Internet use and online safety in adults with Williams syndrome.

BACKGROUND: Individuals with intellectual and developmental disabilities (IDD) increasingly have access to the Internet. Whilst Internet access increases opportunities for social connection for individuals with IDD, it also may increase risk of victimisation. Adults with Williams syndrome (WS), who display an extreme pro-social drive to engage with both familiar and unfamiliar people, might be especially vulnerable to online victimisation. This study first explores how often and why individuals with WS use the Internet and social networking sites. Next, the online vulnerability of individuals with WS is assessed through responses to hypothetical scenarios of potentially dangerous online interactions. METHOD: Twenty-eight young adults with WS (mean age = 27.7 years) and their parents completed questionnaires about their Internet and social networking use and parental oversight. Participants with WS then responded to hypothetical scenarios assessing their likelihood to take social and non-social risks online. RESULTS: Most participants with WS frequently use the Internet and the majority visit social networking sites every day or almost every day, with little parental supervision or oversight. Individuals with WS interact with both known and unknown individuals through social networking sites. Participants are more likely to agree to engage in socially risky behaviours compared to risky behaviours that are not social in nature when online. For example, participants were more likely to agree to meet an 'online friend' in person than they were to give their bank account information for winning a 'contest'. CONCLUSIONS: Individuals with WS, who are a socially vulnerable group in the real world, display behaviours that could also lead to victimisation online as well. As the Internet continues to become more accessible, more research is needed to increase online safety of individuals with WS and other IDDs. Implications for intervention and future research are discussed.

Longitudinal trajectories of intellectual and adaptive functioning in adolescents and adults with Williams syndrome.

BACKGROUND: Williams syndrome (WS) is associated with a distinct cognitive-behavioural phenotype including mild to moderate intellectual disability, visual-spatial deficits, hypersociability, inattention and anxiety. Researchers typically characterise samples of individuals with WS by their intellectual functioning and adaptive behaviour. Because of the low prevalence of the syndrome, researchers often include participants with WS across a broad age range throughout childhood and adulthood and assume participants demonstrate consistent cognitive development across ages. Indeed, IQ scores are generally stable for children and adolescents with WS, although there are significant individual differences. It is less clear whether this pattern of stable intellectual ability persists into adulthood. Furthermore, while adaptive behaviour is an important indicator of an individual's ability to apply their conceptual skills to everyday functioning, conflicting findings on the trajectories of adaptive behaviour in adolescents and adults with WS have been reported. The current study examined longitudinal profiles of cognitive and adaptive functioning in adolescents and adults with WS. METHOD: To examine cognitive functioning, participants included 52 individuals with WS (51.9% men) who were assessed with the Kaufman Brief Intelligence Test, 2nd edition (KBIT-2) between two and seven times. At their first assessment, participants had a mean age of 25.4 years (SD = 8.4), ranging in age from 14.2 to 48.9 years. To assess adaptive behaviour, participants included a subset of 28 individuals with WS whose parents completed the Vineland Adaptive Behavior Scale, 2nd edition (VABS-II) between two and five times. At their initial administration, participants ranged from 17.1-40.2 years of age, with a mean age of 26.5 years (SD = 7.3). A series of multilevel models were used to examine changes in KBIT-2 Composite IQ, Verbal IQ and Nonverbal IQ standard scores over time, as well as the Adaptive Behavior Composite, and the Communication, Daily Living Skills and Socialization subdomains of the VABS-II. RESULTS: Consistent with the WS cognitive profile, IQ scores were significantly lower than the general population IQ score of 100, and there was significant variability in individual IQ scores and slopes. KBIT-2 IQ scores were generally stable across adolescents and adults with WS. Adaptive behaviour scores were significantly lower than the population mean score of 100, and there was significant variability in individuals' adaptive behaviour scores but not trajectories. However, in contrast to the findings with the KBIT-2, VABS-II scores were observed to significantly decrease over time. CONCLUSION: Findings suggest that while intellectual functioning remains stable, adaptive functioning does not remain stable across adolescence and adulthood in individuals with WS. Implications for the relation between cognitive and adaptive functioning across development are discussed, with a focus on how this relates to specific aspects of the WS phenotype.

Three-dimensional rendering of otolith growth using phase contrast synchrotron tomography.

