Are Mental Health, Family and Childhood Adversity, Substance Use and Conduct Problems Risk Factors for Offending in Autism?

Mental health difficulties, family and childhood adversity factors, substance use and conduct problems have all been linked to offending behaviour in the general population. However, no large-scale study with comparison groups has investigated these risk factors in relation to autistic offenders. The current research included 40 autistic offenders, 40 autistic non-offenders, 40 typically developed (TD) offenders and 39 TD non-offenders. Conduct problems risk factors differentiated autistic offenders from both non-offender groups (autistic and TD) and mental health risk factors differentiated autistic offenders from both TD groups (offenders and non-offenders). Further research is required to understand more about the role of both conduct problems risk factors in autistic offenders (e.g., age at onset, frequency of behaviours) and the mental health needs of autistic offenders.

Self-reported motivations for engaging or declining to engage in cyber-dependent offending and the role of autistic traits.

Cyber-dependent offending, i.e. criminal behaviour reliant on computing and the online domain, has been reportedly associated with particular characteristics and motivations such as being young, male, autistic and motivated by challenge. These associations are anecdotal however and empirical evidence is limited. The present study investigated reasons for engaging or declining to commit cyber-dependent offending in cyber-skilled non-offenders (n = 175) and offenders (n = 7) via an online survey measuring cyber-dependent criminality. The potential role of autism and autistic traits was also considered. Qualitative interviews about motivations for offending were carried out with the offenders. The cyber-dependent offenders reported seven main reasons for engaging in cyber-dependent offending: (1) lack of understanding; (2) entertainment; (3) peer influence; (4) experience and career; (5) anonymity and risk perception; (6) life events; and (7) morals. Twenty-nine (approximately 17 %) of the non-offenders had been asked to engage in cyber-dependent offending but had declined. Their reasons and motivations for declining to commit cyber-dependent offences were compared with the cyber-dependent offenders reasons and motivations for engaging in cybercrime. Seven main reasons for declining to offend were identified: (1) moral principles; (2) perception of risk; (3) fear of consequences; (4) not wanting to; (5) wanting to adhere to the law; (6) behaviour being too complicated; and (7) price being too low. Implications for practise are discussed.

Adapting Psychological Therapies for Autism - Therapist Experience, Skills and Confidence.

BACKGROUND: Psychological interventions informed by cognitive behavioural theory have proven efficacy in treating mild-moderate anxiety and depression. They have been successfully adapted for autistic children and adults who experience disproportionately high rates of co-occurring emotional problems. There has been little research into the perspectives and experience of psychological therapists adapting cognitive behavioural therapy (CBT) as part of routine clinical practice. We surveyed therapist skills, experience and confidence in working psychologically with autistic people, in order to highlight gaps and needs, as well as strengths in terms of therapist skills when working with this group. METHOD: Fifty therapists attending a training event completed a survey about their experience of adapting CBT for autistic clients, alongside a measure of therapist confidence. RESULTS: Almost all therapists reported making adaptations to CBT practice when working with autistic clients. Key challenges identified were rigidity in thinking and pacing sessions appropriately. Therapists were relatively confident about core engagement and assessment skills but reported less confidence in using their knowledge to help this group. Therapist confidence was not associated with years of practice or number of adaptations made, but was positively associated with level of therapy training received. CONCLUSIONS: This study highlights a need for training and ongoing supervision to increase therapist confidence in and ability to make appropriate adaptations to CBT treatment protocols for autistic people.

Cognitive-behavioural therapy for adult attention-deficit hyperactivity disorder: a proof of concept randomised controlled trial.

OBJECTIVE: To investigate efficacy, patient acceptability and feasibility of formulation-based cognitive-behavioural therapy (CBT) for adults with attention-deficit hyperactivity disorder (ADHD). NICE guidelines for adult ADHD recommend further research into psychological treatments. METHOD: Sixty participants with adult ADHD were randomly allocated to treatment as usual (TAU) vs. TAU plus up to 16 sessions of individual formulation-based CBT for ADHD. RESULTS: Adding formulation-based CBT to TAU for ADHD significantly improved ADHD symptoms on the Barkley Current Symptoms Scale and scores on the Work and Social Adjustment Scale. Adjusted effect sizes (ES) were 1.31 and 0.82 respectively. There were also significant improvements on secondary outcomes including independently evaluated clinical global improvement, self-rated anxiety, depression, global distress and patient satisfaction (adjusted effect sizes 0.52-1.01). CONCLUSIONS: This is the first randomised controlled trial to provide preliminary evidence of efficacy and acceptability of individual formulation-based CBT for ADHD when added to TAU over TAU alone. This approach now needs to be tested in a larger multicentred randomised controlled trial.

