Enhanced malignant conversion of benign mouse skin tumors by cisplatin.

The chemotherapeutic agent cisplatin, reported to be a complete carcinogen in rodents and a tumor initiator for mouse skin, was tested for activity to enhance the conversion of carcinogen-induced skin papillomas to carcinomas. Initiation of mouse skin by 7,12-dimethylbenz[a]anthracene followed by 12 weeks of promotion by 12-O-tetradecanoylphorbol-13-acetate produced seven to eight papillomas/mouse. Ten weekly injections of 100 micrograms of cisplatin into these papilloma-bearing mice induced a 2.3-fold enhancement of conversion relative to the spontaneous rate of 1.9%. Even a single exposure to cisplatin in tumor-bearing mice increased the carcinoma incidence to the same extent as 10 exposures to urethane, an agent previously shown to enhance malignant conversion. At the dose tested, cisplatin was inactive as a complete carcinogen or a tumor promoter. Cisplatin-DNA adducts, measured in samples from skin, liver, and kidneys, were persistent for at least 4 weeks after the last exposure to cisplatin. Thus cisplatin is a relatively potent inducer of the putative genotoxic changes required for conversion of skin tumors from a benign to a malignant phenotype. The activity of cisplatin in the initiation and malignant conversion stages in this animal model for carcinogenesis suggests that patients given cisplatin-based chemotherapy are at increased risk for the development of treatment-induced second cancers.

Sensitivity of subpopulations of mouse skin papillomas to malignant conversion by urethane or 4-nitroquinoline N-oxide.

Papillomas induced in SENCAR mice by initiation with 7,12-dimethylbenz(a)anthracene and promotion by treatment for 10-12 weeks with 12-O-tetradecanoylphorbol-13-acetate (TPA) convert to malignancy at a low frequency. The rate of malignant conversion can be increased by either (a) promoting with TPA for a shorter duration or (b) treatment of papilloma-bearing mice with certain genotoxic chemicals, such as 4-nitroquinoline N-oxide (4-NQO) or urethane. The spontaneous conversion rate of papillomas promoted by 5 weeks of TPA exposure is severalfold higher than that of papillomas arising later during TPA promotion. Here, we compared the sensitivity to the converting agents 4-NQO and urethane of papillomas promoted by TPA for either 5, 10, or 20 weeks. In the mice promoted for 5 weeks with TPA, the already high spontaneous conversion frequency was increased 2.5 times by 4-NQO. A 2-fold increase was found after 10 weeks of TPA promotion. In contrast, no increase was seen with 4-NQO exposure begun after 20 weeks of TPA promotion. Similar results were found with urethane as converting agent. The sensitivity of the papillomas induced by short-term TPA treatment to induced conversion remains high even after a 16-week period without TPA treatment; when urethane exposure was delayed until week 21 after TPA promotion for weeks 1-5, a 2.4-fold increase in the conversion frequency was observed.

Inhibition of initiator-promoter-induced skin tumorigenesis in female SENCAR mice fed a vitamin A-deficient diet and reappearance of tumors in mice fed a diet adequate in retinoid or beta-carotene.

