Evidence for distinct genetic and environmental influences on fear acquisition and extinction.

BACKGROUND: Anxiety disorders are highly prevalent with an early age of onset. Understanding the aetiology of disorder emergence and recovery is important for establishing preventative measures and optimising treatment. Experimental approaches can serve as a useful model for disorder and recovery relevant processes. One such model is fear conditioning. We conducted a remote fear conditioning paradigm in monozygotic and dizygotic twins to determine the degree and extent of overlap between genetic and environmental influences on fear acquisition and extinction. METHODS: In total, 1937 twins aged 22-25 years, including 538 complete pairs from the Twins Early Development Study took part in a fear conditioning experiment delivered remotely via the Fear Learning and Anxiety Response (FLARe) smartphone app. In the fear acquisition phase, participants were exposed to two neutral shape stimuli, one of which was repeatedly paired with a loud aversive noise, while the other was never paired with anything aversive. In the extinction phase, the shapes were repeatedly presented again, this time without the aversive noise. Outcomes were participant ratings of how much they expected the aversive noise to occur when they saw either shape, throughout each phase. RESULTS: Twin analyses indicated a significant contribution of genetic effects to the initial acquisition and consolidation of fear, and the extinction of fear (15, 30 and 15%, respectively) with the remainder of variance due to the non-shared environment. Multivariate analyses revealed that the development of fear and fear extinction show moderate genetic overlap (genetic correlations 0.4-0.5). CONCLUSIONS: Fear acquisition and extinction are heritable, and share some, but not all of the same genetic influences.

Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.

Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation.

BACKGROUND: Despite its promise as a highly useful therapy for pancreatic cancer (PC), the addition of external beam radiation therapy to PC treatment has shown varying success in clinical trials. Understanding PC radioresistance and discovery of methods to sensitise PC to radiation will increase patient survival and improve quality of life. In this study, we identified PC radioresistance-associated pathways using global, unbiased techniques. METHODS: Radioresistant cells were generated by sequential irradiation and recovery, and global genome cDNA microarray analysis was performed to identify differentially expressed genes in radiosensitive and radioresistant cells. Ingenuity pathway analysis was performed to discover cellular pathways and functions associated with differential radioresponse and identify potential small-molecule inhibitors for radiosensitisation. The expression of FDPS, one of the most differentially expressed genes, was determined in human PC tissues by IHC and the impact of its pharmacological inhibition with zoledronic acid (ZOL, Zometa) on radiosensitivity was determined by colony-forming assays. The radiosensitising effect of Zol in vivo was determined using allograft transplantation mouse model. RESULTS: Microarray analysis indicated that 11 genes (FDPS, ACAT2, AG2, CLDN7, DHCR7, ELFN2, FASN, SC4MOL, SIX6, SLC12A2, and SQLE) were consistently associated with radioresistance in the cell lines, a majority of which are involved in cholesterol biosynthesis. We demonstrated that knockdown of farnesyl diphosphate synthase (FDPS), a branchpoint enzyme of the cholesterol synthesis pathway, radiosensitised PC cells. FDPS was significantly overexpressed in human PC tumour tissues compared with healthy pancreas samples. Also, pharmacologic inhibition of FDPS by ZOL radiosensitised PC cell lines, with a radiation enhancement ratio between 1.26 and 1.5. Further, ZOL treatment resulted in radiosensitisation of PC tumours in an allograft mouse model. CONCLUSIONS: Unbiased pathway analysis of radioresistance allowed for the discovery of novel pathways associated with resistance to ionising radiation in PC. Specifically, our analysis indicates the importance of the cholesterol synthesis pathway in PC radioresistance. Further, a novel radiosensitiser, ZOL, showed promising results and warrants further study into the universality of these findings in PC, as well as the true potential of this drug as a clinical radiosensitiser.

Reviewing current knowledge in snatch performance and technique: the need for future directions in applied research.

