Self-injurious behaviours in children and adults with autism spectrum disorder (ASD).

BACKGROUND: Self-injurious behaviours (SIB) are concerning, maladaptive behaviours that commonly occur in people with neurodevelopmental conditions and delays but seem to be particularly prevalent in children and adults with autism spectrum disorder (ASD). There has been increasing research examining the risk markers associated with the presence of SIB in people with ASD. Some of the factors associated with SIB have included cognitive abilities, adaptive functioning deficits and behaviour regulation impairments (e.g. impulsivity and repetitive behaviours). However, many of the findings in the literature are mixed and only explain a small proportion of the variance contributing to SIB. Limitations in the previous literature have centred on lack of availability of large and diverse samples, restricted age ranges and constraints of measurement. METHOD: This study characterises a clinic-referred sample of children and adults currently presenting with and without SIB using a range of standardised and parent-report measures. The sample includes 144 individuals with ASD between the ages of 2.5 and 60.1 years. RESULTS: After adjusting for multiple tests, none of the variables maintained statistical significance between the group of individuals with and without SIB, but medium to large effect sizes were noted. These variables include parent-reported early motor and toileting delays and perinatal risk, and current cognitive and social impairment. The remaining variables, including current autism severity levels, early ASD symptomatology, impulsivity, executive functioning impairments, adaptive functioning, mood and anxiety, did not differ between those with and without current engagement in SIB. CONCLUSIONS: Utilising a diverse clinic-referred sample and standardised diagnostic tools, this study explored retrospective and current correlate risk markers of SIB in individuals with ASD. In addition to impairments in current functioning, specific early developmental delays and perinatal risk factors were preliminarily associated with the presence of SIB in individuals with ASD. Together these findings suggest that a set of specific characteristics may be related to both early risk and concurrent manifestation of SIB. Identifying this set of characteristics in early development may lead to faster identification and better intervention services, but future work utilising longitudinal design and multivariate analysis is warranted.

A programmable soft chemo-mechanical actuator exploiting a catalyzed photochemical water-oxidation reaction.

We describe a composite hydrogel containing an embedding coupled chemistry for light-sensitized catalytic reactions that enables chemo-mechanical actuation of poly(acrylic acid)-based gels. In these materials, a photosensitizer and catalyst-ruthenium trisbipyridine and iridium dioxide nanoparticles, respectively-are incorporated into the hydrogel where together, with visible light irradiation, they undergo a catalytic water-oxidation reaction that lowers the pH and induces a dissipative/chemically-driven strain change in the gel. To demonstrate the capacity for 3D chemo-mechanical actuation, a layer of non-pH responsive poly(2-hydroxyethyl methacrylate) is added to the photo-active composite gel to create a model bimorph actuator. Triggering and terminating the water-oxidation reaction leads to a programmatic expansion and contraction of the active layer, which induces different modes of biomimetic curling motions in the bimorph actuator in light and dark environments. The efficiency of this system is fundamentally limited by the system-level design, which provides no capacity to sustain a local pH gradient against diffusive mixing. Even so, if the initial pH of the background solution is reestablished either actively or passively between each reaction cycle, it is possible to realize multiple cycles of reversible actuation. We describe a thermodynamic analysis of this system which identifies specific features mediating efficiency losses and conceptual requirements for mesoscopic design rules for optimization of this system and for advancing soft actuation systems in general.

Polygenic risk score and heritability estimates reveals a genetic relationship between ASD and OCD.