Inhibition of prolyl 4-hydroxylase decreases muscle fibrosis following chronic rotator cuff tear.

OBJECTIVES: Rotator cuff tears are among the most frequent upper extremity injuries. Current treatment strategies do not address the poor quality of the muscle and tendon following chronic rotator cuff tears. Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor that activates many genes that are important in skeletal muscle regeneration. HIF-1α is inhibited under normal physiological conditions by the HIF prolyl 4-hydroxylases (PHDs). In this study, we used a pharmacological PHD inhibitor, GSK1120360A, to enhance the activity of HIF-1α following the repair of a chronic cuff tear, and measured muscle fibre contractility, fibrosis, gene expression, and enthesis mechanics. METHODS: Chronic supraspinatus tears were induced in adult rats, and repaired 28 days later. Rats received 0 mg/kg, 3 mg/kg, or 10 mg/kg GSK1120360A daily. Collagen content, contractility, fibre type distribution and size, the expression of genes involved in fibrosis, lipid accumulation, atrophy and inflammation, and the mechanical properties of the enthesis were then assessed two weeks following surgical repair. RESULTS: At two weeks following repair, treatment groups showed increased muscle mass but there was a 15% decrease in force production in the 10 mg/kg group from controls, and no difference between the 0 mg/kg and the 3 mg/kg groups. There was a decrease in the expression of several gene transcripts related to matrix accumulation and fibrosis, and a 50% decrease in collagen content in both treated groups compared with controls. Additionally, the expression of inflammatory genes was reduced in the treated groups compared with controls. Finally, PHD inhibition improved the maximum stress and displacement to failure in repaired tendons. CONCLUSIONS: GSK1120360A resulted in improved enthesis mechanics with variable effects on muscle function. PHD inhibition may be beneficial for connective tissue injuries in which muscle atrophy has not occurred.Cite this article: J. P. Gumucio, M. D. Flood, A. Bedi, H. F. Kramer, A. J. Russell, C. L. Mendias. Inhibition of prolyl 4-hydroxylase decreases muscle fibrosis following chronic rotator cuff tear. Bone Joint Res 2017;6:57-65. DOI: 10.1302/2046-3758.61.BJR-2016-0232.R1.

The effect of socioeconomic status on treatment and pregnancy outcomes in women with epilepsy in Scotland.

Compared to the background population, people with epilepsy tend to have lower rates of education and employment, lower rates of marriage and childbearing, and lower overall socioeconomic status (SES). Disparities in epilepsy care based on sociodemographic factors have been observed in the literature, but it is not known whether any such disparities exist in the UK. The UK Epilepsy and Pregnancy Register is a prospective, observational, registration and follow-up study that was set up to determine the relative safety of all AEDs taken in pregnancy. Here, we report outcomes of registered pregnancies to women with epilepsy living in Scotland from December 1996 to June 2012, based on the degree of socioeconomic deprivation of their postcode area. The Scottish Index of Multiple Deprivation (SIMD) quintile scores from 2006 were used to determine degree of socioeconomic deprivation, and group 1 (most deprived) and group 5 (least deprived) were compared. There were 1526 pregnancies with complete outcome data to women living in Scotland. Of these, 1453 (95.1%) resulted in a live birth and 68 (4.7%) had a major congenital malformation (MCM). Postcodes could not be reliably identified or verified for an additional three women, who have been excluded from SIMD group analysis. Of all women included in this study, 32.4% were in group 1 and 13.2% in group 5. No difference in MCM rate was observed between the two groups (4.4% in group 1 compared to 4.7% in group 5, p=0.84). Women in group 5 were more likely to take preconceptual folic acid (56.8% compared to 14.0%, relative risk: 4.1; 95% CI: 3.1-5.2) and less likely to have generalized tonic-clonic seizures in pregnancy (13.0% compared to 29.2%, relative risk: 0.4; 95% CI: 0.3-0.7) than those in group 1. Women in group 5 were more likely to be on monotherapy regimens (80.2% compared to 65.9%, relative risk: 1.2; 95% CI: 1.1-1.3), less likely to be on valproate (19.5% compared to 28.0%, p=0.05), and more likely to be on lower doses of the drug (825.9mg/day compared to 1012.0mg/day, p=0.05) compared to those in group 1. Although no change in MCM rate was seen based on SES, differences in treatment between socioeconomic groups do exist, particularly for preconceptual folic acid consumption, AED regimen, and seizure frequency. Greater emphasis on the importance of preconceptual counseling, both to discuss AED choice and folic acid intake, would be of benefit, particularly to those living in areas of high socioeconomic deprivation, to improve equity of healthcare delivery for women with epilepsy in Scotland.

