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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.

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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.

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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.

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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.

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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.

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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)

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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.

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Bryostatin 1, like the phorbol esters, activates protein kinase C. However, bryostatin 1 induces only some of the effects in cultured cells which result from phorbol ester treatment, whereas it blocks other responses to the phorbol esters. In mouse keratinocytes in particular, bryostatin 1 induces ornithine decarboxylase, a marker of proliferation, but blocks induction of markers of differentiation. Because of the postulated role of induction of differentiation in tumor promotion, we have now examined bryostatin 1 as a tumor promoter and as an inhibitor of phorbol ester tumor promotion in the initiation-promotion model of skin carcinogenesis. After initiation with 7,12-dimethylbenz[a]anthracene, weekly topical treatments of the backs of mice with 1 microgram (1.1 nmol) bryostatin 1 induced epidermal hyperplasia and inflammation, although not to the extent seen after treatment with the promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Treatment with bryostatin 15 min before each TPA exposure reduced the phorbol ester-induced hyperplasia. Bryostatin 1 was ineffective as a complete tumor promoter and displayed very weak activity as a second stage promoter upon treatment of initiated mice for 30 weeks. Combined exposure of mice to bryostatin 1 and TPA resulted in a substantial inhibition of promotion by TPA. Our in vivo results extend earlier in vitro findings that bryostatin 1 acts as a partial inhibitor of protein kinase C function.

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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.

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Rapid, synchronous and repeating cycles of marginal retinoic acid sufficiency and deficiency were produced in rats by following an established protocol. During cycles 11-15 (343-464 days after weaning), 17 of 24 rats (71%) developed tumor-like masses in the connective tissue surrounding the formative ends of one or both upper incisor teeth. The masses were composed of cords of odontogenic epithelium surrounded by a mantle of mesenchyme. Lakes of predentine, associated with foci of keratinized epithelium, were randomly distributed. On the basis of current understanding of odontogenesis, we propose that periodically disturbed differentiation of pulpal mesenchymal cells to dentin-secreting odontoblasts was pivotal to development of the masses. During deficiency, dentin secretion is impaired, the dentin wall perforates and with time the odontogenic epithelium and pulp herniate into the surrounding connective tissues. We propose that the incisal masses arose because the pulpal mesenchyme continued to grow and its secretion product, dentine, continued to be deposited (during periods of vitamin A sufficiency) in an ectopic site where functional attrition from mastication could not occur.

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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)

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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.

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Papillomas induced by standard initiation-promotion protocols progress to carcinomas at a low frequency. Experimental protocols were developed to elicit papillomas with a higher probability of malignant conversion. SENCAR mice initiated by 7,12-dimethylbenz[a]anthracene were promoted by treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 5, 10, 20 or 40 weeks. With promotion for 10 weeks or more, a peak of papilloma incidence at 16-20 weeks was followed by a 35-40% decrease within 3 months. A much lower papilloma response was seen in mice promoted for 5 weeks, but these papillomas persisted. The yield of malignant tumors was similar in all four groups, with 20-25 carcinomas per group of 30 mice. Thus, the papillomas induced by the first few TPA treatments are much more likely to progress to carcinomas than those which appear later. In a separate study, initiated Charles River CD-1 mice were promoted with TPA for either 12 or 52 weeks. Acetone solvent treatment was begun at Week 13 in the group treated 12 weeks with TPA. At Week 16, the papilloma incidence was identical in the two groups of mice. However, by Week 28, the papilloma yield in the continuous TPA group had increased and was twice that of the acetone group, in which papillomas had regressed. The first carcinoma arose 14 weeks earlier with continuous TPA, but the final number of carcinomas per group of 40 mice was 17 with TPA and 20 with acetone. Neither the increase in papillomas in TPA-treated mice nor the regression of papillomas after cessation of promotion with TPA affected the final carcinoma yield. This result suggests that TPA-dependent papillomas are very unlikely to progress to carcinomas. In a third experiment, promotion of initiated SENCAR mice with mezerein resulted in a small number of papillomas which had a much higher probability of progression to carcinomas than the large number of papillomas promoted by TPA. The ability to induce papillomas promoted by TPA. The ability to induce papillomas with a known probability of conversion to carcinomas will facilitate the identification of markers associated with malignant progression.

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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.

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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.

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The Parsons visual acuity test (PVAT) uses modified Allen test targets for visual acuity assessment in young children and persons who are difficult to test. Using this method, we were able to obtain a visual acuity threshold in 44% of 18- to 24-month-old children and in 90% of children aged 25 to 36 months. At all ages tested, the mode for visual acuity was 20/30; however, the percentage of those with 20/20 increased with age. The decision whether to refer was correctly made by means of the PVAT criterion 83% of the time.

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Refractive errors in 311 children between the ages of 18 and 48 months were assessed utilizing standard cycloplegic retinoscopy and a noncycloplegic near retinoscopy technique as promulgated by Mohindra. Results from this study indicate little agreement between the two objective refraction methods.

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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.

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Multi-stage carcinogenesis (initiation-promotion) was first demonstrated in mouse skin. The first stage, initiation, is accomplished by a low dose of carcinogen that causes no tumours. Promotion by repeated treatment of initiated mice with certain non-carcinogenic hyperplastic agents results in the rapid production of numerous benign papillomas, a few of which progress to squamous cell carcinomas. Although this models system produces mostly benign tumours, many of the concepts concerning carcinogenesis in epithelial tissues have been derived from mouse skin studies. The permanent change in growth potential accomplished by tumour initiators is generally considered to be a mutagenic event; cell selection and clonal expansion of initiated cells may be involved in promotion. In initiation-promotion experiments, more than 90% of the squamous cell carcinomas develop from papillomas, but the conversion rate is low. The factors necessary for this conversion of benign to malignant tumours have not been defined but tumour promoters have been assumed to be involved. However, we report here that the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is ineffective in the conversion of papillomas to carcinomas whereas three initiators, urethane, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and 4-nitroquinoline-N-oxide (4-NQO) are effective. This suggests that malignant conversion may result from a further genetic change in papilloma cells and that the ineffectiveness of TPA may be due to its inactivity as a mutagen.

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