Obsessive-compulsive disorder (OCD) and Autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders that conceivably share genetic risk factors. However, the underlying genetic determinants remain largely unknown. In this work, the authors describe a combined genome-wide association study (GWAS) of ASD and OCD. The OCD dataset includes 2998 individuals in nuclear families. The ASD dataset includes 6898 individuals in case-parents trios. GWAS summary statistics were examined for potential enrichment of functional variants associated with gene expression levels in brain regions. The top ranked SNP is rs4785741 (chromosome 16) with P value=6.9×10-7 in our re-analysis. Polygenic risk score analyses were conducted to investigate the genetic relationship within and across the two disorders. These analyses identified a significant polygenic component of ASD, predicting 0.11% of the phenotypic variance in an independent OCD data set. In addition, we examined the genomic architecture of ASD and OCD by estimating heritability on different chromosomes and different allele frequencies, analyzing genome-wide common variant data by using the Genome-wide Complex Trait Analysis (GCTA) program. The estimated global heritability of OCD is 0.427 (se=0.093) and 0.174 (se=0.053) for ASD in these imputed data.

Dependent personality, separation anxiety disorder and other anxiety disorders in OCD.

BACKGROUND: The purpose of this study was to investigate whether dependent personality and/or general personality dimensions might explain the strong relationships between separation anxiety disorder (Sep-AD) and three other anxiety disorders (agoraphobia, panic disorder and social anxiety disorder) in individuals with obsessive compulsive disorder (OCD). METHODS: Using data from 509 adult participants collected during the OCD Collaborative Genetic Study, we used logistic regression models to evaluate the relationships between Sep-AD, dependent personality score, general personality dimensions and three additional anxiety disorders. RESULTS: The dependent personality score was strongly associated with Sep-AD and the other anxiety disorders in models adjusted for age at interview, age at onset of OC symptoms and worst ever OCD severity score. Several general personality dimensions, especially neuroticism, extraversion and conscientiousness, were also related to Sep-AD and the other anxiety disorders. Sep-AD was not independently related to these anxiety disorders, in multivariate models including general personality and dependent personality disorder scores. CONCLUSIONS: The results suggest that Sep-AD in childhood and these other anxiety disorders in adulthood are consequences of dependent personality disorder (for agoraphobia and panic disorder) or introversion (for social phobia). It is unknown whether these results would be similar in a non-OCD sample.

Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed.

Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples.

Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders.

Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability.

Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies.

Second-generation antipsychotic exposure, in both children and adults, carries significant risk for excessive weight gain that varies widely across individuals. We queried common variation in key energy balance genes (FTO, MC4R, LEP, CNR1, FAAH) for their association with weight gain during the initial 8 weeks in the two NIMH Research Units on Pediatric Psychopharmacology Autism Network trials (N=225) of risperidone for treatment of irritability in children/adolescents aged 4-17 years with autism spectrum disorders. Variants in the cannabinoid receptor (CNR)-1 promoter (P=1.0 × 10(-6)), CNR1 (P=9.6 × 10(-5)) and the leptin (LEP) promoter (P=1.4 × 10(-4)) conferred robust-independent risks for weight gain. A model combining these three variants was highly significant (P=1.3 × 10(-9)) with a 0.85 effect size between lowest and highest risk groups. All results survived correction for multiple testing and were not dependent on dose, plasma level or ethnicity. We found no evidence for association with a reported functional variant in the endocannabinoid metabolic enzyme, fatty acid amide hydrolase, whereas body mass index-associated single-nucleotide polymorphisms in FTO and MC4R showed only trend associations. These data suggest a substantial genetic contribution of common variants in energy balance regulatory genes to individual antipsychotic-associated weight gain in children and adolescents, which supersedes findings from prior adult studies. The effects are robust enough to be detected after only 8 weeks and are more prominent in this largely treatment naive population. This study highlights compelling directions for further exploration of the pharmacogenetic basis of this concerning multifactorial adverse event.

Meta-analysis of association between obsessive-compulsive disorder and the 3' region of neuronal glutamate transporter gene SLC1A1.

