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.