This is a review of current research trends in weightlifting literature relating to the understanding of technique and its role in successful snatch performance. Reference to the world records in the snatch from the 1960s onwards indicates little progress across all weight categories. With such mediocre advances in performance at the International level, there is a need to better understand how snatch technique can improve performance even if only by a small margin. Methods of data acquisition for technical analysis of the snatch have involved mostly 2-dimensional barbell and joint kinematics. Although key variables which play a role in the successful outcome of a snatch lift have been heavily investigated, few studies have combined variables relating both the barbell and the weightlifter in their analyses. This suggests the need for a more detailed approach integrating both barbell-related and weightlifter-related data to enhance understanding of the mechanics of a successful lift. Currently, with the aid of technical advances in motion analysis, data acquisition, and methods of analysis, a more accurate representation of the movement can be provided. Better ways of understanding the key characteristics of technique in the snatch could provide the opportunity for more effective individualized feedback from the coach to the athlete, which should in turn lead to improved performance in competition.

Zoocin A and lauricidin in combination reduce Streptococcus mutans growth in a multispecies biofilm.

Dental caries is the most prevalent human infection. It is a multifactorial disease in which the microbial composition of dental plaque plays a major role in the development of clinical symptoms. The bacteria most often implicated in the development of caries are that group of streptococci referred to as the mutans streptococci, in particular Streptococcus mutans and Streptococcus sobrinus. One approach to the prevention of caries is to reduce the numbers of mutans streptococci in plaque to a level insufficient to support demineralization of the tooth. In this study, zoocin A, a peptidoglycan hydrolase, combined with lauricidin, a cell membrane active lipid, was shown over a 72 h period to selectively suppress the growth of S. mutans in a triple species biofilm. Growth of the non-target species Streptococcus oralis and Actinomyces viscosus was not inhibited. In treated systems the amount of extracellular polysaccharide matrix produced was much reduced as determined by use of fluorescein isothiocyanate conjugated wheat germ agglutinin. The pH of treated biofilms remained above neutral as opposed to a value of 4.3 in untreated controls. We conclude that use of antimicrobial compounds that specifically target cariogenic bacteria should be further explored.

Validating the use of a smartphone app for remote administration of a fear conditioning paradigm.

Fear conditioning models key processes related to the development, maintenance and treatment of anxiety disorders and is associated with group differences in anxiety. However, laboratory administration of tasks is time and cost intensive, precluding assessment in large samplesnecessary for the analysis of individual differences. This study introduces a newly developed smartphone app that delivers a fear conditioning paradigm remotely using a loud human scream as an aversive stimulus. Three groups of participants (total n = 152) took part in three studies involving a differential fear conditioning experiment to assess the reliability and validity of a smartphone administered fear conditioning paradigm. This comprised of fear acquisition, generalisation, extinction, and renewal phases during which online US-expectancy ratings were collected during every trial with evaluative ratings of negative affect at three time points. We show that smartphone app delivery of a fear conditioning paradigm results in a pattern of fear learning comparable to traditional laboratory delivery and is able to detect individual differences in performance that show comparable associations with anxiety to the prior group differences literature.

Genome-wide expression and response to exposure-based psychological therapy for anxiety disorders.

Exposure-based psychological treatments for anxiety have high efficacy. However, a substantial proportion of patients do not respond to therapy. Research examining the potential biological underpinnings of therapy response is still in its infancy, and most studies have focussed on candidate genes. To our knowledge, this study represents the first investigation of genome-wide expression profiles with respect to treatment outcome. Participants (n=102) with panic disorder or specific phobia received exposure-based cognitive behavioural therapy. Treatment outcome was defined as percentage reduction from baseline in clinician-rated severity of their primary anxiety diagnosis at post treatment and 6 month follow-up. Gene expression was determined from whole blood samples at three time points using the Illumina HT-12v4 BeadChip microarray. Linear regression models tested the association between treatment outcome and changes in gene expression from pre-treatment to post treatment, and pre-treatment to follow-up. Network analysis was conducted using weighted gene co-expression network analysis, and change in the detected modules from pre-treatment to post treatment and follow-up was tested for association with treatment outcome. No changes in gene expression were significantly associated with treatment outcomes when correcting for multiple testing (q<0.05), although a small number of genes showed a suggestive association with treatment outcome (q<0.5, n=20). Network analysis showed no association between treatment outcome and change in gene expression for any module. We report suggestive evidence for the role of a small number of genes in treatment outcome. Although preliminary, these findings contribute to a growing body of research suggesting that response to psychological therapies may be associated with changes at a biological level.

Confluence-induced alterations in CpG island methylation in cultured normal human fibroblasts.