The neuronal glutamate transporter gene SLC1A1 is a candidate gene for obsessive-compulsive disorder (OCD) based on linkage studies and convergent evidence implicating glutamate in OCD etiology. The 3' end of SLC1A1 is the only genomic region with consistently demonstrated OCD association, especially when analyzing male-only probands. However, specific allele associations have not been consistently replicated, and recent OCD genome-wide association and meta-analysis studies have not incorporated all previously associated SLC1A1 SNPs. To clarify the nature of association between SLC1A1 and OCD, pooled analysis was performed on all available relevant raw study data, comprising a final sample of 815 trios, 306 cases and 634 controls. This revealed weak association between OCD and one of nine tested SLC1A1 polymorphisms (rs301443; uncorrected P = 0.046; non-significant corrected P). Secondary analyses of male-affecteds only (N = 358 trios and 133 cases) demonstrated modest association between OCD and a different SNP (rs12682807; uncorrected P = 0.012; non-significant corrected P). Findings of this meta-analysis are consistent with the trend of previous candidate gene studies in psychiatry and do not clarify the putative role of SLC1A1 in OCD pathophysiology. Nonetheless, it may be important to further examine the potential associations demonstrated in this amalgamated sample, especially since the SNPs with modest associations were not included in the more highly powered recent GWAS or in a past meta-analysis including five SLC1A1 polymorphisms. This study underscores the need for much larger sample sizes in future genetic association studies and suggests that next-generation sequencing may be beneficial in examining the potential role of rare variants in OCD.

Effects of methamphetamine abuse and serotonin transporter gene variants on aggression and emotion-processing neurocircuitry.

Individuals who abuse methamphetamine (MA) exhibit heightened aggression, but the neurobiological underpinnings are poorly understood. As variability in the serotonin transporter (SERT) gene can influence aggression, this study assessed possible contributions of this gene to MA-related aggression. In all, 53 MA-dependent and 47 control participants provided self-reports of aggression, and underwent functional magnetic resonance imaging while viewing pictures of faces. Participants were genotyped at two functional polymorphic loci in the SERT gene: the SERT-linked polymorphic region (SERT-LPR) and the intron 2 variable number tandem repeat polymorphism (STin2 VNTR); participants were then classified as having high or low risk for aggression according to individual SERT risk allele combinations. Comparison of SERT risk allele loads between groups showed no difference between MA-dependent and control participants. Comparison of self-report scores showed greater aggression in MA-dependent than control participants, and in high genetic risk than low-risk participants. Signal change in the amygdala was lower in high genetic risk than low-risk participants, but showed no main effect of MA abuse; however, signal change correlated negatively with MA use measures. Whole-brain differences in activation were observed between MA-dependent and control groups in the occipital and prefrontal cortex, and between genetic high- and low-risk groups in the occipital, fusiform, supramarginal and prefrontal cortex, with effects overlapping in a small region in the right ventrolateral prefrontal cortex. The findings suggest that the investigated SERT risk allele loads are comparable between MA-dependent and healthy individuals, and that MA and genetic risk influence aggression independently, with minimal overlap in associated neural substrates.

A new in vivo model for luteolysis using systemic pulsatile infusions of PGF(2α).

A new in vivo model for studying luteolysis was developed in sheep to provide a convenient method for collecting corpora lutea for molecular, biochemical, and histological analysis during a procedure that mimics natural luteolysis. It was found that the infusion of prostaglandin F(2α) (PGF(2α)) at 20 µg/min/h into the systemic circulation during the mid luteal phase of the cycle allowed sufficient PGF(2α) to escape across the lungs and thus mimic the transient 40% decline in the concentration of progesterone in peripheral plasma seen at the onset of natural luteolysis in sheep. Additional 1h-long systemic infusions of PGF(2α), given at physiological intervals, indicated that two infusions were not sufficient to induce luteolysis. However, an early onset of luteolysis and estrus was induced in one out of three sheep with three infusions, two out of three sheep with four infusions, and three out of three sheep with five infusions. Reducing the duration of each systemic infusion of PGF(2α) from 1h to 30 min failed to induce luteolysis and estrus even after six systemic infusions indicating that, not only are the amplitude and frequency of PGF(2α) pulses essential for luteolysis, but the actual duration of each pulse is also critical. We conclude that a minimum of five systemic pulses of PGF(2α), given in an appropriate amount and at a physiological frequency and duration, are required to mimic luteolysis consistently in all sheep. The five pulse regimen thus provides a new accurate in vivo model for studying molecular mechanisms of luteolysis.

