Profiles of atypical sensory processing in Angelman, Cornelia de Lange and Fragile X syndromes.

BACKGROUND: There is growing evidence to suggest that children with neurodevelopmental disorders may evidence differences in their sensory processing. The aim of this study was to compare sensory processing patterns in three genetic syndromes associated with sensory difference. METHODS: Sensory processing in Angelman syndrome (n = 91), Cornelia de Lange syndrome (n = 28) and Fragile X syndrome (n = 40) was examined using the informant report measure the Sensory Experiences Questionnaire (SEQ). RESULTS: All three groups were associated with a heightened prevalence of unusual sensory processing in comparison with normative data, evidenced in over 80% of all participants. Cross-syndrome comparisons highlighted syndrome-specific sensory processing profiles, with heightened hypo responsivity in Cornelia de Lange syndrome and sensory seeking in Angelman syndrome. CONCLUSIONS: The results have important implications for the understanding of sensory processing in genetic syndromes and the development of tailored behavioural interventions.

A cross-syndrome cohort comparison of sleep disturbance in children with Smith-Magenis syndrome, Angelman syndrome, autism spectrum disorder and tuberous sclerosis complex.

BACKGROUND: Sleep disturbance is common in children with neurodevelopmental disorders, with high rates identified in children with Smith-Magenis syndrome (SMS), Angelman syndrome (AS), autism spectrum disorder (ASD) and tuberous sclerosis complex (TSC). Phenotypic sleep profiles for these groups may implicate different pathways to sleep disturbance. At present, cross-group comparisons that might elucidate putative phenotypic sleep characteristics are limited by measurement differences between studies. In this study, a standardised questionnaire was administered across groups affording comparison of the prevalence and profile of sleep disturbance between groups and contrast to chronologically age-matched typically developing (TD) peers. METHODS: The modified version of Simonds and Parraga's sleep questionnaire, adapted for use in children with intellectual disabilities, was employed to assess sleep disturbance profiles in children aged 2-15 years with SMS (n = 26), AS (n = 70), ASD (n = 30), TSC (n = 20) and a TD contrast group (n = 47). Associations between sleep disturbance and age, obesity, health conditions and overactivity/impulsivity were explored for each neurodevelopmental disorder group. RESULTS: Children with SMS displayed severe night waking (81%) and early morning waking (73%). In contrast, children with ASD experienced difficulties with sleep onset (30%) and sleep maintenance (43%). Fewer children with ASD (43%) and AS (46%) experienced severe night waking compared to children with SMS (both p < .01). Higher sleep-disordered breathing scores were identified for children with SMS (p < .001) and AS (p < .001) compared to the TD group. Sleep disturbance in children with AS and TSC was associated with poorer health. Children experiencing symptoms indicative of gastro-oesophageal reflux had significantly higher sleep-disordered breathing scores in the AS, SMS and ASD groups (all p < .01). A number of associations between overactivity, impulsivity, gastro-oesophageal reflux, age and sleep disturbance were found for certain groups. CONCLUSIONS: These data reveal syndrome-specific profiles of sleep disturbance. The divergent associations between sleep parameters and person characteristics, specifically symptoms of gastro-oesophageal reflux, overactivity and impulsivity and age, implicate aetiology-specific mechanisms underpinning sleep disturbance. The differences in prevalence, severity and mechanisms implicated in sleep disturbance between groups support a syndrome-sensitive approach to assessment and treatment of sleep disturbance in children with neurodevelopmental disorders.

Discrimination training reduces high rate social approach behaviors in Angelman syndrome: proof of principle.

This proof of principle study was designed to evaluate whether excessively high rates of social approach behaviors in children with Angelman syndrome (AS) can be modified using a multiple schedule design. Four children with AS were exposed to a multiple schedule arrangement, in which social reinforcement and extinction, cued using a novel stimulus, were alternated. Twenty-five to 35 discrimination training sessions were conducted and levels of approach behaviors were measured before and after the discrimination training for two children. All four participants evidenced discrimination between conditions of reinforcement and extinction after 16-20 teaching sessions as indicated by lower rates of social approach behaviors in the presence of the S(Δ) for extinction. Reversal effects for the two children for whom this design was implemented were evident. The results demonstrate that after repeated training, the use of a novel stimulus can serve as a cue for children with AS to discriminate adult availability. This is a potentially effective component of a broader intervention strategy but highlights the need for sustained teaching procedures within this population.

Preservation of thoracic spine microarchitecture by alendronate: comparison of histology and microCT.

