A conversation analytic approach to schizophrenic interaction: methodological reflections on disruptions of the common-sense world.

Certain schools of phenomenological psychiatry conceive of schizophrenia as a pathology of common-sense. Ethnomethodological enquiry, with its roots in Schutzian social phenomenology, takes as its domain, topic, and substance of study the ongoing achievement of a common-sense world between social members. Yet, dialogue between psychiatry and ethnomethodological approaches is thin. In this article, we discuss a conversation analytic approach to schizophrenic interaction which has generated and utilized a model of a five-world manifold to frame analyses of talk-in-interaction. 'Worlds' are conceived, after Schutz, as finite domains of meaning, and the model operates as a breach of natural attitude assumptions to examine mechanisms of the constitution of the one-world-in-common of common-sense. It is suggested that certain aspects of schizophrenic talk might receive account in terms of a loss of integration between these five domains of meaning. Conversation Analytic methods were applied to transcripts of audio recordings of psychiatric interviews but encountered hurdles that motivated the broadening of methodological scope. Such hurdles included a weakening of the next turn proof procedure, implicit reification of the schizophrenia construct, and problems of translation presented by the analyst's normative membership encountering non-normative life-worlds of schizophrenic experience. Strategic responses to these hurdles included exploring linkages between phenomenological psychiatry and ethnomethodological approaches, as well as an engagement of ethnomethodological self-reflection and conceptual clarification of the schizophrenia construct in line with Garfinkel's unique adequacy requirement. The manifold model is glossed, and interaction between two of its worlds - a world of concrete, situational immediacies and another of abstract organizations - is explored in more detail via analysis of conversational data. It is suggested that the five-world model, along with further micro-analysis of talk-in-interaction, might have implications in psychiatry for topics such as autism, double bookkeeping, concretism, theories of disturbed indexicality, and insight attribution. We conclude that the consideration of atypical interaction obliges the interaction analyst to take account of their own implicit normative world-frames and that the use of domain-specific top-down models in conjunction with the inductive approach of Conversation Analysis may extend the reach of CA to facilitate productive dialogue with other disciplines.

James Meyrick Croker: A Model for Professional Behavior.

The rationale that underpins volunteering has long fascinated behavioral scientists. James Meyrick Croker's personal life, professional career and community engagement conform to the classic twentieth century model for professional behavior. Accordingly, the authors use historical methods of investigation to evaluate the influences on and the legacies from a remarkable contribution to the professions and the community. The narrative demonstrates elements of altruism, collaboration, conviction, compassion, drive, entrepreneurialism, familial and grammar school influence, leadership, pragmatism and vision. Croker's professional and community service was multi-organizational. Concurrent demands on his time warranted discipline, energy and expertise. For the behavioral scientist, achievement, affiliation, nature and nurture appear relevant to the outcome. Available archives provide no evidence of ego-driven motivation. Leadership style was transformational not transactional. Major legacies to the national and state Australian Dental Associations are ADAQ Christensen House (1972-1980), the eventual financial stability for the Australian Dental Association Queensland Branch, formal dental assistant training, policies of the Australian and Queensland Councils of Professions, a notable Goddard Oration and the successful 24th Australian Dental Congress.

Capromorelin increases food consumption, body weight, growth hormone, and sustained insulin-like growth factor 1 concentrations when administered to healthy adult Beagle dogs.

This study's objective was to determine the effects in dogs of oral capromorelin, a ghrelin agonist, at different doses for 7 days on food consumption, body weight and serum concentrations of growth hormone (GH), insulin-like growth factor 1 (IGF-1), and cortisol. Adult Beagles (n = 6) were dosed with placebo BID, capromorelin at 3.0 mg/kg SID, 4.5 mg/kg SID, or 3.0 mg/kg BID. Food consumption, body weight, serum capromorelin, GH, IGF-1, and cortisol were measured at intervals on days 1, 4, 7, and 9. Capromorelin increased food consumption and body weight compared to placebo and caused increased serum GH, which returned to the baseline by 8 h postdose. The magnitude of the GH increase was less on days 4 and 7 compared to Day 1. IGF-1 concentrations increased on Day 1 in capromorelin-treated dogs and this increase was sustained through Day 7. Serum cortisol increased postdosing and returned to the baseline concentrations by 8 h. The magnitude of the increase was less on days 4 and 7 compared to Day 1. A dose of 3 mg/kg was chosen for further study in dogs based on this dose causing increased food consumption and sustained IGF-1 serum concentrations that may increase lean muscle mass when administered over extended periods.