Evaluation of the field efficacy of an avirulent live Lawsonia intracellularis vaccine in foals.

Equine proliferative enteropathy caused by Lawsonia intracellularis is an emerging disease with as yet unaddressed preventative measures. The hypothesis of this study was that vaccination will prevent clinical and sub-clinical disease. Weanling Thoroughbreds (n=202) from Central Kentucky were randomly assigned into two groups (vaccinated and non-vaccinated). Vaccinated foals received 30 mL of an avirulent, live L. intracellularis vaccine intra-rectally twice, 30 days apart. Foals were monitored for clinical disease, total solids and average weight gain until yearling age. There was an overall decreased disease incidence on the farms involved in the study that did not differ significantly between the groups. This decreased disease prevalence in the study population may be associated with the ongoing vaccine trial on these farms, as disease prevalence in Central Kentucky did not change in 2009 compared to 2008.

Is obsessive-compulsive disorder an anxiety disorder, and what, if any, are spectrum conditions? A family study perspective.

BACKGROUND: Experts have proposed removing obsessive-compulsive disorder (OCD) from the anxiety disorders section and grouping it with putatively related conditions in DSM-5. The current study uses co-morbidity and familiality data to inform these issues. METHOD: Case family data from the OCD Collaborative Genetics Study (382 OCD-affected probands and 974 of their first-degree relatives) were compared with control family data from the Johns Hopkins OCD Family Study (73 non-OCD-affected probands and 233 of their first-degree relatives). RESULTS: Anxiety disorders (especially agoraphobia and generalized anxiety disorder), cluster C personality disorders (especially obsessive-compulsive and avoidant), tic disorders, somatoform disorders (hypochondriasis and body dysmorphic disorder), grooming disorders (especially trichotillomania and pathological skin picking) and mood disorders (especially unipolar depressive disorders) were more common in case than control probands; however, the prevalences of eating disorders (anorexia and bulimia nervosa), other impulse-control disorders (pathological gambling, pyromania, kleptomania) and substance dependence (alcohol or drug) did not differ between the groups. The same general pattern was evident in relatives of case versus control probands. Results in relatives did not differ markedly when adjusted for demographic variables and proband diagnosis of the same disorder, though the strength of associations was lower when adjusted for OCD in relatives. Nevertheless, several anxiety, depressive and putative OCD-related conditions remained significantly more common in case than control relatives when adjusting for all of these variables simultaneously. CONCLUSIONS: On the basis of co-morbidity and familiality, OCD appears related both to anxiety disorders and to some conditions currently classified in other sections of DSM-IV.

Homeobox genes in obsessive-compulsive disorder.

BACKGROUND: Despite evidence that obsessive-compulsive disorder (OCD) is a familial neuropsychiatric condition, progress aimed at identifying genetic determinants of the disorder has been slow. The OCD Collaborative Genetics Study (OCGS) has identified several OCD susceptibility loci through linkage analysis. METHODS: In this study we investigate two regions on chromosomes 15q and 1q by first refining the linkage region using additional short tandem repeat polymorphic (STRP) markers. We then performed association analysis on single nucleotide polymorphisms (SNP) genotyped (markers placed every 2-4 kb) in the linkage regions in the OCGS sample of 376 rigorously phenotyped affected families. RESULTS: Three SNPs are most strongly associated with OCD: rs11854486 (P = 0.00005 [0.046 after adjustment for multiple tests]; genetic relative risk (GRR) = 11.1 homozygous and 1.6 heterozygous) and rs4625687 [P = 0.00007 (after adjustment = 0.06); GRR = 2.4] on 15q; and rs4387163 (P = 0.0002 (after adjustment = 0.08); GRR = 1.97) on 1q. The first SNP is adjacent to NANOGP8, the second SNP is in MEIS2, and the third is 150 kb between PBX1 and LMX1A. CONCLUSIONS: All the genes implicated by association signals are homeobox genes and are intimately involved in neurodevelopment. PBX1 and MEIS2 exert their effects by the formation of a heterodimeric complex, which is involved in development of the striatum, a brain region involved in the pathophysiology of OCD. NANOGP8 is a retrogene of NANOG, a homeobox transcription factor known to be involved in regulation of neuronal development. These findings need replication; but support the hypothesis that genes involved in striatal development are implicated in the pathogenesis of OCD.

