Social and community inclusion outcomes for adults with autism with and without intellectual disability in Australia.

BACKGROUND: Research suggests that adults with autism tend to have poor outcomes. Outcomes have mostly been defined using summary outcome ratings, with less focus on specific outcomes such as employment, living situation, social satisfaction, loneliness, and friendships. This study aimed to explore social and community outcomes, including employment, education, living arrangements, friendships, and social satisfaction, for autistic adults with and without intellectual disability. METHOD: Eighty-four adults with autism (mean age 34.2 years, SD = 4.5; 67% with co-occurring intellectual disability), recruited as children and adolescents, participated in the current study. Adult social and community inclusion outcomes were explored through interview and questionnaire, both parent/carer-report and self-report. RESULTS: Participants predominantly lived with family or in supported accommodation, did not pursue higher education, and mostly participated in day activity programmes. Most had limited friendships as reported by parents/carers; however, self-report data (n = 28) indicated that adults were largely satisfied with their social relationships. Overall outcome was poor for 57%, and good/very good for 34%. Adults with intellectual disability generally had poorer outcomes. CONCLUSION: Autistic adults encountered numerous difficulties in leading an independent life. Adults with co-occurring intellectual disability were most likely to experience difficulties; however, outcomes ranged from poor to very good for adults without intellectual disability. Discrepancies in parent/carer-report and self-reported experiences of friendships highlight the need to ensure individual experiences are captured in addition to parent/carer-report. Appropriate resources and programmes are crucial for adults with autism to support them to have the choice to live independently.

In vivo imaging of specific drug-target binding at subcellular resolution.

The possibility of measuring binding of small-molecule drugs to desired targets in live cells could provide a better understanding of drug action. However, current approaches mostly yield static data, require lysis or rely on indirect assays and thus often provide an incomplete understanding of drug action. Here, we present a multiphoton fluorescence anisotropy microscopy live cell imaging technique to measure and map drug-target interaction in real time at subcellular resolution. This approach is generally applicable using any fluorescently labelled drug and enables high-resolution spatial and temporal mapping of bound and unbound drug distribution. To illustrate our approach we measure intracellular target engagement of the chemotherapeutic Olaparib, a poly(ADP-ribose) polymerase inhibitor, in live cells and within a tumour in vivo. These results are the first generalizable approach to directly measure drug-target binding in vivo and present a promising tool to enhance understanding of drug activity.

Merotelic kinetochores in mammalian tissue cells.

Merotelic kinetochore attachment is a major source of aneuploidy in mammalian tissue cells in culture. Mammalian kinetochores typically have binding sites for about 20-25 kinetochore microtubules. In prometaphase, kinetochores become merotelic if they attach to microtubules from opposite poles rather than to just one pole as normally occurs. Merotelic attachments support chromosome bi-orientation and alignment near the metaphase plate and they are not detected by the mitotic spindle checkpoint. At anaphase onset, sister chromatids separate, but a chromatid with a merotelic kinetochore may not be segregated correctly, and may lag near the spindle equator because of pulling forces toward opposite poles, or move in the direction of the wrong pole. Correction mechanisms are important for preventing segregation errors. There are probably more than 100 times as many PtK1 tissue cells with merotelic kinetochores in early mitosis, and about 16 times as many entering anaphase as the 1% of cells with lagging chromosomes seen in late anaphase. The role of spindle mechanics and potential functions of the Ndc80/Nuf2 protein complex at the kinetochore/microtubule interface is discussed for two correction mechanisms: one that functions before anaphase to reduce the number of kinetochore microtubules to the wrong pole, and one that functions after anaphase onset to move merotelic kinetochores based on the ratio of kinetochore microtubules to the correct versus incorrect pole.

Modality specific neural correlates of auditory and somatic hallucinations.

Somatic hallucinations occur in schizophrenia and other psychotic disorders, although auditory hallucinations are more common. Although the neural correlates of auditory hallucinations have been described in several neuroimaging studies, little is known of the pathophysiology of somatic hallucinations. Functional magnetic resonance imaging (fMRI) was used to compare the distribution of brain activity during somatic and auditory verbal hallucinations, occurring at different times in a 36 year old man with schizophrenia. Somatic hallucinations were associated with activation in the primary somatosensory and posterior parietal cortex, areas that normally mediate tactile perception. Auditory hallucinations were associated with activation in the middle and superior temporal cortex, areas involved in processing external speech. Hallucinations in a given modality seem to involve areas that normally process sensory information in that modality.

Failure to confirm NOTCH4 association with schizophrenia in a large population-based sample from Scotland.