Growth constraint of bacterial and human cells has been shown to trigger genetic mutation. We questioned whether growth constraint might also trigger epigenetic mutation in the form of CpG island methylation. Logarithmically growing normal human fibro-blasts (NHF) displayed little (0-15%) CpG methylation in select regions of three CpG islands [estrogen receptor (ER), E-cadherin (ECAD) and O (6)-methylguanine-DNA methyltransferase (MGMT)] examined. NHF grown to and left at confluence for 2-21 days showed little (<10%) CpG methylation in the ER and ECAD CpG islands. These confluent, growth-arrested cells, however, displayed extensive ( approximately 50%) methylation of the MGMT CpG island. CpG methylation in the MGMT CpG island was not associated with cellular senescence. The methylation was, however, heritable, but not permanent, as the level of CpG methylation in the MGMT CpG island of cells 4 population doublings following replating after confluence were no different from those in confluent cultures, but returned to levels noted in logarithmically growing cells by 10 population doublings following replating. These results suggest that growth constraint can trigger transient epigenetic change even in normal non-senescent human cells.

Susceptibility of goldsinny wrasse, Ctenolabrus rupestris L. (Labridae), to viral haemorrhagic septicaemia virus (VHSV) genotype III: Experimental challenge and pathology.

Cleaner fish, such as wrasse, are being increasingly used to combat the sea lice infestation of Atlantic salmon (Salmo salar L.) in many European countries. To determine susceptibility of the goldsinny wrasse (Ctenolabrus rupestris L.) and pathogenesis of the viral haemorrhagic septicaemia virus (VHSV) genotype III isolate 12-654, previously associated with VHSV infection in the Shetland Islands in 2012, fish were experimentally challenged by intraperitoneal injection (IP), bath immersion and cohabitation routes. Cumulative proportion of moribund wrasse reached 17% following the virus immersion challenge while by the IP-route moribunds exceeded 50% within 14days post-challenge. Typical signs of VHS as reported in rainbow trout (Oncorhynchus mykiss), were not observed in moribund goldsinny wrasse. The most pronounced histopathological changes, consistent regardless of the route of infection, were observed within the heart and included atrium myofibril degeneration, focal infiltration and multifocal necrosis, with prominent swelling of the endocardium and occasional detachment. Pathological changes in the atrium were associated with presence of the viral antigen as confirmed by a positive immunohistochemical staining. Virus clearance and heart tissue recovery were noted although further experiments are required to confirm these observations. The results of a cohabitation experiment confirmed that goldsinny wrasse shed viable virus and therefore represent a risk of virus transmission to other VHSV susceptible species. Similarities between the pathology in goldsinny wrasse induced through the controlled experimental challenges and that of wrasse spp. from an infection occurrence in Shetland are discussed.

Paediatric Obsessive-Compulsive Disorder and Depressive Symptoms: Clinical Correlates and CBT Treatment Outcomes.

Depression frequently co-occurs with paediatric obsessive-compulsive disorder (OCD), yet the clinical correlates and impact of depression on CBT outcomes remain unclear. The prevalence and clinical correlates of depression were examined in a paediatric specialist OCD-clinic sample (N = 295; Mean = 15 [7 - 18] years, 42 % female), using both dimensional (Beck Depression Inventory-youth; n = 261) and diagnostic (Development and Wellbeing Assessment; n = 127) measures of depression. The impact of depressive symptoms and suspected disorders on post-treatment OCD severity was examined in a sub-sample who received CBT, with or without SSRI medication (N = 100). Fifty-one per-cent of patients reported moderately or extremely elevated depressive symptoms and 26 % (95 % CI: 18 - 34) met criteria for a suspected depressive disorder. Depressive symptoms and depressive disorders were associated with worse OCD symptom severity and global functioning prior to CBT. Individuals with depression were more likely to be female, have had a psychiatric inpatient admission and less likely to be attending school (ps < 0.01). OCD and depressive symptom severity significantly decreased after CBT. Depressive symptoms and depressive disorders predicted worse post-treatment OCD severity (ßs = 0.19 and 0.26, ps < 0.05) but became non-significant when controlling for pre-treatment OCD severity (ßs = 0.05 and 0.13, ns). Depression is common in paediatric OCD and is associated with more severe OCD and poorer functioning. However, depression severity decreases over the course of CBT for OCD and is not independently associated with worse outcomes, supporting the recommendation for treatment as usual in the presence of depressive symptoms.

