Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease.

Somatic inactivation of PTEN occurs in different human tumors including glioblastoma, endometrial carcinoma and prostate carcinoma. Germline mutations in PTEN result in a range of phenotypic abnormalities that occur with variable penetrance, including neurological features such as macrocephaly, seizures, ataxia and Lhermitte-Duclos disease (also described as dysplastic gangliocytoma of the cerebellum). Homozygous deletion of Pten causes embryonic lethality in mice. To investigate function in the brain, we used Cre-loxP technology to selectively inactivate Pten in specific mouse neuronal populations. Loss of Pten resulted in progressive macrocephaly and seizures. Neurons lacking Pten expressed high levels of phosphorylated Akt and showed a progressive increase in soma size without evidence of abnormal proliferation. Cerebellar abnormalities closely resembled the histopathology of human Lhermitte-Duclos disease. These results indicate that Pten regulates neuronal size in vivo in a cell-autonomous manner and provide new insights into the etiology of Lhermitte-Duclos disease.

Evaluation of 3-(p-fluorophenyl)-L-alanyl-3-[m-bis-(2-chloroethyl) aminophenyl]-L-alanyl-L-methionine ethyl ester HCl (PTT.119) against xenografts of human rhabdomyosarcoma.

PTT.119 [p-F-phe-m-bis(2-chloroethyl)amino-L-phe-met ethoxy HCl], a synthetic tripeptide mustard, was evaluated for therapeutic efficacy against a spectrum of childhood rhabdomyosarcomas (RMS) maintained as xenografts in immune-deprived mice. These xenografts were established from previously untreated tumors, and sublines were selected in mice for resistance to L-phenylalanine mustard (L-PAM). PTT.119 caused regression of four of six RMS lines established from untreated tumors, and demonstrated activity similar to that of L-PAM in this model. Against tumors Rh18/L-PAM and Rh28/L-PAM, selected in situ for L-PAM resistance, PTT.119 had no significant activity. Rh28/L-PAM was cross-resistant also to oxazophosphorine mustards (ifosfamide, cyclophosphamide), and both tumors were cross-resistant to adriamycin and vincristine. PTT.119 caused hematologic toxicity similar to that of L-PAM, characterized by a marked decrease in white blood cells and thrombocytopenia.

Differential strain susceptibility following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration acts in an autosomal dominant fashion: quantitative analysis in seven strains of Mus musculus.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been used as a potent neurotoxin to approximate, in animals, the pathology that is observed in human Parkinson's disease. In this study, we examine the toxicity of MPTP in seven strains of mice, spanning a genetic continuum of Mus musculus as a prelude to uncovering complex traits associated with MPTP toxicity. Seven days following injection of 80 mg/kg MPTP (4x20 mg/kg every 2 h), we find that the individual mouse strains exhibit dramatic differences in SNpc neuron survival, ranging from 63% cell loss in C57BL/6J mice to 14% cell loss in Swiss-Webster (SW) mice. In order to determine if the susceptibility trait was dominant, additive or recessive, we crossed C57Bl/6J mice with either SWR/J or AKR/J mice and examined the effect of MPTP on F1 C57BL/6JxSWR/J or F1 C57BL/6JxAKR/J animals. We find that all of the F1 animals were phenotypically identical to the C57BL/6J animals. In addition, no gender differences were noted in any of the MPTP-treated inbred mice or in the F1 animals. These results suggest that susceptibility to cell loss following MPTP is autosomal dominant and this polymorphism is carried on the C57BL/6J allele.

Cultural diversity and treatment of children.

The increasing cultural diversity of child clients has produced a cascade of new issues and concerns for psychological practice, theory, and research. Available evidence and pertinent theory are reviewed on such topics as the predictive utility and treatment consequences of ethnic membership, whether treatments should be generic or specific to cultural groups, the degree of privilege that should be accorded to same-culture therapists, and the relative desirability of different modalities of treatment for children of different cultural groups. The concept of cultural compatibility of treatment is explored and evaluated. A broad agenda of hypotheses for research and development is suggested, and some guidelines for clinical practice and policy are proposed. It is concluded that insofar as possible, treatment for all children should be contextualized in their family's and community's structure of meanings, relationships, and language.

The logical status of metacognitive training.

It is argued that knowing-how (to perform) is not dependent on knowing-that (knowing propositions about performance). Existing evidence allows any benefits from "metacognitive" training to be attributed to generalization training, not to the announcement of rules. Rules may encourage the subject to learn new tasks, but these tasks must be learned in the contexts of eventual application.

Effects of Von Langenbeck palatoplasty on facial growth.