DNA methylation and substance-use risk: a prospective, genome-wide study spanning gestation to adolescence.

Epigenetic processes have been implicated in addiction; yet, it remains unclear whether these represent a risk factor and/or a consequence of substance use. Here, we believe we conducted the first genome-wide, longitudinal study to investigate whether DNA methylation patterns in early life prospectively associate with substance use in adolescence. The sample comprised of 244 youth (51% female) from the Avon Longitudinal Study of Parents and Children (ALSPAC), with repeated assessments of DNA methylation (Illumina 450k array; cord blood at birth, whole blood at age 7) and substance use (tobacco, alcohol and cannabis use; age 14-18). We found that, at birth, epigenetic variation across a tightly interconnected genetic network (n=65 loci; q<0.05) associated with greater levels of substance use during adolescence, as well as an earlier age of onset amongst users. Associations were specific to the neonatal period and not observed at age 7. Key annotated genes included PACSIN1, NEUROD4 and NTRK2, implicated in neurodevelopmental processes. Several of the identified loci were associated with known methylation quantitative trait loci, and consequently likely to be under significant genetic control. Collectively, these 65 loci were also found to partially mediate the effect of prenatal maternal tobacco smoking on adolescent substance use. Together, findings lend novel insights into epigenetic correlates of substance use, highlight birth as a potentially sensitive window of biological vulnerability and provide preliminary evidence of an indirect epigenetic pathway linking prenatal tobacco exposure and adolescent substance use.

Environmental risk, Oxytocin Receptor Gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study.

Youth with high callous-unemotional traits (CU) are at risk for early-onset and persistent conduct problems. Research suggests that there may be different developmental pathways to CU (genetic/constitutional vs environmental), and that the absence or presence of co-occurring internalizing problems is a key marker. However, it is unclear whether such a distinction is valid. Intermediate phenotypes such as DNA methylation, an epigenetic modification regulating gene expression, may help to clarify etiological pathways. This is the first study to examine prospective inter-relationships between environmental risk (prenatal/postnatal) and DNA methylation (birth, age 7 and 9) in the prediction of CU (age 13), for youth low vs high in internalizing problems. We focused on DNA methylation in the vicinity of the oxytocin receptor (OXTR) gene as it has been previously implicated in CU. Participants were 84 youth with early-onset and persistent conduct problems drawn from the Avon Longitudinal Study of Parents and Children. For youth with low internalizing problems (46%), we found that (i) OXTR methylation at birth associated with higher CU (age 13) as well as decreased experience of victimization during childhood (evocative epigenetic-environment correlation; birth-age 7), (ii) higher prenatal parental risks (maternal psychopathology, criminal behaviors, substance use) associated with higher OXTR methylation at birth and (iii) OXTR methylation levels were more stable across time (birth-age 9). In contrast, for youth with high internalizing problems, CU were associated with prenatal risks of an interpersonal nature (that is, intimate partner violence, family conflict) but not OXTR methylation. Findings support the existence of distinct developmental pathways to CU.

DNA methylation in interleukin-11 predicts clinical response to antidepressants in GENDEP.

