for persons with moderate or severe mental retardation. The teaching procedure used was the Task Demonstration Model, a program based on stimulus-control research and the fading techniques of behavioral psychology. Three teachers and three groups of students participated. Results showed that the teachers increased their rates of questions and instructions, positive feedback, and use of functional materials, but they reduced their rate of prompts to almost zero. Students increased their percentage and rate of correct responding as well as their engaged time. In addition, maladaptive responding, for which there were never any direct consequences, decreased from 45% to 10% for 8 of the 14 students. Results are discussed primarily in two areas: (a) changing stimulus control from teacher prompts to critical elements of the items being taught, and (b) reasons for the reduction of maladaptive behavior for 8 of the subjects.

Ecobehavioural analysis of stereotypic and adaptive behaviours: activities as setting events.

The effects of activities and task demands on the rate of stereotypic and adaptive behaviour were analysed within the conceptual framework of setting events. Data on 12 mentally retarded subjects were collected in real time using portable microcomputers during six activities: leisure, pre-vocational training, gym, academic instruction, home living, and lunch. Results showed that stereotypic and adaptive responses occurred in all settings, with the two behaviours occurring simultaneously across both subjects and activities some of the time. Micro-level analysis showed that teacher covert task demand provided the setting event for most of the stereotypic and adaptive responding during each activity. The importance of ecobehavioural analysis in understanding the nature of stereotypy and adaptive behaviour, and the contribution of such an analysis to appropriate and effective intervention were highlighted.

Pediatric feeding disorders.

Feeding problems occur in children who have normal development, who have failure to thrive, and who have developmental disabilities. This article focuses on the latter two groups. The characteristics and developmental concerns include family characteristics, parent-child interactions, cognitive development, and oral-motor development. The evaluation process for children with feeding problems should include an interdisciplinary approach with a medical, nutritional, occupational therapy, and behavioral evaluation. The behavioral treatments include the Premack principle, time-out plus reinforcement, and negative reinforcement. Future research should focus on the parent-child interaction process in both mealtime and nonmealtime situations, along with demonstrating parents' and teachers' ability to implement mealtime treatment protocols.

The effects of initial interval size on the efficacy of DRO schedules of reinforcement.

The differential reinforcement of other behavior (DRO) is a behavior-reduction procedure that has been popular for several years. In classroom settings, it provides reinforcement when a student does not display inappropriate responding for a particular interval of time. Unfortunately, relatively little is known about how to use DRO effectively in applied settings. Most research has been conducted in laboratory settings; the purpose of the present study was to provide a replication of one of those studies. This study examined the effect of the size of the initial DRO interval on the disruptive behavior of students with moderate disabilities. In the first experiment, a group of six students was observed during baseline in two classes. Two different DRO values were then used. In one classroom, it was equal to the mean number of 10-second intervals between disruptions during baseline. In the other classroom, it was twice the mean number during baseline. In the final phase, behavior in both classrooms was put under the same DRO program. In the second experiment, the disruptive behavior of three students was studied in a different design in which both methods of determining the initial DRO value were compared. The results of both experiments showed that an initial DRO value equal to the mean number of intervals between responses in baseline was much more effective than a value twice that size in reducing disruptions.

The relationship of staff:client ratios, interactions, and residential placement.

The behavior of staff and persons with severe handicaps was surveyed in nine settings, including four traditional institutions, three large community-based units, and two groups of small homes. Data were collected that established the relationship among staff:client interactions, client responding, and the size of staff:client groups. The latter showed that the institutions were characterized by larger client and staff groups than the large community units. Large client and staff groups were virtually absent in the small homes. Two general conclusions could be drawn about the relationship between staff:client ratios and client behavior: (a) when one or two staff were together, improvements in the level of the staff interactions and client adaptive functioning occurred as the client group decreased in size and the staff size remained constant; (b) improvement in staff performance and client behavior arising from the addition of staff to a client group of a given size was marginal or nonexistent. The results were discussed in terms of their implications for the design of residential environments.

The use of functional analyses to test causes of self-injurious behaviour: rationale, current status and future directions.

Self-injurious behaviour (SIB) is a relatively common phenomenon among severely retarded persons and involves various repetitious behaviours resulting in tissue damage. Perhaps because of the damage it does, the behaviour has generated a considerable amount of applied research and discussion, and much of this research has involved attempts to reduce SIB through the manipulation of antecedents or consequences. The purpose of this paper was to determine the extent to which those conducting this research used a functional analysis of SIB to determine why the behaviour was occurring and subsequently matched treatment to one of these reasons. Results showed that only a small proportion of the studies reported analyses that would allow the experimenter to determine reasons for the self-injurious behaviour. The discussion centres on why functional analyses are not conducted in ways that would lend treatment to be based on hypotheses of why SIB occurs.

Discrimination training for persons with developmental disabilities: a comparison of the task demonstration model and the standard prompting hierarchy.