The conclusion derived from this study is that the Von Langenbeck palastoplasty as performed on the cleft individuals evaluated here did not produce gross discrepancies in the dento-facial structures or relations examined. On the average, the skeletal and profile relations of the maxilla to the mandible can be considered within the acceptable range. With this in mind, speech becomes a more crucial parameter in evaluating the over-all results of this procedure. Other dental parameters, e.g., incidence of crossbite, arch collapse, etc., need to be examined if a complete evaluation of the results of palatal surgery is described. This should be done after all orthodontic treatment has been completed and all retainers removed.

Observation procedure, observer gender, and behavior valence as determinants of sampling error in a behavior assessment analogue.

Several factors thought to influence the representativeness of behavioral assessment data were examined in an analogue study using a multifactorial design. Systematic and unsystematic methods of observing group behavior were investigated using 18 male and 18 female observers. Additionally, valence properties of the observed behaviors were inspected. Observers' assessments of a videotape were compared to a criterion code that defined the population of behaviors. Results indicated that systematic observation procedures were more accurate than unsystematic procedures, though this factor interacted with gender of observer and valence of behavior. Additionally, males tended to sample more representatively than females. A third finding indicated that the negatively valenced behavior was overestimated, whereas the neutral and positively valenced behaviors were accurately assessed.

A verbal behavior analysis of auditory hallucinations.

A review of recent research on the non-medical control of auditory hallucinations is presented. It is suggested that the decreases in hallucinatory behavior obtained in studies using aversive contingencies may be attributable to the disruption of the chains of behavior involved. The results of several additional studies are interpreted as indicating that methods of stimulus control and the use of incompatible behaviors may be effective in reducing the rate of auditory hallucinations. Research relating auditory hallucinations to subvocalizations is presented in support of the view that hallucinatory phenomena are sometimes related to the subject's own vocal productions. Skinner's views (1934, 1936, 1953, 1957, 1980) are then presented as possible explanations of some hallucinatory behavior. It is suggested that some auditory hallucinations consit of the mishearing of environmental and physiological stimuli as voices in a fashion similar to that which Skinner observed in his work with the verbal summator. The maintenance of long chains of such responses may be largely attributable to self-intraverbal influences (such as are present during automatic writing). With some auditory hallucinations, this progression involves first mishearing ambiguous stimuli as voices and then attributing the voices to some cause (e.g., insanity, the television, radio, or God). Later, the frequent and ongoing chains of such behavior may contaminate other verbal responses. Such verbal behavior may be parasitic on "normal verbal behavior" (and hence, not directly dependent on consquences for maintenance), may be cued by various stimuli (including respiration), and may interfere with other covert and overt behavior. Several studies to investigate this view are presented. It is hoped that such research will lead to a better understanding of the major issues involved in the etiology and treatment of auditory hallucinations in particular and perhaps of psychosis in general.

A comparative study of results of the von Langenbeck and the V-Y pushback palatoplasties.

The incidence of velopharyngeal competence noted in 267 cleft palate patients following palatoplsty has been reviewed. Comparisons have been drawn with regard to the cleft type and the surgical technique performed. Since there were relatively small numbers of subjects in some categories, differences in age at last examination between the von Langenbeck and V-Y palatoplasty groups, some patients were very young at time of evaluation, and a number of different surgeons at different levels of training and experience performed the surgery, the differences in velopharyngeal competence found should be viewed as trends and this report as preliminary. In general, there was a trend toward smaller percentages of patients attaining acceptable velopharyngeal competence as the severity of the cleft increased. Of those with clefts of the soft palate only 86 per cent achieved competence. Among those patients with clefts of the palate only, 67 per cent achieved competence, whereas only 57 per cent of those with clefts of the lip and palate were able to do so. When comparing all cleft types, the V-Y palatoplasty resulted in a significantly higher percentage of velopharyngeal competence (74 per cent) than did the von Langenbeck method (56 per cent), although the data for the V-Y group are probably less reliable than those for the von Langenbeck group. In the soft palate only category, the results were slightly better with the von Langenbeck technique, though not significantly so. In all other cleft types, the results with the V-Y method were better than those with the von Langenbeck.

Cephalometric comparisons of the results of the Wardill-Kilner and Von Langenbeck palatoplasties.

Two groups of individuals with isolated clefts of the palate were compared. One group had had the Von Langenbeck procedure performed at the University of Iowa and the other the V/W-Y (Wardill-Kilner) procedure performed in Denmark. All individuals in both groups were Caucasians. In order to avoid the influence of any possible ethnic differences on the interpretation of the results, each cleft group was initially compared to a matched non-cleft group from the same geographical area. Differences were then statistically evaluated using the Student t-test. The incidence of malocclusion in the two operated groups was compared using Chi Square. Different landmarks were pricked on duplicate cephalograms. Nine angular and four linear parameters were measured. Two ratios derived from these linear parameters were also computed. The results of this study tend to indicate that these two procedures have similar effects upon antero-posterior and vertical growth of the craniofacial complex as determined from cephalometric roentgenograms. While there were no statistically significant differences in the incidence of malocclusion, the need for a detailed study of the effects of different palatoplasties on dental occlusion was emphasized. Speech results and dental occlusion emerge as critical factors in the evaluation of the effects of these two surgical techniques.