The NOTCH4 gene was recently reported to be associated with schizophrenia based on TDT analysis of 80 British trios. The strongest evidence for association derived from two microsatellites. We genotyped both loci in a large sample of unrelated Scottish schizophrenics and controls, but failed to replicate the reported association, finding instead that each putative schizophrenia-associated allele had a somewhat lower frequency in schizophrenics than in controls.

Dendritic organization of actin comet tails.

Polymerization of actin filaments is necessary for both protrusion of the leading edge of crawling cells and propulsion of certain intracellular pathogens, and it is sufficient for generating force for bacterial motility in vitro. Motile intracellular pathogens are associated with actin-rich comet tails containing many of the same molecular components present in lamellipodia, and this suggests that these two systems use a similar mechanism for motility. However, available structural evidence suggests that the organization of comet tails differs from that of lamellipodia. Actin filaments in lamellipodia form branched arrays, which are thought to arise by dendritic nucleation mediated by the Arp2/3 complex. In contrast, comet tails have been variously described as consisting of short, randomly oriented filaments, with a higher degree of alignment at the periphery, or as containing long, straight axial filaments with a small number of oblique filaments. Because the assembly of pathogen-associated comet tails has been used as a model system for lamellipodial protrusion, it is important to resolve this apparent discrepancy. Here, using a platinum replica approach, we show that actin filament arrays in comet tails in fact have a dendritic organization with the Arp2/3 complex localizing to Y-junctions as in lamellipodia. Thus, comet tails and lamellipodia appear to share a common dendritic nucleation mechanism for protrusive motility. However, comet tails differ from lamellipodia in that their actin filaments are usually twisted and appear to be under significant torsional stress.

Recruitment of T cells to the lung in response to antigen challenge.

T-cell recruitment to the lungs is thought to represent a key step in airway allergic inflammation. T cells coordinate and amplify effector functions of antigen-specific and nonspecific proinflammatory cells, such as B cells and eosinophils. The T(H)2 cell, in particular, promotes allergic inflammation through the expression of IL-4, IL-5, and IL-13, proinflammatory cytokines that are important in the induction of B-cell switching and the promotion of eosinophil proliferation and survival. This cytokine profile has been implicated in asthma; elevations in bronchoalveolar lavage IL-4 and IL-5 levels have been observed in asthmatic patients. The recruitment of T(H) cells to the site of allergic inflammation (lung) is the subject of this review.

Secrets of actin-based motility revealed by a bacterial pathogen.

Actin-based cell motility is a complex process involving a dynamic, self-organizing cellular system. Experimental problems initially limited our understanding of this type of motility, but the use of a model system derived from a bacterial pathogen has led to a breakthrough. Now, all the molecular components necessary for dynamic actin self-organization and motility have been identified, setting the stage for future mechanistic studies.

Airway epithelium expresses interleukin-18.

Interleukin (IL)-18 is an interferon (IFN)-gamma-inducing cytokine suggested to be important in regulating inflammatory responses. This study investigated the pulmonary expression of IL-18 under conditions characterized by T-helper (Th)1 (lipopolysaccharide (LPS) treatment/sarcoidosis) and Th2 (ovalbumin (OVA) challenge/asthma) cytokine production. In situ hybridization and immunocytochemistry were used to determine the number of cells expressing IL-18, IFN-gamma, IL-5 and major basic protein (MBP) within lung tissue from Balb/c mice stimulated with LPS, OVA and in normal control mice. Bronchial biopsies from patients with sarcoidosis, asthma and control individuals were also examined. IL-18 was localized primarily to airway epithelium and mononuclear cells. Constitutive expression was observed within the lungs of control mice. Animals challenged with LPS exhibited more IL-18 messenger ribonucleic acid (mRNA)-positive and IFN-gamma immunoreactive cells, compared to control mice (p<0.01). OVA-challenged mice had fewer IL-18 mRNA positive and more IL-5 and MBP immunoreactive cells, compared to control mice (p<0.01). Similarly, constitutive expression of IL-18 protein was observed within the airway epithelium of control individuals, with more positive cells found within sarcoidosis tissue (p<0.01) and fewer within asthmatic tissue (p<0.01), compared to controls. These results demonstrate the expression of interleukin-18 within airway epithelium and the regulation of this cytokine under conditions of both T-helper1 and T-helper2 cytokine production.

Motility of ActA protein-coated microspheres driven by actin polymerization.

Actin polymerization is required for the generation of motile force at the leading edge of both lamellipodia and filopodia and also at the surface of motile intracellular bacterial pathogens such as Listeria monocytogenes. Local catalysis of actin filament polymerization is accomplished in L. monocytogenes by the bacterial protein ActA. Polystyrene beads coated with purified ActA protein can undergo directional movement in an actin-rich cytoplasmic extract. Thus, the actin polymerization-based motility generated by ActA can be used to move nonbiological cargo, as has been demonstrated for classical motor molecules such as kinesin and myosin. Initiation of unidirectional movement of a symmetrically coated particle is a function of bead size and surface protein density. Small beads (

Understanding alcohol abuse in American Indian/Alaskan Native youth.