Intensity pattern of snoring sounds as a predictor for sleep-disordered breathing.

The relationship between a new operational definition of sleep sounds and apnea was examined in a population of 69 patients referred for overnight evaluations in a sleep disorders center. The sample contained 18 women (mean age 53.6 years) and 51 men (mean age 48.4 years). Subjects underwent polysomnography (PSG) with concurrent graphical recording of sleep sound intensities throughout the night. An acoustical signature event (ASE) was defined as a loud sound preceded by at least 10 but no more than 90 seconds of silence. Multiple regression was performed using known correlates of apnea and ASE to predict PSG levels of respiratory disturbance. Of the commonly known correlates, only self-reported estimate of snoring and apnea severity explained significant variance to the respiratory disturbance index (RDI; R2 = 0.24, p < 0.0001). ASE was entered into the equation as the last step, significantly improving explained variance (R2delta = 0.54, p < 0.0001). The final equation R2 was 78% (p < 0.0001). An alternative analysis compared ASE findings to polysomnographic findings in each matched 30-second interval (60,231 observations) in an analysis of receiver's operating characteristics. This analysis resulted in d' = 2.67, indicating acceptable accuracy for screening.

Relaxation and sleep compression for late-life insomnia: a placebo-controlled trial.

Older adults with insomnia were recruited from the community and randomized to treatments: relaxation, sleep compression, and placebo desensitization. Questionnaire data collected at baseline, posttreatment, and 1-year follow-up and polysomnography data collected at baseline and follow-up yielded the following conclusions: All treatments improved self-reported sleep, but objective sleep was unchanged. Clinical significance analyses yielded the strongest findings supporting the active treatments and suggested that sleep compression was most effective. Results partially supported the conclusion that individuals with high daytime impairment (i.e., fatigue) respond best to treatments that extend sleep, as in relaxation, and individuals with low daytime impairment respond best to treatments that consolidate sleep, as in sleep compression. Strong methodological features including a placebo condition and a treatment implementation scheme elevate the confidence due these findings.

Occult sleep apnea in a recruited sample of older adults with insomnia.

Although costly polysomnography (PSG) is not routinely performed with people with insomnia, it may be more necessary with recruited older adults with insomnia because this population may pose a greater risk of veiled sleep disorders compared with younger age groups and with referred samples. The present PSG screening of a recruited sample of older adults with insomnia found a 29%-43% rate of undiagnosed sleep apnea (SA), depending on whether an apnea-hypopnea index of 15 or 5 was used, after interviews had already screened out obvious cases of SA. Also, PSGs revealed a 4% rate of occult periodic limb movements. A discriminant analysis identified overweight men reporting dry mouth at highest risk for occult SA, with an apnea-versus-insomnia classification success rate of 78%. Using PSG evaluations in research on insomnia in recruited older adults is requisite to preclude substantial representation of occult SA.

A description of the molar enamel of a middle Miocene monotreme (Obdurodon, Ornithorhynchidae).

The dentine and enamel of a newly discovered well-formed tooth of a Tertiary monotreme, Obdurodon sp., was examined for ultrastructural information relevant to the phylogenetic interpretation of monotremes. Obdurodon sp. presents a unique combination of mammalian structural features in the fractured enamel surfaces examined: tubules in great number; prisms of small diameter; a substantial and coherent inter-prismatic component and, in the middle third enamel, inter-row sheet; a simple non-decussating prism course; a predominantly pattern 1 prism packing in the innermost enamel; and a predominantly pattern 2 prism packing in the middle third enamel; and non-prismatic outer enamel. Although the particular combination of structural characteristics suggests that monotremes represent a possibly unique and relatively plesiomorphic group of mammals, many of the features are very similar to those seen in multituberculates. If multituberculates and monotremes are monophyletic, it would help to explain what has otherwise been a puzzling zoogeographic pattern in the distribution of each group.

Scanning microscopy of platypus teeth.