Retinoids have chemopreventive activity for epithelial tumors in a variety of systems, including the two-stage tumorigenesis system of mouse skin in which only the promotion stage is inhibited. We asked whether dietary vitamin A deficiency could affect the skin tumorigenic response, prior to major changes in body weight or general health of the animals. Two regimens were tested to induce vitamin A deficiency. SENCAR mice were either (a) fed a vitamin A-deficient diet from 4 or 9 weeks of age or (b) their mothers were fed the diet from the time of birth of the experimental animals which were then weaned on the same diet. The latter regimen produced typical symptoms of vitamin A deficiency in the offspring by Weeks 12-14 and all the mice died by Week 19; the former regimen permitted sufficient accumulation of retinol and its esters to sustain life for up to 45 and 75 weeks, respectively, in the majority of mice. For our experiments, vitamin A depletion was produced by placing the mothers on the deficient diet at birth of the experimental animals. A single topical dose of 20 micrograms of 7,12-dimethylbenz(a)anthracene (DMBA) was used as the initiator at 3 weeks of age and 1 to 2 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA) once weekly as the tumor promoter for 10 weeks (from Week 4 through 13 of the experiment). Fifty-five % of mice (n = 40) on Purina laboratory chow (mean body weight, 31.4 g) developed skin tumors (2.58 per mouse) at 12 weeks, versus 2.5% (0.05 papillomas per mouse) of mice (n = 40) kept on the purified vitamin A-deficient diet (mean body weight, 30.3 g), a 98% decrease in tumor/mouse. Retinoic acid (RA) (1-3 micrograms/g diet) supplementation after Week 12 caused a rapid tumorigenic response in 95% of the mice by week 22. This tumor response occurred to a reduced extent in the absence of continued TPA treatment up to Week 13. Even though tumor incidence increased within 1 week of RA and 95% of the mice showed the tumorigenic response, the number of tumors per mouse was about 50% of that observed in mice maintained on standard Purina diet. This was confirmed in an experiment in which the mice were maintained for life either on Purina or on the RA (3 micrograms/g) containing purified diet, the latter being the control group for the effect of vitamin A deficiency on skin tumorigenesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Efficacy, pharmacokinetics, and in vivo antiviral activity of UC781, a highly potent, orally bioavailable nonnucleoside reverse transcriptase inhibitor of HIV type 1.

A series of compounds related to oxathiin carboxanilide has been identified as nonnucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1, and structure-activity relationships have been described (Buckheit RW, et al.: Antimicrob Agents Chemother 1995;39:2718-2727). Three new analogs (UC040, UC82, and UC781) inhibited laboratory and clinical isolates of HIV-1, including isolates representative of the various clades of HIV-1 found worldwide, in both established and fresh human cells. Virus isolates with the amino acid changes L100I, K103N, V106I, and Y181C in the reverse transcriptase were partially resistant to these compounds. However, UC781 inhibited these virus isolates at low nontoxic concentrations, presenting a broad in vitro therapeutic index. As with other NNRTIs, each of the compounds synergistically interacted with AZT to inhibit HIV-1 replication. UC781 possesses a favorable pharmacokinetic profile in mice with a high level of oral bioavailability. Plasma concentrations reached maximum levels within 2 to 4 hr of oral administration and remained in excess of those required for in vitro anti-HIV activity for at least 24 hr after a single oral dose. When evaluated in a murine hollow fiber implant model of HIV infection, UC781 dosed orally or parenterally was able to suppress HIV replication completely in this model system, providing evidence of the in vivo efficacy of the compound.

Malignant conversion and metastasis of mouse skin tumors: a comparison of SENCAR and CD-1 mice.

The progression of papillomas to squamous cell carcinomas (malignant conversion) was studied in the skin of SENCAR and Charles River CD-1 mice, using a three-stage treatment protocol. After initiation with 7,12-dimethylbenz(a)anthracene (DMBA) (stage 1) and limited promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) (stage II), papilloma-bearing mice were treated (stage III) with either tumor initiators, such as urethane, N-methyl-N'nitro-N-nitrosoguanidine (MNNG) or 4-nitroquinoline-n-oxide (R-NQO), the promoter TPA, or solvent (acetone). Similar final carcinoma yields were found in the mice treated in stage III with TPA or acetone, although carcinomas developed earlier in the TPA-treated mice. In contrast, treatment with tumor initiators in stage III increased both the rate of appearance and the final yield of carcinomas. Similar results were obtained in both SENCAR and CD-1 mice. A papilloma stage appears to be necessary for carcinoma development since elimination of TPA treatment in stage II greatly reduced the incidence of both papillomas and carcinomas in both stocks of mice. The heterogeneity of papillomas with regard to progression to carcinomas is demonstrated by the low rate of conversion of TPA-dependent papillomas and the high rate of conversion of persistent papillomas in CD-1 mice. The carcinomas that develop using the three-stage regimen vary in metastatic potential. In CD-1 mice, the frequency of metastases to lymph nodes were similar in groups treated in stage III with MNNG, urethane, 4-NQO, TPA, or acetone, but treatment with urethane substantially increased metastases to the lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental prosthetic vein valve.