Association of SLC6A4 variants with obsessive-compulsive disorder in a large multicenter US family study.

Genetic association studies of SLC6A4 (SERT) and obsessive-compulsive disorder (OCD) have been equivocal. We genotyped 1241 individuals in 278 pedigrees from the OCD Collaborative Genetics Study for 13 single-nucleotide polymorphisms, for the linked polymorphic region (LPR) indel with molecular haplotypes at rs25531, for VNTR polymorphisms in introns 2 and 7 and for a 381-bp deletion 3' to the LPR. We analyzed using the Family-Based Association Test (FBAT) under additive, dominant, recessive and genotypic models, using both OCD and sex-stratified OCD as phenotypes. Two-point FBAT analysis detected association between Int2 (P = 0.0089) and Int7 (P = 0.0187) (genotypic model). Sex-stratified two-point analysis showed strong association in females with Int2 (P<0.0002), significant after correction for linkage disequilibrium, and multiple marker and model testing (P(Adj) = 0.0069). The SLC6A4 gene is composed of two haplotype blocks (our data and the HapMap); FBAT whole-marker analysis conducted using this structure was not significant. Several noteworthy nonsignificant results have emerged. Unlike Hu et al., we found no evidence for overtransmission of the LPR L(A) allele (genotype relative risk = 1.11, 95% confidence interval: 0.77-1.60); however, rare individual haplotypes containing L(A) with P<0.05 were observed. Similarly, three individuals (two with OCD/OCPD) carried the rare I425V SLC6A4 variant, but none of them passed it on to their six OCD-affected offspring, suggesting that it is unlikely to be solely responsible for the 'OCD plus syndrome', as reported by Ozaki et al. In conclusion, we found evidence of genetic association at the SLC6A4 locus with OCD. A noteworthy lack of association at the LPR, LPR-rs25531 and rare 425V variants suggests that hypotheses about OCD risk need revision to accommodate these new findings, including a possible gender effect.

Evidence for a potential role of neuropeptide Y in ovine corpus luteum function.