A three-dimensional computer reconstruction of a plaice Pleuronectes platessa otolith is presented from data acquired by the Diamond Light synchrotron, beamline I12, X-ray source, a high energy (53-150 keV) source particularly well suited to the study of dense objects. The data allowed non-destructive rendering of otolith structure, and for the first time allows otolith annuli (internal ring structures) to be analysed in X-ray tomographic images.

Evaluation of a stranger safety training programme for adults with Williams syndrome.

BACKGROUND: Individuals with Williams syndrome (WS) are reported to display increased sociability towards strangers, leading to increased social vulnerability. No research has examined real life interactions of adults with WS towards strangers and no interventions have been implemented to teach stranger safety skills to this population. METHOD: Twenty-one adults with WS participated in 3 days of behaviour skills training to learn how to respond to a stranger lure. Skill acquisition was assessed in situ; confederate strangers approached participants, presented a lure and recorded the participants' response. RESULTS: Prior to intervention, 14% of participants walked away from a stranger. Participants were able to accurately use the skills in role play. After training, 62% of participants said 'no' and walked away and only 14% agreed to leave with the stranger during in situ assessments. CONCLUSIONS: Individuals with WS are at-risk but can learn how to appropriately respond to lures from strangers. Further research is needed to increase use of safety skills in various conditions.

Ivermectin: a potent new antiparasitic agent.

Ivermectin is the 22,23-dihydro derivative of avermectin B1, a macrocyclic lactone produced by an actinomycete, Streptomyces avermitilis. It is active at extremely low dosage against a wide variety of nematode and arthropod parasites, apparently by virtue of its action on the mediation of neurotransmission by gamma-aminobutyric acid. It is now in commercial use in various countries for the treatment and control of parasites in cattle, horses, and sheep, and is expected to become available for use in swine and dogs. Since studies with the drug in man are in a preliminary stage, it is not yet known whether ivermectin will be useful in human medicine.

A selective human beta3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys.

Activation of beta3 adrenergic receptors on the surface of adipocytes leads to increases in intracellular cAMP and stimulation of lipolysis. In brown adipose tissue, this serves to up-regulate and activate the mitochondrial uncoupling protein 1, which mediates a proton conductance pathway that uncouples oxidative phosphorylation, leading to a net increase in energy expenditure. While chronic treatment with beta3 agonists in nonprimate species leads to uncoupling protein 1 up-regulation and weight loss, the relevance of this mechanism to energy metabolism in primates, which have much lower levels of brown adipose tissue, has been questioned. With the discovery of L-755,507, a potent and selective partial agonist for both human and rhesus beta3 receptors, we now demonstrate that acute exposure of rhesus monkeys to a beta3 agonist elicits lipolysis and metabolic rate elevation, and that chronic exposure increases uncoupling protein 1 expression in rhesus brown adipose tissue. These data suggest a role for beta3 agonists in the treatment of human obesity.

Using neural networks and just nine patient-reportable factors of screen for AMI.

The study investigated the effect of different input selections on the performance of artificial neural networks in screening for acute myocardial infarction (AMI) in Malaysian patients complaining of chest pain. We used hospital data to create neural networks with four input selections and used these to diagnose AMI. A 10-fold cross-validation and committee approach was used. All the neural networks using various input selections outperformed a multiple logistic regression model, although the difference was not statistically significant. The neural networks achieved an area under the ROC curve of 0.792 using nine inputs, whereas multiple logistic regression achieved 0.739 using 64 inputs. Sensitivity levels of over 90 per cent were achieved using low output threshold levels. Specificity levels of over 90 per cent were achieved using threshold levels of 0.4-0.5. Thus neural networks can perform as well as multiple logistic regression models even when using far fewer inputs.

Combined modalities of resistance in etoposide-resistant human KB cell lines.