Anorganic unerupted developing teeth and air-dried erupted teeth of the platypus (Ornithorhynchus anatinus) were examined in a scanning electron microscope and in a tandem scanning reflected light microscope. Typically mammalian developing fronts of enamel and dentine were identified in the anorganic unerupted specimens. The developing teeth were particularly small and fragile and the enamel elusive and difficult to examine in the normal way for morphological detail. Prepared fractured surfaces of unerupted specimens revealed preferentially oriented crystallite groups in the enamel generally perpendicular to the developing front and a highly globular, mineralized pattern in the dentine with fine diameter, sparsely distributed dentinal tubules. Although optically homogeneous, the enamel of both developing and mature teeth displayed well-defined incremental lines, radial clefts, crystallite domains of variable size and outline, and fine tubules when examined by high contrast, back-scattered electron imaging. The enamel is prismatic only in part; well-formed, regular prisms not being a primary feature of platypus enamel. This can be related to the variability inherent in the developing surface and the thinness of the enamel layer. No surface was found which could be confidently identified as cementum; those developing surfaces not covered by enamel displaying small calcospherites which elsewhere marked the outer aspect of the dentine.

Interventions based on the multiple connections model of reading for developmental dyslexia and acquired deep dyslexia.

This paper deals with intervention strategies for developmental and acquired dyslexia. In Study 1 two alternative strategies for developmental surface dyslexia (dysfunctional connection between the whole word orthographic code and the phonetic or name code) were compared. In both the initial study and replication study, a modification of the selective reminding technique was superior to a traditional multisensory technique in beginning readers, presumably because it facilitated word finding or prelexical access to a phonetic code. In Study 2 an adolescent with acquired deep dyslexia (dysfunctional connection between letter and phonemic codes) who had had his angular gyrus (site of grapheme-phoneme correspondence) surgically removed, recovered reading function after a four-month phonemic analysis training program. Further research is needed to evaluate the efficacy of theory-based intervention strategies in children with developmental reading disorders unrelated to focal lesions and in adults with acquired reading disorders related to focal lesions.

The psychologist's role in the Garrison mission of combat stress control units.

Active duty psychologists frequently are called upon to provide services that extend beyond the model of direct patient care. Army psychologists in combat stress control teams or division mental health services, Navy psychologists deployed to surgical companies, and Air Force psychologists deployed with air-transportable hospitals or mental health rapid response teams may find themselves acting as organizational consultants as well as clinicians. Psychologists assigned to hospitals and clinics also have opportunities to make contact with their units for purposes of consultation and education. Organizational consultations that offer interventions for improving unit readiness and/or increasing combat effectiveness are often welcomed by commanders and provide a mechanism for the application of training and experience directly to military populations. Transferring skills from patient care to performance enhancement may not be a clear progression for many clinicians. This article describes the strategies and materials developed as part of a combat stress control garrison mission at Fort Lewis, Washington, as an example of one approach to working with combat units. The article also calls for the development of a formal mechanism to train psychologists for such roles and for the maintenance and dissemination of research materials to support organizational interventions.

A short history of Westmead Centre Dental Clinical School.

Westmead Centre is a large teaching hospital of 925 acute treatment beds planned to provide a comprehensive range of general and specialist referral services to the rapidly expanding population of the western suburbs of Sydney. The hospital was conceived in 1968 and opened for patient treatment in 1978. The Dental Clinical School is an integral part of Westmead Centre. The School was planned to provide diagnostic, treatment, recovery, and support facilities. When fully commissioned, it will offer 230 dental chairs, a fully equipped Operating Suite, and extensive laboratory, teaching and research areas. The School is meant to provide clinical undergraduate training for dental students of the University of Sydney and facilities for graduate, postgraduate, and continuing education. At the same time it is to fulfil a general and specialist service role in the Western Metropolitan Health Region. The Dental Clinical School opened for patient treatment in 1980 and accepted its first intake of final year students in 1981. It is anticipated that in 1982 the School will be fully commissioned and making a significant contribution to the dental education and care of the people of New South Wales.

Burs, teeth and hand instruments.

Scanning electron microscope studies demonstrate deficiencies in the surfaces of cavity preparations made with conventional cutting instruments. Better surface preparation can be achieved by using appropriate shaped tungsten rotary instruments, and by sharp hand instruments used with a scraping action. The direction of rotation of the cutting alters the quality of the enamel margin. The SEM image should not be interpreted as the sole criterion of clinical success.