The effect of bisphosphonates on trabecular microarchitecture may contribute to the reduced risk of vertebral fracture with treatment independent of the bone volume. Trabecular structure was examined at the twelfth thoracic vertebra after 2 years of treatment of two groups of ovariectomized baboons on high and low doses of alendronate, compared with ovariectomized and non-ovariectomized controls. Standard 2D histological measurements showed that alendronate treatment of ovariectomized animals resulted in significantly higher total trabecular length and a lower marrow star volume in comparison with ovariectomized controls indicating preservation of connectivity. Similarly when the vertebrae were examined using a novel thick slice technique that combines 2D and 3D information, ovariectomy produced a significantly higher number of "real" trabecular termini in comparison with normal. When ovariectomized animals were treated with increasing doses of alendronate, fewer "real" termini were seen. MicroCT analysis (2D and 3D) correlated well with the histological measurements, although more variability and less discrimination between groups was seen, with no statistically significant differences with alendronate treatment. Reduced vertebral fracture risk with alendronate may be due to a combination of factors including the increased bone volume, reduced turnover and greater mineralization reported by others. Added to this is now suggested the preservation of several aspects of vertebral cancellous architecture, with microscopy the most sensitive method of analysis.

Concentrations of inhibin, progesterone and oestradiol in fluid from dominant and subordinate follicles from mares during spring transition and the breeding season.

Dominant and subordinate follicles were collected from mares on the day after the dominant follicle reached 30 mm in diameter, to investigate regulation of folliculogenesis during spring transition and the breeding season. Concentrations of oestradiol-17beta, progesterone and inhibin A, but not inhibin isoforms with pro- and alpha C-immunoreactivity, were significantly higher in preovulatory follicles than in dominant anovulatory transitional follicles. Steroidogenic activity was regained gradually in the dominant follicles of successive anovulatory waves through spring transition. The dominant follicles, during both spring transition and cyclicity, contained higher concentrations of oestradiol, progesterone and inhibin A, but not inhibin pro- and alpha C-isoforms, than subordinate follicles. The results indicate that high follicular levels of oestradiol, progesterone and inhibin A are associated with continued follicle growth and ovulation. The low concentrations of oestradiol and progesterone in transitional follicles indicate that the deficiency in steroidogenesis exists early in the steroidogenic pathway. The similarity in patterns of follicular hormones in spring transition and during cyclicity strongly suggests that the mechanism of dominance is the same in both types of follicle.

Plasma FSH, inhibin A and inhibin isoforms containing pro- and -alphaC during winter anoestrus, spring transition and the breeding season in mares.

Ten mares were studied from February (winter anoestrus) to their second ovulation in the breeding season to investigate the relationship between resumption of ovarian cyclicity in the spring and circulating concentrations of FSH, inhibin A and inhibin isoforms containing pro- and -alphaC immunoreactivity. An additional four mares were studied during one oestrous cycle. Growth and regression of ovarian follicles were monitored by transrectal ultrasonography. The frequency of blood sampling varied from three times a week to once a day, depending on the follicular activity present. Concentrations of FSH, oestradiol, inhibin A and pro- and -alphaC isoforms were low during deep winter anoestrus when minimal follicular activity was present in the ovaries. During spring transition, an increase in FSH concentration preceded the emergence of each follicular wave. Concentrations of inhibins were significantly higher (P < 0.05) during growth of anovulatory follicles in spring transition than during winter anoestrus. Plasma concentrations of oestradiol and inhibin A were significantly higher (P < 0.001, P < 0.05, respectively) during the growth of preovulatory follicles than during the growth of transitional anovulatory follicles, but concentrations of inhibin pro-alphaC isoforms did not differ between the two types of follicle. During the oestrous cycle, there was a significant inverse relationship (P < 0.001) between concentrations of FSH and the inhibins. Plasma inhibin pro-alphaC isoforms, but not inhibin A, reached a peak on the day of ovulation. The results strongly indicate that FSH regulates growth of spring anovulatory and preovulatory follicles. Inhibins are likely to contribute to negative feedback on the release of FSH from the pituitary gland both during the transitional period and the breeding season in mares.

Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5-HT1B- and 5-HT1F-receptor activation.