Transcriptional differences in interleukin-11 (IL11) after antidepressant treatment have been found to correspond to clinical response in major depressive disorder (MDD) patients. Expression differences were partly mediated by a single-nucleotide polymorphism (rs1126757), identified as a predictor of antidepressant response as part of a genome-wide association study. Here we attempt to identify whether DNA methylation, another baseline factor known to affect transcription factor binding, might also predict antidepressant response, using samples collected from the Genome-based Therapeutic Drugs for Depression project (GENDEP). DNA samples from 113 MDD individuals from the GENDEP project, who were treated with either escitalopram (n=80) or nortriptyline (n=33) for 12 weeks, were randomly selected. Percentage change in Montgomery-Åsberg Depression Rating Scale scores between baseline and week 12 were utilized as our measure of antidepressant response. The Sequenom EpiTYPER platform was used to assess DNA methylation across the only CpG island located in the IL11 gene. Regression analyses were then used to explore the relationship between CpG unit methylation and antidepressant response. We identified a CpG unit predictor of general antidepressant response, a drug by CpG unit interaction predictor of response, and a CpG unit by rs1126757 interaction predictor of antidepressant response. The current study is the first to investigate the potential utility of pharmaco-epigenetic biomarkers for the prediction of antidepressant response. Our results suggest that DNA methylation in IL11 might be useful in identifying those patients likely to respond to antidepressants, and if so, the best drug suited to each individual.

Fractional anisotropy distributions in 2- to 6-year-old children with autism.

BACKGROUND: Increasing evidence suggests that autism is a disorder of distributed neural networks that may exhibit abnormal developmental trajectories. Characterisation of white matter early in the developmental course of the disorder is critical to understanding these aberrant trajectories. METHODS: A cross-sectional study of 2- to 6-year-old children with autism was conducted using diffusion tensor imaging combined with a novel statistical approach employing fractional anisotropy distributions. Fifty-eight children aged 18-79 months were imaged: 33 were diagnosed with autism, 8 with general developmental delay, and 17 were typically developing. Fractional anisotropy values within global white matter, cortical lobes and the cerebellum were measured and transformed to random F distributions for each subject. Each distribution of values for a region was summarised by estimating δ, the estimated mean and standard deviation of the approximating F for each distribution. RESULTS: The estimated δ parameter, , was significantly decreased in individuals with autism compared to the combined control group. This was true in all cortical lobes, as well as in the cerebellum, but differences were most robust in the temporal lobe. Predicted developmental trajectories of across the age range in the sample showed patterns that partially distinguished the groups. Exploratory analyses suggested that the variability, rather than the central tendency, component of was the driving force behind these results. CONCLUSIONS: While preliminary, our results suggest white matter in young children with autism may be abnormally homogeneous, which may reflect poorly organised or differentiated pathways, particularly in the temporal lobe, which is important for social and emotional cognition.

The role of starburst amacrine cells in visual signal processing.

Starburst amacrine cells (SBACs) within the adult mammalian retina provide the critical inhibition that underlies the receptive field properties of direction-selective ganglion cells (DSGCs). The SBACs generate direction-selective output of GABA that differentially inhibits the DSGCs. We review the biophysical mechanisms that produce directional GABA release from SBACs and test a network model that predicts the effects of reciprocal inhibition between adjacent SBACs. The results of the model simulations suggest that reciprocal inhibitory connections between closely spaced SBACs should be spatially selective, while connections between more widely spaced cells could be indiscriminate. SBACs were initially identified as cholinergic neurons and were subsequently shown to contain release both acetylcholine and GABA. While the role of the GABAergic transmission is well established, the role of the cholinergic transmission remains unclear.

Trigger features and excitation in the retina.

This review focuses on recent advances in our understanding of how neural divergence and convergence give rise to complex encoding properties of retinal ganglion cells. We describe the apparent mismatch between the number of cone bipolar cell types, and the diversity of excitatory input to retinal ganglion cells, and outline two possible solutions. One proposal is for diversity in the excitatory pathways to be generated within axon terminals of cone bipolar cells, and the second invokes narrow-field glycinergic amacrine cells that can apparently act like bipolar cells by providing excitatory drive to ganglion cells. Finally we highlight two advances in technique that promise to provide future insights; automation of electron microscope data collection and analysis, and the use of the ideal observer to quantitatively compare neural performance at all levels.

Association with HLA DQ of early onset myasthenia gravis in Southeast Texas region of the United States.