Neuropeptide Y (NPY) is a neurohormone that is typically associated with food intake, but it has also been reported to affect the production of progesterone from luteal tissue in vitro. However, NPY has not been previously immunolocalized in the ovine ovary or in the corpus luteum (CL) of any species, and the effects of this neurohormone on luteal function in vivo are not known. Thus, we performed fluorescent immunohistochemistry (IHC) to localize NPY in the ovine ovary and used avidin-biotin immunocytochemistry (ICC) to further define the intracellular localization within follicles and the CL. We then infused NPY directly into the arterial supply of the autotransplanted ovaries of sheep to determine the in vivo effect of exogenous NPY on ovarian blood flow and on the luteal secretion rate of progesterone and oxytocin. Immunohistochemistry revealed that the NPY antigen was localized to cells within the follicles and CL, in the nerve fibers of the ovarian stroma, and in the vessels of the ovarian hilus. In the follicle, the NPY antigen was localized to nerves and vessels within the theca interna layer, and strong staining was observed in the granulosal cells of antral follicles. In the CL, NPY was localized in large luteal cells and in the vascular pericytes and/or endothelial cells of blood vessels, found dispersed throughout the gland and within the luteal capsule. In vivo incremental infusions of NPY at 1, 10, 100, and 1,000 ng/min, each for a 30-min period, into the arterial supply of the transplanted ovary of sheep bearing a CL 11 d of age increased (P< or =0.05) ovarian blood flow. The intra-arterial infusions of NPY also increased (P< or =0.05) in a dose-dependent manner the secretion rate of oxytocin, which was positively correlated (P< or =0.05) with the observed increase in ovarian blood flow. The infusions of NPY had a minimal effect on the secretion rate of progesterone, and similar intra-arterial infusions of NPY into sheep with ovarian transplants bearing a CL over 30 d of age had no significant effect on ovarian blood flow or on the secretion rate of progesterone. These results suggest that NPY acts on the luteal vascular system and the large luteal cells to rapidly stimulate blood flow and the secretion of oxytocin, respectively, which collectively implies a putative role for NPY during the process of luteolysis when increasing amounts of oxytocin are secreted from the ovine CL in response to uterine pulses of prostaglandin F2alpha.

A screen of SLC1A1 for OCD-related alleles.

SLC1A1, which encodes the neuronal and epithelial glutamate transporter, is a promising candidate gene for obsessive-compulsive disorder (OCD). In this study, we conducted capillary electrophoresis single-strand conformation polymorphism (CE-SSCP) screen for all 12 identified exons, including all coding regions and approximately 50 bp of flanking introns of the human SLC1A1 in 378 OCD-affected individuals. Full sequencing was completed on samples that showed an aberrant SSCP tracing for identification of the underlying sequence variants. Our aim was to determine if there are differences in the frequencies of relatively common alleles, or rare functional alleles, in 378 OCD cases and 281 ethnically matched controls. We identified one nonsynonymous coding SNP (c.490A > G, T164A) and three synonymous coding SNP (c.81G > C, A27A; c.414A > G, T138T; c.1110T > C, T370T) in case samples. We found no statistical differences in genotype and allele frequencies of common cSNPs in SLC1A1 between the OCD cases and controls. The rare variant T164A was found only in one family. Further investigation of this variant is necessary to determine whether and how it is related to OCD. There was no other evidence of significant accumulation of deleterious coding mutations in SLC1A1 in the OCD cases.

Broiler performance and in vivo viscosity as influenced by a range of xylanases, varying in ability to effect wheat in vitro viscosity.