AIMS: Sumatriptan is a 5-HT1B/1D-receptor agonist which also has affinity for 5-HT1F-receptors. The vasoconstrictor effects of sumatriptan are thought to be 5-HT1B-receptor mediated and these receptors have been shown to be expressed in human cranial blood vessels. However, in the same tissue mRNA coding for 5-HT1F-receptors has also been identified and this study addresses the possibility of whether 5-HT1F-receptor activation contributes to vasoconstriction. METHODS: The ability of two selective 5-HT1B/1D-receptor antagonists (GR125,743 and GR127,935) with no affinity for 5-HT1F-receptors, to inhibit sumatriptan evoked contractions in human isolated middle meningeal artery was investigated. Using a series of 5-HT1B/1D-receptor agonists (sumatriptan, zolmitriptan, CP122,288, L-741,519 and L-741,604), some with high affinity for 5-HTIF-receptors and the non-selective 5-HT-receptor agonists 5-HT and 5-CT, we compared the vasoconstrictor potency of these drugs in human isolated middle meningeal artery with their affinities at cloned human 5-HT1B-, 5-HT1D-and 5-HT1F-receptors expressed in CHO cell lines. RESULTS: GR125,743 antagonized sumatriptan evoked contractions in a competitive manner (apparent pA2 9.1) and GR127,935 antagonized sumatriptan-induced responses in a non-competitive manner (reducing the maximum contraction to 27%). There was a significant correlation between vasoconstrictor potency and 5-HT1B-receptor affinity (r=0.93, P=0.002) but not with 5-HT1D- or 5-HT1F-receptor affinity (r=0.74, P=0.06; r= 0.31, P= 0.49, respectively). CONCLUSIONS: These experiments show that in human middle meningeal artery vasoconstriction to sumatriptan-like agents is 5-HT1B-receptor mediated with little if any contribution from 5-HT1F-receptor activation.

Pharmacological characterisation of a cloned dog 5-HT1B receptor cell line.

In this study, the binding of [3H]5-HT to the cloned dog 5-hydroxytryptamine1B (dog 5-HT1B) receptor, stably expressed in Chinese hamster ovary cells (ATCC CCL 61)(CHO-K1), was characterised and its pharmacology compared with that of the cloned human and rat 5-HT1B receptors. [3H]5-HT specifically labeled, with high affinity, an apparently homogeneous population of binding sites in the dog 5-HT1B receptor cell line yielding a pKd of 8.1. [3H]5-HT inhibition and agonist-induced [35S] guanosine 5'[gamma-thio] triphosphate ([35S]GTPgammaS) binding studies revealed comparable results with the human but not the rat 5-HT1B receptor. In all three recombinant receptor cell lines, methiothepin displayed inverse agonism and GR127935 (N-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-2'-methyl-4'-(5-me thyl-1,2,4-oxadiazole-3-yl)[1,1'-biphenyl]-carboxamide) weak partial agonism.

Pressure-equalization (PE) tubes in treatment of otitis media: national survey of otolaryngologists.

This study was designed to describe those indicators for the insertion of pressure-equalization (PE) tubes given highest priority by board-certified otolaryngologists. An original questionnaire was mailed to 1000 board-certified otolaryngologists practicing in the United States. The respondents rated the relative importance of 22 indicators on a 6-point scale. These indicators were grouped into four categories: Medical History, Physical Examination, Audiologic Evaluation, and Related Indicators. With a return rate of 52.7%, approximately 1 of every 9 board-certified, practicing otolaryngologists in the United States was represented in the study. The five indicators with the highest ratings were: "persistence of fluid for 3 or more months per episode," "presence of speech-language delay," "presence of bilateral conductive hearing loss of 20 dB or more," "total number of episodes of otitis media," and "lack of response to suppressive antibiotic therapy." Additional analyses of the data yielded information regarding characteristics of the responding physicians and the self-generated indicators.

Tetronic 701-a novel hypocholesterolaemic agent.

The Tetronic series of polymeric surface-active agents were screened for hypocholesterolaemic activity in rats fed on a semi-synthetic hypercholesterolaemic diet. Only Tetronics 701 and 702 were active and the former was further investigated. Tetronic 701 lowered serum and liver cholesterol in rats fed on a semi-synthetic diet, with or without cholesterol, but not in rats fed on stock laboratory diet. A dose-related growth depression was observed. The compound was hypocholesterolaemic in chicks and rabbits fed on cholesterol-containing diets. The uptake of a single dose of cholesterol into liver and serum was inhibited in rats given Tetronic 701. Tetronics 701 and 702 were effective in precipitating cholesterol from mixed micelles in vitro. Non-hypocholesterolaemic Tetronics were inactive in this respect. A series of tetraesters of tetronic 701 were prepared and tested in rats fed on a semi-synthetic hypercholesterolaemic diet. Several were hypocholesterolaemic and the tetrabenzoate was of especial interest in that it depressed growth less than did Tetronic 701 itself.

Hypolipidemic imidazoles.

A series of analogs of N-benzylimidazole was prepared and tested for hypolipidemic activity. Both plasma cholesterol and triglyceride-lowering activity were found in several members of the series. The most active compounds were N-3-methoxy-, N-4-methoxy-, and N-4-methylbenzylimidazole. Structure-activity relationships are discussed.