The alkaloid derivative 4'-demethylepipodophyllotoxin 9-(4,6-O-ethylidene)-beta-D-glucopyranoside (etoposide, VP-16) is believed to exert cytotoxicity by causing double-stranded DNA breaks through interruption of the breaking-resealing reaction of topoisomerase II (topo II). Thus it was conceivable that cells could become resistant to VP-16 by a decrease in topo II enzyme level, since this would lead to fewer DNA breaks. As well, given the structure of VP-16, it was also possible that a pleiotropic mechanism of resistance could decrease sensitivity to this drug. To study these possibilities, a series of VP-16-resistant human KB cell lines was established by stepwise selection. The concentrations of VP-16 required to inhibit cell proliferation by 50% in the parent line and KB/1c, KB/7d, KB/20a, and KB/40a lines were, respectively, 0.16, 4.7, 24, 31, and 47 microM. These cell lines expressed cross-resistance to 4'-(9-acridinylamino)methanesulfon-m-anisidide, doxorubicin, vincristine, and methotrexate, although the pattern of relative drug sensitivity was quite different from that of pleiotropic resistant cell lines reported elsewhere. The resistance to vincristine and methotrexate did not increase above the level of the KB/1c cells, and resistance to VP-16, doxorubicin, and especially vincristine was unstable in VP-16-resistant cells cultured in the absence of drug. Although the drug resistance marker Mr 180,000 glycoprotein could not be detected in any of our cell lines, cellular accumulation of [3H]VP-16 was reduced 50-75% in the resistant lines compared with parent KB. With increasing VP-16 resistance, the level of topo II protein, detected by antibody staining, decreased at each step of selection, concomitant with a general decrease in topo II unknotting activity. Sensitivity of the topo II unknotting assay to inhibition by VP-16 was the same for the parent and all resistant cell lines. The level of topo I activity and enzyme increased slightly in the resistant cells. Thus, these cell lines are resistant to VP-16 by virtue of at least two mechanisms: (a) reduced levels of topo II, which confers cross-resistance to other compounds which are topo II-dependent cytotoxic agents; and (b) reduced accumulation of drug, which is likely also responsible for vincristine and methotrexate resistance. However, the possible existence of other mechanisms of resistance cannot be ruled out.

Activity of the new antifolate N10-propargyl-5,8-dideazafolate and its polyglutamates against human dihydrofolate reductase, human thymidylate synthetase, and KB cells containing different levels of dihydrofolate reductase.

The action of N10-propargyl-5,8-dideazafolate (PDDF) and its gamma-polyglutamyl analogues against human thymidylate synthetase and dihydrofolate reductase was examined. PDDF inhibited thymidylate synthetase in a noncompetitive fashion with respect to 5,10-methylenetetrahydrofolate and dihydrofolate reductase in a competitive fashion with respect to dihydrofolate. Ki values were estimated to be 20 and 250 nM, respectively. The addition of glutamyl moieties through gamma-linkage enhanced the inhibitory activity of PDDF against thymidylate synthetase without significant effect on dihydrofolate reductase. PDDF inhibited human KB cell growth, and its potency was found to be influenced less than that of methotrexate by the amount of cellular dihydrofolate reductase.

Selective transcription of p53 target genes by zinc finger-p53 DNA binding domain chimeras.

Active p53 stimulates the transcription of a number of key genes, including the pro-apoptotic gene bax, as well as p21, a cell cycle regulator. In this study we constructed novel chimeric zinc finger-p53 DNA binding domain (DBD) transcription factors designed to bind to the promoters of specific p53 regulated genes. In order to selectively increase the expression of Bax, we coupled a pre-selected three-zinc finger (Zif) peptide targeted to a sequence in the bax promoter to a minimal p53 DBD. This chimeric protein could increase reporter gene transcription from a minimal bax promoter (up to 10-fold) but not from a minimal p21 promoter in p53-deficient Saos-2 cells. However, fusion proteins carrying longer p53 DBDs displayed entirely different selectivity and potency. Thus, Zif-p53 DBD chimeras containing N- and C-terminal extensions of the minimal DBD could increase transcription driven by a minimal p21 promoter up to 800-fold. These chimeras preferred the minimal p21 promoter up to 500-fold over the minimal bax promoter. Additionally, endogenous p21 message and protein levels were increased in cells expressing the p21 selective Zif-p53 DBD chimera and expression of the chimeric proteins resulted in partial cell cycle arrest. Cell fractionation experiments indicated that the Zifs enhanced nuclear localization of the Zif-p53 DBD chimera. These studies suggest that it is possible to create chimeric transcription factors able to strongly and selectively activate genes downstream of p53.

Stimulation of growth hormone release from rat primary pituitary cells by L-692,429, a novel non-peptidyl GH secretagogue.