The incidence of venous insufficiency is increasing, approximately 800,000 new cases are reported yearly in the United States. Medical treatment of venous insufficiency syndrome has been associated with a high incidence of failure. Although vein valve transplantation has resulted in improvement in the majority of cases, late degeneration and incompetency of the valve prompted us to devise a prosthetic vein valve for experimental use. Ten dogs underwent insertion of a prosthetic vein valve without anticoagulants. Between 3 and 8 months after insertion, ascending and descending venography revealed patency and competency of these valves.

Vein valve transplantation.

The vein valve transplantation has, in our experience, subjectively relieved symptoms in the majority of patients. More importantly, elevated venous pressure has been decreased in most patients. Thus, patients exhibiting signs of venous insufficiency syndrome as well as elevated venous pressure and proved valvular incompetence should be considered candidates for vein valve transplantation after an unsuccessful trial of medical management.

Continuous ambulatory venous pressure for diagnosis of venous insufficiency. Preliminary report.

We have found that the venous pressure slope during minimal exercise is a sensitive measurement of venous disease. This parameter differed greatly in our two study populations. Due to increased venous pressure, venous insufficiency syndrome patients have a greater volume of pooled blood, which results in smaller pressure changes with each muscle contraction. In patients with incompetent valves, blood flows in a retrograde fashion in the vein, which leads to a higher steady state minimal pressure and notably to a decreased venous pressure slope. Venous pressure slope is a particularly sensitive measurement and a good prognosticator of venous insufficiency syndrome before symptoms become disabling to the patient. Our data indicate a strong correlation between venous pressure slope and venographic results. In fact, patients with abnormal venographic results invariably have demonstrated venous pressure slopes in the abnormal range.

Increasing social interactions of severely handicapped autistic children.

A peer-initiation training procedure was implemented across multiple peer trainers to investigate social interactions between severely withdrawn autistic children and their nonhandicapped peers. For one subject, substantial increases in spontaneous interactions with training and nontraining peers occurred after the peer-initiation procedure was applied across two training exemplars. Spontaneous social interactions continued even after the training procedure was removed. Although experimental control was established with the second subject during training, spontaneous interactions during nontraining periods were primarily with training peers. The results contribute to an emerging data base on the social interactions of autistic and severely withdrawn handicapped children and on peer-initiation training procedures.

Particle Total Exposure Assessment Methodology (PTEAM) 1990 study: method performance and data quality for personal, indoor, and outdoor monitoring.

The Particle Total Exposure Assessment Methodology (PTEAM) study provided the opportunity to test methodologies for measuring personal and microenvironmental PM10 and PM2.5 concentrations in a full-scale probability-based sample of 178 persons and homes in Riverside, California during the fall of 1990. The purpose of the study was to estimate frequency distributions of exposure to PM10, PM2.5, and selected elements in an urban population. Quality control samples and analyses were used to evaluate method performance. These included collocated sample collection, field and lab blank filters, sampler and balance field audits, and intra- and interlaboratory replicate elemental analyses. A portion of the study was also designed to include side-by-side operation of the personal and microenvironmental samplers with reference method (high-volume and dichotomous) samplers to provide an evaluation of method comparability. Over 95% of the approximately 2,900 scheduled samples were collected and analyzed, with very few losses due to equipment failure. The method limit of detection for the personal and microenvironmental monitor PM10 sampling was 8 micrograms/m3. Mean relative standard deviations (RSDs) of 2% to 8% were obtained for collocated personal and microenvironmental samples. Sampler flow rates were within the +/- 10% accuracy criterion during two field audits. Balances operated in a specially designed mobile laboratory were within specified tolerances for precision (+/- 4 micrograms) and accuracy (+/- 50 micrograms). Elemental analysis accuracy was measured with standard reference materials with biases ranging from 2% to 7%. Measurement precision for most elements ranged from 2.5% to 25% mean RSD. Personal and microenvironmental samplers gave median PM10 concentrations that were approximately 9% higher than the dichotomous sampler and 16% higher than the high-volume sampler across 96 monitoring periods at a fixed outdoor location.

Maintaining social initiations of withdrawn handicapped and nonhandicapped preschoolers through a response-dependent fading tactic.