By almost any measure, the health status of American Indian/Alaskan Native (AI/AN) teenagers in the United States is below that of the general adolescent population. These youth exhibit more serious problems than the U.S. "all races" population in such areas as depression, suicide, anxiety, substance use, general health status, and school dropout rates. Alcohol misuse is the leading and perhaps most costly risk factor among AI/AN youth today, underlying many major causes of premature death and contributing to an array to physical morbidities. While AI/AN youth generally report that they use alcohol as frequently or more frequently than other youth, major differences are a younger age of first involvement, greater frequency and amount of use, and negative consequences that are more common. The unique historical legacy of dislocation for AI/AN peoples, coupled with the intensity of contemporary threats to the physical, social, and economic vitality of their communities, form the backdrop for this health risk behavior. Heightened concern and attention toward alcohol use in AI/AN youth is warranted by Indian communities and health care providers not only because of the substance use itself, but also because of the other potential accompanying risk behaviors.

Expression of IL-4, Cepsilon RNA, and Iepsilon RNA in the nasal mucosa of patients with seasonal rhinitis: effect of topical corticosteroids.

BACKGROUND: Nasal allergen provocation has demonstrated that allergen-induced rhinitis is associated with an increase in local IL-4 mRNA and IgE heavy chain (Cepsilon) and IgE heavy chain promoter (Iepsilon) RNA and that pretreatment with topical glucocorticosteroids inhibits the increase in these transcripts. OBJECTIVE: This study was undertaken to determine whether observations made after acute allergen provocation can be extended to the case of chronic exposure experienced during the pollen season. METHODS: Biopsy specimens were obtained from the inferior turbinate of 33 pollen-sensitive subjects with allergic rhinitis before and during pollen season. Patients were randomized in a double-blind fashion and treated with either topical steroids (200 microg fluticasone propionate twice daily; n = 16) or matched placebo nasal spray (n = 17) before the pollen season. Alkaline phosphatase anti-alkaline phosphatase immunocytochemistry was used to identify B cells (CD20+), and in situ hybridization was used to detect IL-4, Cepsilon, and Iepsilon RNA+ cells. RESULTS: Baseline examination revealed IL-4 and Cepsilon RNA but virtually no Iepsilon RNA+ cells in the nasal mucosa. Analysis revealed a significant difference in the expression of Cepsilon and Iepsilon RNA+ cells (p < 0.001). Biopsy specimens taken after antigen exposure exhibited highly significant increases in placebo-treated (p < 0.001) but not steroid-treated patients. In both groups, the number of CD20+ cells was unchanged when preexposure and postexposure biopsy specimens were compared. CONCLUSIONS: These results show strong support for the hypothesis that IgE class switching occurs locally within the nasal mucosa of subjects with seasonal allergic rhinitis and that this response can be inhibited through strategies directed against local IgE production.

Studies on endothelin receptors in the zonae fasciculata/reticularis of the rat adrenal cortex: contrast with the zona glomerulosa.

This study investigated the ET(A) and ET(B) receptor subtypes in rat adrenal cortex. The ET(A) antagonist, BQ-123, inhibited the zona glomerulosa (zg), but not the inner zone (iz) response to ET-1. RES-701-1, the ET(B) antagonist, abolished the iz response to ET-1, but had less effect on the zg. [125I]ET-1 binding studies revealed two receptor subtypes in both zones, with ET(A) predominating in the zg, and ET(B) in the iz. These data suggest that the ET(A) subtype is functionally more important in the zg while the ET(B) receptor is the major subtype in the inner zones.

Regulation of adrenal vascular tone: role of endothelin-1 and nitric oxide.

The adrenal gland is a highly vascular organ, with a highly conserved and well-regulated blood supply. This study was designed to determine the roles of the local vascular regulators, nitric oxide (NO) and endothelin-1 (ET-1), in the regulation of adrenal vascular tone. Using the in situ intact perfused rat adrenal preparation it was found that the ETA receptor antagonist, BQ123, caused a significant increase in perfusion medium flow rate, while the ETB antagonist, RES-701-1, had no effect. Administration of the NO synthesis, inhibitor, L-NAME, or perfusing medium lacking the substrate for NO synthesis, resulted in a significant decrease in perfusion medium flow rate through the adrenal gland. These results suggest that endogenous endothelin causes a tonic vasoconstriction in the rat adrenal gland, mediated by the ETA receptor and that endogenous NO exerts a tonic vasodilatory effect on the rat adrenal.

Differential effects of endogenous and exogenous nitric oxide on the release of endothelin-1 from the intact perfused rat adrenal gland in situ.