Forty-four Caucasian American myasthenia gravis (MG) patients from Southeast Texas underwent high resolution HLA DQ analysis. For the majority of patients who were late onset or male, no significant associations with DQ were observed. However, associations with DQ increased in female patients and early onset patients. At the allele level, DQB1 *0503, *0604, *0502 and *0402 collectively contributed to a positive association of the DQ locus with early onset MG (EOMG), while individually failing to show significant association. At DQ level, the novel haplotype DQA1*0401:DQB1*0201 was the primary factor in the association of combined DQ loci with early onset. In addition, *0104:*0503, *0102:*0604, *0102:*0502 and *0303:*0402 collectively contributed to the positive association of the haplotype loci. DR3-DQ2.5cis, a well known risk factor for MG in Western Eurasia, was not found associated with disease in any group. For typical EOMG [early onset, no thymoma, anti-acetylcholine receptor (AChR) antibody (Ab) positive] no association with DQA1 locus was found, however DQB1*0604 demonstrated an 'uncorrected' positive association. A few DQ haplotype (DQA1:DQB1) were positively associated with typical EOMG; a positive individual association for *0401:*0201 was complimented by the contributions of *0102:*0604 and *0303:*0402 haplotypes. A small minority of patients that were atypical and EOMG had a strong genetic association with DQA1*0104:DQB1*0503, the group included an anti-MuSK Ab positive and an anti-AChR negative patient. This report finds common ground with European studies regarding MuSK association; however similarities in association for typical early onset disease resembled HLA risk factors in East Asia and Southern Europe.

Multiple squamous hyperplastic-fibrous inflammatory polyps of the oesophagus: a new feature of eosinophilic oesophagitis?

This report describes the unusual case of a 12-year-old boy with multiple polyps in the oesophagus and concurrent eosinophilic oesophagitis (EoE). Polyps were of a fibrous-inflammatory composition featuring eosinophils, mast cells, hyperplastic epithelium and fibrosis, which are all features described with EoE. EoE is an increasingly recognised clinicopathological disorder characterised by large numbers of eosinophils infiltrating the oesophageal mucosa. Polyps in the oesophagus are rare, have not previously been associated with EoE, and may represent a new feature of the disease.

Estimation of parameters for a mathematical model of growth hormone secretion.

Here, we describe partial calibration of a parsimonious mathematical model of growth hormone (GH) secretion. From first principles, we derived a model of the effects on GH secretion from pituitary somatotrophs of stimulation by GH-releasing factor (GRF) or GH secretagogue, and of inhibition by somatostatin. We obtained a concise model by collapsing the many processes of the signal transduction cascade into a single step broadly reflecting the initial binding of GRF to its receptors. In the model, GH secretion is proportional to the rate of binding of GRF to activatable receptors. Desensitization occurs because of reduction of free receptors/available effector units, and resensitization occurs as those lost are replaced. This replacement is speeded up in the presence of somatostatin, which also inhibits GH secretion by reducing the constant of proportionality between the rate of GH secretion and the rate of GRF binding. We derived simple mathematical equations for the rate of GH secretion and cumulative secretion. Using these, we tested the model against data obtained from experiments performed in vitro, and made it quantitative using rigorous statistical approaches to optimize parameter estimates. The behaviour of the calibrated model matches experimental observations closely.

Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden.

BACKGROUND: Markers of oxidative stress and immune activation are significantly elevated in postmortem ALS CNS tissue, although the relevance to pathogenesis is unclear. OBJECTIVE: To determine the degree and distribution of oxidative stress and immune activation in living ALS patients and whether these levels correlate with the rate of progression or extent of disease. METHOD: Serum and CSF samples from sporadic ALS (sALS) patients were assayed for 4-hydroxy-2,3-nonenal (HNE), a lipid peroxidation product, and monocyte chemoattractant protein-1alpha (MCP-1alpha), a beta-chemokine, by high-performance liquid chromatography and ELISA and compared with levels measured in disease and normal control subjects by one-way analysis of variance. SALS serum levels were analyzed in relation to rate of progression, stage of disease, and drug therapy. RESULTS: HNE levels were significantly elevated in the sera and spinal fluid of sALS patients compared with control populations and positively correlated with extent of disease but not rate of progression. MCP-1alpha levels were also elevated in the sera of sALS patients, with the exception of the neurodegenerative disease control subjects, but decreased with advancing disease. CSF MCP-1alpha levels were not different between the sampled populations. There was no correlation between serum HNE and MCP-1alpha levels in sALS patients and extent of disease. However, an inverse relationship between HNE and MCP-1alpha was demonstrable in vitro. Low levels of HNE stimulated release of MCP-1alpha from cultured human macrophages, whereas high levels inhibited release of MCP-1alpha. CONCLUSIONS: These data confirm the presence of increased oxidative stress and immune activation in ALS patients. HNE is also suggested as a possible biomarker of disease.

Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein.

Ghrelin, a stomach-derived orexigenic hormone, has stimulated great interest as a potential target for obesity control. Pharmacological evidence indicates that ghrelin's effects on food intake are mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP) in the central nervous system. These include intracerebroventricular application of antibodies to neutralize NPY and AgRP, and the application of an NPY Y1 receptor antagonist, which blocks some of the orexigenic effects of ghrelin. Here we describe treatment of Agrp(-/-);Npy(-/-) and Mc3r(-/-);Mc4r(-/-) double knockout mice as well as Npy(-/-) and Agrp(-/-) single knockout mice with either ghrelin or an orally active nonpeptide ghrelin agonist. The data demonstrate that NPY and AgRP are required for the orexigenic effects of ghrelin, as well as the involvement of the melanocortin pathway in ghrelin signaling. Our results outline a functional interaction between the NPY and AgRP pathways. Although deletion of either NPY or AgRP caused only a modest or nondetectable effect, ablation of both ligands completely abolished the orexigenic action of ghrelin. Our results establish an in vivo orexigenic function for NPY and AgRP, mediating the effect of ghrelin.

Early dissemination of foot-and-mouth disease virus through sheep marketing in February 2001.

The results of epidemiological investigations suggest that livestock on up to 79 premises, spread widely throughout the British Isles, may have been exposed to infection by foot-and-mouth disease (FMD) virus by the movement of infected sheep before the first case of the disease was confirmed at an abattoir in Essex on February 20, 2001. A further 36 premises may have been infected by this route before the national livestock movement ban was imposed on February 23.

Effects of noise on the spike timing precision of retinal ganglion cells.

Information in a spike train is limited by variability in the spike timing. This variability is caused by noise from several sources including synapses and membrane channels; but how deleterious each noise source is and how they affect spike train coding is unknown. Combining physiology and a multicompartment model, we studied the effect of synaptic input noise and voltage-gated channel noise on spike train reliability for a mammalian ganglion cell. For tonic stimuli, the SD of the interspike intervals increased supralinearly with increasing interspike interval. When the cell was driven by current injection, voltage-gated channel noise and background synaptic noise caused fluctuations in the interspike interval of comparable amplitude. Spikes initiated on the dendrites could cause additional spike timing fluctuations. For transient stimuli, synaptic noise was dominant and spontaneous background activity strongly increased fluctuations in spike timing but decreased the latency of the first spike.

A new method of plaque scoring: a laboratory comparison with other plaque indices.

AIM: The aim of this study was to propose a simple, clear and as sensitive as possible numerical plaque index for the use in clinical oral hygiene trials known as the New Method of Plaque Scoring (NMPS), and to evaluate this index for simplicity, clarity and examiner agreement in comparison with the Distal Mesial Plaque Index, Proximal Marginal Index and a modification to the modified Navy plaque Index. MATERIAL AND METHODS: The scoring system proposed for the NMPS is based on a numerical range from 0 to 10 representing the total stained plaque on the facial or lingual tooth surfaces with the greatest weight of scores placed at the gingival and proximal regions of the surface. For scoring purposes, a horizontal boundary is imagined on the smooth facial or lingual tooth surfaces between the gingival third (A) and coronal two/thirds, the latter being subdivided vertically into thirds, mesial (B), middle (D) and distal (C). Depending on the extent of plaque coverage, whole number scores 0-3 are assigned to A, B, C and 0 or 1 for D. Ten examiners scored four selected tooth surfaces on an acrylic model according to the NMPS and the three comparative indices. The time required for each examiner to score according to each index was recorded. The scores obtained from this trial were analyzed for examiner agreement and correlation between the four indices. RESULTS: The time required for scoring according to the NMPS was found to be significantly less than the three comparative indices. The variability between examiners was found to be least for the NMPS compared to the three comparative indices. A strong correlation was found between all pairs of indices. CONCLUSION: The proposed new method of plaque scoring seems to be simpler, clearer and more reproducible than the three comparative indices. However, clinical testing is warranted.