L-692,429, a benzolactam derivative, stimulated GH release from rat primary pituitary cells in a dose-dependent manner. The concentration of L-692,429 required for half-maximal stimulation were 59.6 +/- 7.3 nM. Under the same conditions, GHRP-6 and GRF had EC50 values of 10.3 +/- 1.9 nM and 0.47 +/- 0.09 nM, respectively. L-692,428, the enantiomer of L-692,429, was inactive at a concentration as high as 2 microM. Like GHRP-6, L-692,429 had no effect on intracellular cAMP level; however, it synergized with GRF to further increase not only the accumulation of cAMP but also the release of GH. The magnitude of GH release stimulated by maximal concentrations of L-692,429 and GHRP-6 was comparable. Interestingly, when presented together in maximal concentrations, L-692,429 and GHRP-6 did not cause additional GH release when compared with either secretagogue alone. The L-692,429-stimulated GH release was completely inhibited by 20 nM somatostatin. To our knowledge, L-692,429 is the first non-peptidyl GH secretagogue which has a direct effect on the release of growth hormone from rat primary pituitary cells. Its effect is most likely mediated through a mechanism which is similar to that of GHRP-6.

5,11-dimethyl-2,9-bis(phenylacetyl)-5,11-diazatetracyclo[6.2.2.0(2,7).0(4,9)]dodecane, a potent, novel analgesic.

5,11-Dimethyl-2,9-bis(phenylacetyl)-5,11-diazatetracyclo[6.2.2.0(2,7)90(4,9)]dodecane (2a) has been found to be a potent narcotic analgesic of unusual structure. All of the analgesic activity was attributable to the levorotatory isomer 2b which was approximately three times as potent as morphine in the rat. Removal of one N-methyl group from 2a reduced, but did not abolish, the analgesic activity. However N-allyl analogues were neither agonists nor antagonists. Replacement of one of the phenyls of 2a with a cyclohexyl group yielded an analogue with considerable activity. Structural similarities with derivatives of ethenooripavine are noted.

Avermectin acyl derivatives with anthelmintic activity.

Avermectins A2a, B1a, and B2a (1, 2, and 3) were acetylated to give 4"- and 23-acetates 4 and 5 and 4",23-diacetate 6 from 1, the 4"-and 5-acetates 7 and 8 and 4",5-diacetate 9 from 2, and triacetate 10 from 3. Structure proof by 300-MHz 1H NMR and mass spectral fragmentation is discussed for 10. Forcing acetylation conditions generated from both 1 and 3 the identical aromatic diacetate 11. Good anthelmintic activities in gerbils and sheep for 4"-acetylated derivatives 4 and especially 7 prompted the preparation of additional 4"-acylated derivatives of 2 with pivaloyl, n-octanoyl, succinoyl, carbamoyl, dimethylcarbamoyl and N-acetylglycyl substituents, prepared from the 5-O-tert-butyldimethylsilyl-protected intermediate 12. Other key intermediates were the trichloroethyoxysuccinoyl derivative 18 and 4-nitrophenyl carbonate 21. Anthelmintic activities against Trichostrongylus colubriformis in gerbils comparable in potency to the natural product 2 are shown by the more polar substituted derivatives 20, 23, and 27. Substitution of the 5-hydroxy group or its loss due to aromatization results in drastically reduced anthelmintic potency.

Syntheses and biological activities of 13-substituted avermectin aglycons.

The reactions of sulfonate esters of the allylic/homoallylic 13-alcohol of 5-O-(tert-butyldimethylsilyl)-22,23-dihydroavermectin B1a aglycon (1a) were investigated. Nucleophilic substitution gave 13 beta-chloro and 13 beta-iodo derivatives, while solvolytic reaction conditions yielded 13 alpha-methoxy, 13 alpha-fluoro, and 13 alpha-chloro products. A mixture of 13 alpha- and 13 beta-fluorides was obtained upon reaction with DAST. The 13 beta-iodide gave, upon elimination with lutidine, the 8(9),10(11),12(13),14(15)-tetraene. The 13 beta-alcohol and the rearranged 15-ol 13(14)-ene and 15-amino 13(14)-ene derivatives were obtained by substitution via the allylic carbonium ion. MEM ethers 11 and 12 of the two epimeric 13-ols were prepared by alkylation with MEM chloride. In contrast, methylation of 1a with MeI and Ag2O in CH2Cl2 occurred exclusively at the tertiary 7-hydroxy group and not at the secondary 13 alpha-ol. Oxidation of the allylic alcohol 1a proceeded under Swern conditions but not with MnO2 to the 13-oxo aglycon, which was reduced by NaBH4 exclusively to the natural 13 alpha-ol, while reductive amination with NaCNBH3-NH4OAc gave the 13 alpha-amine. The methoxime derivative was obtained in the form of the two geometric isomers. Anthelmintic activities against the sheep nematode Trichostrongylus colubriformis, miticidal activities against the two-spotted spider mite (Tetranychus urticae), and insecticidal activities against the southern armyworm (Spodoptera eridania) as well as the binding constants to a free living nematode (Caenorhabditis elegans) derived receptor assay were obtained and compared to avermectin B1a, 22,23-dihydroavermectin B1a, and the 13-deoxy-22,23-dihydroavermectin B1 aglycon related to the milbemycins. None of the newly prepared derivatives exceeded the potency of the three reference compounds. Lipophilic 13-substituents such as halogen, alkoxy, and methoxime retained high biological activities in all assays, while the more polar substituents hydroxy and amino had weaker activities. Rearranged 15-substituted 13(14)-ene derivatives were completely inactive. The 13-oxo and the 12,13-dehydro analogues were only weakly active in vivo despite having good binding affinity to the receptor, possibly due to instability or poor absorption.