1. Exogenous enzymes such as xylanase are used in diets for broilers to eliminate anti-nutritive effects caused by the presence of non-starch polysaccharides (NSP). It has been proposed that the mechanism by which xylanases exert their effect is through reducing in vivo viscosity within the broiler digestive tract. Previous research has reported that in vitro viscosity was a reasonable predictor of in vivo viscosity and that this method could be used to assess the efficacy of xylanases. 2. The objective of this study was to examine the response of broilers offered a wheat-based diet supplemented with a range of xylanases, varying in ability to reduce in vitro viscosity. 3. A total of 18 xylanases (Syngenta Animal Nutrition) were used to investigate the effect of xylanase on wheat in vitro viscosity. For the in vitro viscosity assay, pepsin was dissolved in either 005 or 01 M hydrochloric acid (HCl). 4. A wheat-based diet was formulated, produced and split into 7 batches; xylanase (500 U/kg) was sprayed onto 6 of the batches and the 7th was the control. This was repeated three times to produce a total of 21 diets, 18 of which contained xylanase. 5. The experiment was conducted in three consecutive trials. Each trial utilised 63 male, Ross broilers from 7 to 28 d of age. Dry matter intake (DMI), liveweight gain (LWG) and gain:feed were determined weekly. Excreta were collected from d 14 to 21 for determination of apparent metabolisable energy (AME). Oil and neutral detergent fibre (NDF) digestibility and ileal digestibility of dry matter (DM) and starch were determined. 6. Regression analyses were applied to the mean intestinal viscosity against DMI, LWG, gain:feed and the ratio of metabolisable energy to gross energy (ME:GE). To compare xylanases across the three trials, the data were subjected to REML analysis (Genstat 5). 7. When 01 M HCl was used for dissolution of pepsin, considerable reductions in in vitro viscosity were achieved for the majority of the xylanases-to values less than 12% of the control treatment. When 005 M HCl was used for the dissolution of pepsin, initial viscosity values were lower and the reduction in in vitro viscosity less dramatic than that observed with 01 M HCl. 8. With the exception of diets containing xylanases 9003 and 7162, significant reductions in in vivo viscosity were observed for diets containing xylanase in comparison to the control diet. 9. In terms of gain:feed, ME:GE and AME the xylanases ranked best were 2230 and 9003. Xylanase 2230 also resulted in the highest values for ileal DM and starch digestibility. 10. There were weak but significant relationships between in vitro viscosity and in vivo jenjunal digesta viscosity when in vitro viscosity was determined using either 01 or 005 M HCl (r(2)= 0287 and 0240, respectively). 11. The relationship between jejunal viscosity and DMI was significant (P < 005) but relatively poor (r(2)= 023). There were also significant (P < 005) relationships between jejunal digestal viscosity and gain:feed and ME:GE (r(2)= 034 and 028, respectively). 12. In conclusion, in vitro viscosity may be of some use in predicating xylanase response in vivo.

A family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder in 378 families.

SLC1A encodes the neuronal and epithelial glutamate transporter and was previously tested as a candidate for obsessive-compulsive disorder (OCD) by several research groups. Recently, three independent research groups reported significant association findings between OCD and several genetic variants in SLC1A1. This study reports the results from a family-based association study, which examined the association between 13 single nucleotide polymorphisms (SNPs) within or in proximity to the SLC1A1 gene. Although we did not replicate association findings for those significant SNPs reported by previous studies, our study indicated a strong association signal with the SNP RS301443 (P-value = 0.000067; Bonferroni corrected P-value = 0.0167) under a dominant model, with an estimated odds ratio of 3.5 (confidence interval: 2.66-4.50). Further, we conducted single SNP analysis after stratifying the full data set by the gender status of affected in each family. The P-value for RS301443 in families with the male affected was 0.00027, and the P-value in families with female affected was 0.076. The fact that we identified a signal which was not previously reported by the other research groups may be due to differences in study designs and sample ascertainment. However, it is also possible that this significant SNP may be part of a regulator for SLC1A1, given that it is roughly 7.5 kb away from the boundary of the SLC1A1 gene. However, this potential finding needs to be validated biologically. Further functional studies in this region are planned by this research group.

Gender differences in genetic linkage and association on 11p15 in obsessive-compulsive disorder families.

Several clinical and genetic studies have reported gender differences in obsessive-compulsive disorder (OCD). Previously, we conducted a linkage genome scan using multipoint allele-sharing methods to test for linkage in 219 families participating in the OCD Collaborative Genetics Study. When these families were stratified by proband's gender, suggestive linkage to chromosome 11p15 at marker D11S2362 (KAC(all) = 2.92, P = 0.00012) was detected in families with male probands, but not in the ones with female probands. We have since conducted fine mapping with a denser microsatellite marker panel in the region of 11p15, and detected a significant linkage signal at D11S4146 (KAC(all) = 5.08, P < 0.00001) in the families of male probands. Subsequently, 632 SNPs were genotyped spanning a 4.0 Mb region of the 1 LOD unit interval surrounding the linkage peak in the original families and an additional 165 families. Six SNPs were associated with OCD (P < 0.001): two SNPs were identified when all the families were included, and four SNPs only in male proband families. No SNP showed significant association with the OCD phenotype only in the families with a female proband. The results suggest a possible gender effect in the etiology of OCD.