Parvalbumin overexpression alters immune-mediated increases in intracellular calcium, and delays disease onset in a transgenic model of familial amyotrophic lateral sclerosis.

Intracellular calcium is increased in vulnerable spinal motoneurons in immune-mediated as well as transgenic models of amyotrophic lateral sclerosis (ALS). To determine whether intracellular calcium levels are influenced by the calcium-binding protein parvalbumin, we developed transgenic mice overexpressing parvalbumin in spinal motoneurons. ALS immunoglobulins increased intracellular calcium and spontaneous transmitter release at motoneuron terminals in control animals, but not in parvalbumin overexpressing transgenic mice. Parvalbumin transgenic mice interbred with mutant SOD1 (mSOD1) transgenic mice, an animal model of familial ALS, had significantly reduced motoneuron loss, and had delayed disease onset (17%) and prolonged survival (11%) when compared with mice with only the mSOD1 transgene. These results affirm the importance of the calcium binding protein parvalbumin in altering calcium homeostasis in motoneurons. The increased motoneuron parvalbumin can significantly attenuate the immune-mediated increases in calcium and to a lesser extent compensate for the mSOD1-mediated 'toxic-gain-of-function' in transgenic mice.

Regulation of Pit-1 expression by ghrelin and GHRP-6 through the GH secretagogue receptor.

GH secretagogues are an expanding class of synthetic peptide and nonpeptide molecules that stimulate the pituitary gland to secrete GH through their own specific receptor, the GH-secretagogue receptor. The cloning of the receptor for these nonclassical GH releasing molecules, together with the more recent characterization of an endogenous ligand, named ghrelin, have unambiguously demonstrated the existence of a physiological system that regulates GH secretion. Somatotroph cell-specific expression of the GH gene is dependent on a pituitary-specific transcription factor (Pit-1). This factor is transcribed in a highly restricted manner in the anterior pituitary gland. The present experiments sought to determine whether the synthetic hexapeptide GHRP-6, a reference GH secretagogue compound, as well as an endogenous ligand, ghrelin, regulate pit-1 expression. By a combination of Northern and Western blot analysis we found that GHRP-6 elicits a time- and dose-dependent activation of pit-1 expression in monolayer cultures of infant rat anterior pituitary cells. This effect was blocked by pretreatment with actinomycin D, but not by cycloheximide, suggesting that this action was due to direct transcriptional activation of pit-1. Using an established cell line (HEK293-GHS-R) that overexpresses the GH secretagogue receptor, we showed a marked stimulatory effect of GHRP-6 on the pit-1 -2,500 bp 5'-region driving luciferase expression. We truncated the responsive region to -231 bp, a sequence that contains two CREs, and found that both CREs are needed for GHRP-6-induced transcriptional activation in both HEK293-GHS-R cells and infant rat anterior pituitary primary cultures. The effect was dependent on PKC, MAPK kinase, and PKA activation. Increasing Pit-1 by coexpression of pCMV-pit-1 potentiated the GHRP-6 effect on the pit-1 promoter. Similarly, we showed that the endogenous GH secretagogue receptor ligand ghrelin exerts a similar effect on the pit-1 promoter. These data provide the first evidence that ghrelin, in addition to its previously reported GH-releasing activities, is also capable of regulating pit-1 transcription through the GH secretagogue receptor in the pituitary, thus giving new insights into the physiological role of the GH secretagogue receptor on somatotroph cell differentiation and function.