A comparison was made between two procedures for teaching persons with severe handicaps: (a) the task demonstration model, which is based upon a fading procedure and general case programming, and (b) the standard prompting hierarchy, a least-to-most intrusive prompting procedure commonly used to teach these individuals. Five phases were used in comparing the procedures: pretesting, training, two generalization tests, and a 6-month maintenance test. Eight students learned two discrimination tasks by each procedure, with each task involving two- or three-digit numbers. Results showed that under the task demonstration model all 8 subjects had more unprompted correct responses (about 1.5 times as many) in training, all 8 subjects had fewer errors (about 0.6 times as many) in training, all 8 subjects had more correct responding in the generalization test with untrained stimuli in the training room, 6 of 8 subjects had more correct responding with untrained stimuli in another room, a 7th had equivalent amounts, and 7 of 8 subjects had more correct responding on a 6-month maintenance test. Thus, the task demonstration model proved superior to the standard prompting hierarchy in 29 of 32 tests of correct responding. Results are discussed in terms of implications for stimulus control training strategies.

A comparison of the Task Demonstration Model and the Standard Prompting Hierarchy in teaching word identification to persons with moderate retardation.

Six persons with moderate mental retardation were taught to identify three words by each of two different procedures. One, the Task Demonstration Model, was a fading procedure which relied on presenting many examples of both the correct and incorrect words while systematically increasing their similarity. The other, the Standard Prompting Hierarchy, is one of the most common procedures for teaching persons with mental retardation, and relied on a least-to-most intrusive prompting hierarchy. Data were presented in three phases and show that the Task Demonstration Model produced fewer errors in (a) acquisition (4% to 14%), (b) generalization (9% to 14%), and (c) maintenance (8% to 14%). Results were discussed in terms of the fading procedure and how the Task Demonstration Model provides a simple means for teachers to improve their students' responding in acquisition, generalization, and maintenance.

An evaluation of gentle teaching and visual screening in the reduction of stereotypy.

Gentle teaching and visual screening techniques have been used to control severe behavior problems in persons with mental retardation. An alternating treatments design was used to compare gentle teaching, visual screening, and a task-training condition in the reduction of the high-level stereotypy of 3 persons with mental retardation. Following a baseline phase, a task-training condition using standard behavioral techniques was implemented to establish the effects of training the subjects on the tasks. Results showed a modest decrease in stereotypy. This phase was followed by an alternating treatments phase in which visual screening, gentle teaching, and baseline conditions were compared. Both procedures were superior to the control condition in reducing stereotypic behavior, with visual screening being more effective than gentle teaching. When compared with data from the prior phase, gentle teaching was found to be more effective than task training for 2 subjects but less effective for the 3rd, whose stereotypy increased during gentle teaching. Two succeeding phases in which visual screening was implemented across two and then all three daily conditions reduced stereotypy further to near-zero levels. An additional phase with 1 subject demonstrated that the treatment effects of visual screening were easily replicated across therapists. Mixed and idiosyncratic changes in collateral behaviors occurred. For example, "bonding," the goal of gentle teaching, occurred at the same low levels under both treatments, contrary to the predictions of gentle teaching's proponents. The results indicate that gentle teaching may not be the universal treatment of choice for stereotypy its proponents suggest, and that it requires further empirical evaluation.

Basing the treatment of stereotypic and self-injurious behaviors on hypotheses of their causes.

Stereotypic and self-injurious behaviors are common forms of maladaptive responding demonstrated by severely handicapped persons. Various review papers suggest that no single treatment procedure is universally effective. Although there may be many reasons for this finding, one could be that people engage in these behaviors for various reasons, and that procedures that are incompatible with the cause of the behavior are unlikely to be effective. These studies also suggest many hypotheses for the development and maintenance of these behaviors, three of which are the self-stimulation, positive reinforcement, and negative reinforcement hypotheses. The purpose of this paper was to determine whether one of these hypotheses could be matched to the cause of the behavior and used as an effective treatment procedure. We therefore compared one hypothesis with one other for 3 subjects in a three-phase study. During baseline, data were taken in two classrooms for each subject, and a judgement was made about the hypothesis most likely to be related to the cause of the behavior. During the second phase, a treatment based on that hypothesis was used in one classroom, and a treatment based on another hypothesis was used in the second classroom. During the third phase, the treatment that was most effective in the second phase was used in both classrooms. Results showed that a successful treatment program can be developed on an hypothesis of why the behavior occurred during baseline. Results are discussed in terms of supporting the argument that treatment programs should be based on a functional analysis of the behavior in its environmental context.

Observational studies of staff working with mentally retarded persons: a review.

Experimental or quasi-experimental studies of the behavior of staff working with retarded persons were reviewed and provided the following generalizations: (a) staff often have very low rates of interactions with clients, (b) a disproportionate number of interactions occur with a relatively small number of clients, (c) structured settings promote more interactions, (d) small teaching groups promote interactions, (e) staff involvement in relevant decisions promotes interactions, (f) larger, more global, and ecological assessments of both staff and clients provide important information on the effects of staff management and training, (g) lowering the reading difficulty of training materials increases staff comprehension, (h) lectures tend to improve academic skills while practicum training improves teaching skills, (i) some trained skills generalize while others do not, apparently unsystematically, (j) a system in which supervisors rather than researchers external to the facility do the training is feasible, (k) various low cost systems of public or private feedback can increase staff participation in their duties, (l) implementation of strict administrative policies can reduce tardiness and absenteeism, and (m) staff may be very reactive to announced observation by inspection agencies.