Severe statin-induced rhabdomyolysis mimicking Guillain-Barré syndrome in four patients with diabetes mellitus treated with fusidic acid.

BACKGROUND: An interaction between fusidic acid and HMG coenzyme A reductase inhibitors (statins), resulting in rhabdomyolysis, has been described. Pain and mild weakness are common presenting symptoms. CASE REPORT: We report four patients with Type 2 diabetes prescribed long-term statin treatment who, following treatment with fusidic acid, presented atypically with painless, severe flaccid paralysis suggestive of Guillain-Barré syndrome. This, together with nerve conduction studies consistent with Guillain-Barré syndrome, resulted in the delayed recognition of rhabdomyolysis in these cases. CONCLUSIONS: The addition of fusidic acid can precipitate rhabdomyolysis in patients with diabetes already taking a statin. This can present with rapidly progressive weakness resembling Guillain-Barré syndrome. We recommend that creatine kinase is checked in patients with diabetes on statin therapy who present with profound weakness and routinely in those commenced on prolonged courses of fusidic acid.

The Scar-in-a-Jar: studying potential antifibrotic compounds from the epigenetic to extracellular level in a single well.

BACKGROUND AND PURPOSE: Fibrosis, a pathological accumulation of collagen in tissues, represents a major global disease burden. Effective characterization of potential antifibrotic drugs has been constrained by poor formation of the extracellular matrix in vitro, due to tardy procollagen processing by collagen C-proteinase/BMP-1, and difficulties in relating this matrix to cell numbers in experimental samples. EXPERIMENTAL APPROACH: The Scar-in-a-Jar model provided, in vitro, the complete biosynthetic cascade of collagen matrix formation including complete conversion of procollagen by C-proteinase/BMP-1, its subsequent extracellular deposition and lysyl oxidase-mediated cross-linking, achieved by applying the biophysical principle of macromolecular 'crowding'. Collagen matrix deposition, velocity and morphology can be controlled using negatively charged 'crowders' in a rapid (2 days) mode or a mixture of neutral 'crowders' in an accelerated (6 days) mode. Combined with quantitative optical bioimaging, this novel system allows for in situ assessment of the area of deposited collagen(s) per cell. KEY RESULTS: Optical evaluation of known and novel antifibrotic compounds effective at the epigenetic, post-transcriptional/translational/secretional level correlated excellently with corresponding biochemical analyses. Focusing on quantitation of deposited collagen, the Scar-in-a-Jar was most effective in assessing novel inhibitors that may have multiple targets, such as microRNA29c, found to be a promising antifibrotic agent. CONCLUSIONS AND IMPLICATIONS: This novel screening system supersedes current in vitro fibroplasia models, as a fast, quantitative and non-destructive technique. This method distinguishes a reduction in collagen I deposition, excluding collagen cross-linking, and allows full evaluation of inhibitors of C-proteinase/BMP-1 and other matrix metalloproteinases.

Folic acid use and major congenital malformations in offspring of women with epilepsy: a prospective study from the UK Epilepsy and Pregnancy Register.

OBJECTIVE: In the general population, folic acid supplementation during pregnancy has been demonstrated to reduce the frequency of neural tube defects (NTDs) and other major congenital malformations (MCMs). It is recommended that women with epilepsy contemplating pregnancy take supplemental folic acid because of the known antifolate effect of some antiepileptic drugs (AEDs). Here the aim was to determine the effectiveness of this practice. METHODS: This study is part of a prospective, observational, registration and follow-up study. Suitable cases are women with epilepsy who become pregnant and who are referred before outcome of the pregnancy is known. The main outcome measure is the MCM rate. Outcomes were analysed against folic acid exposure, malformation type and drug group for the most commonly used monotherapy AEDs. RESULTS: In 1935 cases reported to have received preconceptual folic acid, 76 MCMs (3.9%; 95% CI 3.1 to 4.9) and eight NTDs (0.4%; 95% CI 0.2 to 0.8) were identified. For 2375 women who were reported to have received folic acid but not until later in the pregnancy (n = 1825) or not at all (n = 550), there were 53 outcomes with an MCM (2.2%; 95% CI 1.7 to 2.9) and eight NTDs (0.34%; 95% CI 0.2 to 0.7). CONCLUSIONS: The study supports the view that extrapolation from studies carried out in the general population to groups of women with epilepsy may be questionable. It may be that the increased risk of MCM recorded in this group occurs through mechanisms other than that of folic acid metabolism.