Synthesis and biological activity of 13-epi-avermectins: potent anthelmintic agents with an increased margin of safety.

Chemical conversion of the potent anthelmintic natural products avermectin B1 (1) and avermectin B2 (3) to the corresponding 13-epi analogs (15 and 9) is described. The novel analogs retain the full potency of the natural products but are substantially safer.

Affinity probes for the avermectin binding proteins.

The design and synthesis of a series of avermectin affinity probes used in the identification and purification of the avermectin binding proteins is described. These modified avermectins fall into two design classes: ligands to covalently modify specific avermectin binding proteins [an 125I-labeled aryl azide photoprobe (15) and a tritiated aziridine analog (6)] and ligands for affinity chromatography applications [three biotinylated compounds (10, 12, and 13) and one resin-bound derivative (9)]. The binding affinities of these compounds for the Caenorhabditis elegans avermectin binding protein is presented as well as their biological activities against C. elegans and Artemia salina.

Anticoccidial 1-substituted 4(1H)-pyridinone hydrazones.

4-Chlorobenzaldehyde 1-(4-chlorophenyl)-4(1H)-pyridinylidene hydrazone fluorusulfonate (4) was found to have excellent anticoccidial activity in chickens. The synthesis and biological evaluation of related analogues are presented. Presumably 4 shares a common mechanism of action with robenidine (25) since it was not active on a robenidine tolerant strain of E. tenella. Structural comparisons of the two molecules are presented.

Isomeric phenylthioimidazo[1,2-alpha]pyridines as anthelmintics.

A series of isomeric imidazo[1,2-alpha]pyridine-2-carbamates was prepared for testing as anthelmintics. The analogues were synthesized by reacting the appropriate 2-aminopyridine and methyl chloroacetylcarbamate. Steric hindrance in the 2,6-disubstituted derivative resulted in the formation of the isomeric 3-substituted analogue as the major product. Carbon-13 NMR proved useful in the structural assignments in this series. None of the analogues exhibited the potency of methyl 6-(phenylsulfinyl)imidazo[1,2-alpha]pyridine-2-carbamate when tested against Nematospiroides dubius in mice.

A novel 3-substituted benzazepinone growth hormone secretagogue (L-692,429).

The 3-substituted benzazepinone, L-692,429 (compound 1), is the prototype compound of a novel class of compounds that stimulate release of growth hormone (GH). The molecule evolved from efforts to identify a non-peptide mimic of the growth hormone-releasing hexapeptide, GHRP-6. Compound 1 is prepared by sequential attachment of dimethyl-beta-alanine and 2'-biphenylyltetrazole side chains to a chiral 3-aminobenzolactam nucleus. Comparison of the biological activity of 1 with the corresponding six- and eight-membered lactam analogs shows the seven-membered benzazepinone skeleton to be preferred. Molecular modeling of the structurally diverse GH secretagogues, L-692,429 and GHRP-6, was performed.

Ivermectin, a new broad-spectrum antiparasitic agent.

22,23-Dihydroavermectin B1, ivermectin, derived from avermectin B1 by selective hydrogenation using Wilkinson's homogenous catalyst [Ph3P)3RhCl], was shown to be a highly effective drug for the treatment of a wide variety of metazoan parasitic diseases in animals.