The effects of a teacher-implemented intervention and fading package on the social initiations of three withdrawn preschool children were investigated. Subjects' social initiations and any peer responses were recorded sequentially during free play. Intervention involved teacher prompting and contingent praise of specific social initiations (sharing, assisting, verbally organizing play) by each subject toward an available peer. Results indicated that teacher prompts and praise increased the frequency of subjects' target initiation, target initiations typically received a positive peer response, subjects' extended interactions with peers also increased, abrupt, complete removal of teacher prompting resulted in similarly abrupt reductions in subjects' social initiations, whereas response-dependent fading maintained subjects' initiations and interactions above baseline levels. Follow-up data 2 1/2 months later showed that the social initiations and interactions of two of the children remained above baseline levels.

Effects of risperidone on aberrant behavior of persons with developmental disabilities: I. A double-blind crossover study using multiple measures.

The efficacy of the atypical antipsychotic risperidone was evaluated in the treatment of aberrant behavior (e.g., aggression, self-injury) in 20 individuals with developmental disabilities. A double-blind, crossover design was used to compare risperidone with placebo in a 22-week trial with a 6-month follow-up phase. Based on a 50% reduction in mean Aberrant Behavior Checklist--Community total scores, 50% of the participants were identified as responders. Naturalistic observations of a subset of five individuals showed that for 4 out of 5 participants, risperidone was effective in reducing aberrant behavior. Side effects included weight gain (84% of participants) and sedation (40% of participants). The advantages of conducting a comprehensive analysis of the effects of medication on aberrant behavior are discussed.

The school nurse's role in vision screening for the difficult-to-test student.

This article discusses the importance of providing vision screening services to students who are difficult-to-test and describes strategies for providing such services. Included in the discussion is an overview of various instruments that may be used to assess visual acuity. One of the instruments, the Parsons Visual Acuity Test, is described in detail as a tool for assessing visual acuity of the difficult-to-test. In addition, a discussion is presented which emphasizes the importance of providing follow-up services to those children who are referred for professional eye examinations. The authors delineate the vital role of the school nurse in assisting the difficult-to-test students to gain necessary vision care services through screening, referral, obtaining appropriate treatment and providing follow-up services.

Effects of peer social initiations on the behavior of withdrawn preschool children.

Social approach to peers was evaluated as an intervention for isolate preschoolers. During baseline, confederate peers made few social approaches to the target subjects. Confederates greatly increased their rate of social approaches during the first intervention, decreased social approaches during a second baseline, and increased social approaches again in a second intervention phase. Increases in confederate social initiations immediately increased the frequency of subjects' positive social behavior. Additionally, five of six subjects showed an increase in their own positive social initiations during intervention periods. The results suggest that: (a) peers may be programmed to increase the positive social behaviors of their isolate classmates, and (b) remediating social deficits requires assessment and intervention specifically tailored to the individual child.

An experimental analysis of "spillover" effects on the social interaction of behaviorally handicapped preschool children.

The effects of prompting and social reinforcement directed to target subjects on their social behavior and that of peers who never received prompting and reinforcement for positive social behavior, were examined. In a combined reversal and multiple-baseline design, three behaviorally handicapped preschool boys who exhibited divergent social behavior repertoires and varied histories with social reinforcement events were sequentially exposed to intervention conditions in order to investigate "spillover" of treatment effects. Prompting and reinforcement increased positive social behavior and decreased negative social behavior emitted by all target subjects. The results also demonstrated a "spillover" effect on two target subjects, who at various times were not under intervention, and on the peers as well. The findings suggest that: (a) the direct and indirect effects of intervention procedures may be enhanced by designing treatment based on the social repertoire and reinforcement histories of the subjects; and (b) the treatment "spillover" effect may be increased by applying procedures to two children at once, rather than at one at a time.

Changes in peer verbalizations accompanying individual and group contingencies to modify on-task behavior.

Group and individual contingency arrangements were alternately applied to modify the on-task performance of 5 behavior-disordered children. Concurrent records were maintained regarding the children's task-relevant (facilitating) and non-task-relevant (inhibiting) verbalizations to peers. Both contingency arrangements were effective for controlling the children's on-task behavior while only the group contingency was associated with changes in their verbalizations. Specifically, the group contingency, as compared to the baseline and the individual contingency, was accompanied by a significant increase in facilitating verbalizations by peers. Moreover, the group contingency, in relation to the baseline but not the individual contingency, resulted in significantly fewer inhibiting verbalizations. The individual contingency did not affect either facilitating or inhibiting verbalizations of peers.