Studies using an inhibitor of nitric oxide (NO) synthesis have suggested that endogenous NO may have a role in regulating endothelin release. We investigated the effect of endogenous and exogenous nitric oxide (NO) on the release of irET-1. L-NAME stimulated, but L-arginine inhibited irET-1 release. Perfusing sodium nitroprusside (SNP), however, did not inhibit irET-1 secretion. CyclicGMP, the second messenger for NO action, was stimulated by SNP but not by L-arginine. These data demonstrate that endogenous NO inhibits of irET-1, in a manner which is independent of cGMP, and suggest that this action may contribute to the vasodilatory effect of NO.

Isolation and characterization of the Adh2 5' region from Petunia hybrida.

The Adh2 gene from Petunia hybrida has been difficult to clone; exons 1 to 8 were isolated using PCR after unsuccessful screening of three genomic libraries. A combination of inverse and direct PCR strategies has been used to isolate upstream regions of Adh2. Here we report the cloning strategy for the nucleotide sequence of the 5' region of Adh2 from P. hybrida, the locations of the transcriptional start site and putative TATA box, as well as comparative analyses of the upstream regions of petunia Adh2, other Adh genes and other genes induced by hypoxia.

Evidence that oilseed rape (Brassica napus ssp. oleifera) causes respiratory illness in rural dwellers.

A study of 25 residents in a small Scottish village over a two-year period investigated respiratory symptom reporting in the presence or absence of oilseed rape. Symptom reporting in the year when oilseed rape virtually surrounded the village, varied during the growing season of the crop and was at its highest coincident with peak flowering. At the same period of the following year when the crop was absent, symptom reporting was significantly lower. The symptoms which correlated most strongly with peak oilseed rape flowering were sneezing, cough, headache, eye irritation and the total of these and other symptoms. Increased symptoms were reported by 12 of the participants though only seven of these were judged to be atopic. The symptoms did not correlate with levels of oilseed rape pollen but there is no clear evidence as to which of the other factors associated with the crop might be the cause.

Neuropeptide Y modulates the sensitivity of the rat adrenal cortex to stimulation by ACTH.

Neuropeptide Y (NPY) has been identified in nerves supplying the adrenal cortex of several mammalian species, although its function in this tissue is unknown. The present studies, employing adrenocortical cells prepared by collagenase digestion, have shown that NPY, in the absence of other stimulants, has no effect on steroid secretion by the rat adrenal over a range of peptide concentrations (10(-11) to 10(-6) mol/l). However, in the presence of physiological concentrations of ACTH, which are submaximal for the stimulation of aldosterone secretion, NPY (10(-6) mol/l) significantly enhanced the secretion rate of aldosterone by rat zona glomerulosa cells in response to ACTH. This effect was specific to the rat zona glomerulosa as NPY had no effect on the response to ACTH in rat zona fasciculata cells. The effect of NPY appears to be biphasic, however, as NPY significantly attenuated the steroidogenic response to supramaximal ACTH concentrations: in rat zona glomerulosa cells the aldosterone response to 10(-8) mol ACTH/l was significantly inhibited by NPY. The effect of NPY on the ACTH response appeared to be mediated by changes in the cAMP response. NPY had no effect on the steroidogenic response to potassium ions (K+), but enhanced the response to angiotensin II. NPY (10(-6) mol/l) significantly stimulated inositol 1,4,5-trisphosphate (InsP3) production although this concentration of peptide had no effect on steroid secretion. The effects of NPY on InsP3 production were additive with those of angiotensin II. These results suggest that the role of NPY in the adrenal cortex may be to regulate the sensitivity of the zona glomerulosa to peptide stimulation.

The role of neuropeptides in the regulation of adrenal zona fasciculata/reticularis function. Effects of vasoactive intestinal polypeptide, substance P, neuropeptide Y, Met- and Leu-enkephalin and neurotensin on corticosterone secretion in the intact perfused rat adrenal gland in situ.

There is much evidence to suggest that glucocorticoid secretion may be influenced by the splanchnic innervation to the adrenal gland, and that this effect may be mediated by neuropeptides. The present studies investigated the effects of several neuropeptides on corticosterone secretion by the intact perfused rat adrenal gland in situ. Both vasoactive intestinal polypeptide and Met-enkephalin caused a dose-dependent increase in corticosterone secretion, with a maximum response of 450% and 370% increment in corticosterone respectively. Of the other peptides tested, Leu-enkephalin, substance P and neurotensin all stimulated corticosterone secretion, with a maximum response of around 160% increase in each case. Neuropeptide Y on the other hand, had only a minor effect, which was only apparent over a small dose range. These results support the theory that adrenal neuropeptides may have a role in the regulation of glucocorticoid secretion.