Prediction of velopharyngeal competency.

The question posed in this study was, are there measures which are predictive of the need for further palatal management? Articulation scores, lateral x-rays and clinical judgments of velopharyngeal competency were examined for 75 subjects in retrospect to determine their predictive value. Each of the measures resulted in at least 90% appropriate predictions. The combination of articulation score and lateral x-ray rating appeared to be the best predictor for this particular sample in that subsequent treatment was correctly predicted for 96% of the subjects. We view this study as a preliminary attempt in the prediction of further management and in future studies will consider age at the time of prediction and other possible predictor variables.

Palatoplasty: a comparative study.

A comparative analysis of 275 patients who underwent palatoplasty between 1961 and 9171 is presented. Of these, 149 patients had a Langenbeck palatoplasty and 188 a V-Y pushback palatoplasty. Speech results in these patients were carefully assessed by experience speech pathologists using conversational and structured (word articulation tests) speech, manometric ratios, and radiographic evidence of palatal movement. Over all, 73% of the V-Y pushback patients attained acceptable speech compared to 56% in the Langenbeck category. Patients with clefts of the soft palate only had the highest incidence of acceptable speech (91% in Langenbeck, 81% in V-Y). In both categories the results were poorer in the more extensive clefts.

Kinetics of DNA methylation by the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in F344 rats.

The carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was injected intravenously (0.41 mmol/kg) into F344 rats. DNA from target organs (lung, liver) and a non-target organ (kidney) was extracted hydrolysed and analysed for methylated guanines by cation-exchange high-performance liquid chromotography-fluorimetry. Levels of O6-methylguanine, a promutagenic lesion, and 7-methylguanine were three to eight times higher in the liver than in the lung. Neither base could be detected in the kidneys. The extent of methylation of hepatic DNA by NNK was 35 times lower than observed with an equimolar dose of NDMA by Swann et al. (1983). The levels of the two methylated guanines in liver and lung DNA increased between 4 and 24 h following NNK injection. NNK is metabolized rapidly in F344 rats to 4-(methylnitrosamino)-1(3-pyridyl)-butan-1-ol (NNA1). The relatively slow methylation of hepatic DNA after injection of NNK could be due to a slow release of methylating species from the major circulating metabolite NNA1. This low but sustained level of O6-methylguanine induced by NNK could, in part, explain its carcinogenic potency.

Use of active patient follow-up in cancer registries for designing epidemiologic studies.

The two primary functions of a population-based cancer registry are to collect incidence data and survival data, often obtained by active contact methods. Because of the expense and complexities of epidemiological research in determining carcinogenic risk, existing aggregate data collection systems need to be utilized for generating hypotheses. Direct follow-up contact with a patient by mail provides a mechanism for identifying potential risk factors at low cost. This method is being used to solicit information concerning environmental exposure. In addition, analysis of preliminary data on education and occupation collected by the mechanism indicated that staying patterns of cancer differ between rural and urban areas in the state of Iowa. The difference appears to be explained by education and not by occupation.

Creatinine, lactam and cyclic peptide formation by the action of C2N2 on creatine, omega-amino acids and peptides.

Cyanogen, C2N2, affords a means to drive intramolecular conversion of ammonium salts to amides. Unlike other carboxyl activating agents, such as carbodiimides, used in peptide syntheses expressly to drive intermolecular condensations to form amide (peptide) bonds, C2N2 appears restricted to driving only intramolecular condensations. Rates decreased as a function of solvent composition as follows: organic much greater than 70%-80% aqueous organic much greater than 50% aqueous organic greater than H2O. Temperature dependence was also a function of solvent composition. Rates did not strongly reflect steric constraints with beta-lactams and epsilon-lactams forming at comparable rates to rates for gamma- and delta-lactam formation; likewise L-Leu-L-Leu cyclized at about the same rate as L-Leu-D-Leu. Pro-Pro is well documented as having a salt-bridged structure in a variety of solvents where it cyclized extremely rapidly. The reaction is proposed to be dependent on reaction of C2N2 with salt-bridges on the basis of 1) its preponderant if not exclusively intramolecular nature, 2) its solvent dependence, 3) its temperature dependence and 4) the conversion of known salt-bridged structures to amides. This reaction is a model for the observed rapid reaction of salt bridges in proteins.