Detecting seizure origin using basic, multiscale population dynamic measures: preliminary findings.

Many types of electrographic seizures are readily identifiable by direct visual examination of electroencephalographic or electrocorticographic recordings. This process can, however, be painstakingly slow, and much effort has been expended to automate the process using various dynamic properties of epileptiform waveforms. As methods have become more subtle and powerful they have been used for seizure subclassification, seizure prediction, and seizure onset identification and localization. Here we concentrate on the last, with reference to seizures of neocortical origin. We briefly review some of the methods used and introduce preliminary results from a very simple dynamic model based on key electrophysiological properties found in some seizure types: occurrence of very fast oscillations (sometimes called ripples), excess gamma frequency oscillations, electroencephalographic/electrocorticographic flattening, and changes in global synchrony. We show how this multiscale analysis may reveal features unique to seizure onset and speculate on the underlying cellular and network phenomena responsible.

Structure and mechanism of arylamine N-acetyltransferases.

Arylamine N-acetyltransferases (NATs) are a family of phase II drug-metabolising enzymes which are important in the biotransformation of various aromatic and heterocyclic amines and hydroxylamines, arylhydrazines and arylhydrazides. NATs are present in a wide range of eukaryotes and prokaryotes. Humans have two functional NAT isoforms, both of which are highly polymorphic. The pharmacogenetics of NATs is an area which has been extensively studied. The determination of the X-ray crystal structure of NAT from Salmonella typhimurium led to the identification of the catalytically essential triad of residues: Cys-His-Asp, which is present in all functional NAT enzymes. Recent co-crystallisation data and in silico docking studies of NAT from Mycobacterium smegmatis with substrates and inhibitors have aided the identification of important contact residues within the active site. The X-ray crystal structures of four prokaryotic NAT proteins have now been determined, and these have been used to generate structural models of eukaryotic NATs, providing valuable insight into their active-site architecture. In addition to aiding crystallographic experiments, recent progress in the production of recombinant prokaryotic and eukaryotic NATs has allowed comparative studies of the kinetics and activity profiles of these enzymes. In this review we present an overview of recent structural and activity studies on NAT enzymes, and we outline how in silico methods may be used to predict NAT protein-ligand interactions based on the current knowledge.

Gender differences in psychogenic non-epileptic seizures.

PURPOSE: To determine whether male and female populations of patients with psychogenic non-epileptic seizures (PNES) are similar, in terms of demographic and social factors, aetiological factors, the clinical characteristics of events and path to diagnosis. METHODS: Prospective study by semi-structured interview of 160 consecutive patients (117 female and 43 male) with video EEG confirmed diagnosis of PNES + epileptic seizures (ES). RESULTS: Most parameters showed no significant differences. Males were, however, more likely to be unemployed (P = 0.028), and females were six times more likely to self-harm (P = 0.050), though the numbers were small in these categories. Men were more likely to attribute their PNES to a predisposing factor for epilepsy (P = 0.001), and women were over eight times more likely to report sexual abuse (P = 0.001). Event semiology was similar, but women were more likely to weep after events (P = 0.017). The carers and family of men with PNES were three times less likely to accept the diagnosis of PNES (P = 0.017). CONCLUSIONS: Our samples showed few significant gender differences, suggesting that other male and female populations of patients with PNES are likely to be similar also. Some of the differences we found may give insight into causation of PNES.

Pseudosleep events in patients with psychogenic non-epileptic seizures: prevalence and associations.

OBJECTIVES: To determine the prevalence and clinical associations of a history of events during sleep in patients with psychogenic non-epileptic seizures (PNES, pseudoseizures), and to compare the prevalence of a history of sleep events with that in poorly controlled epilepsy. METHODS: Prospective study by semistructured interview of the history of event patterns and their clinical associations in 142 patients with video EEG confirmed PNES, and 100 patients with poorly controlled epilepsy. RESULTS: 84/142 patients with PNES (59%) and 47/100 with epilepsy (47%) gave a history of events during sleep (p = 0.062). In patients with PNES, significant associations were found between a history of sleep events and: convulsive clinical semiology, antiepileptic drug treatment, fatigue, suicide attempts, mood disorder, and physical abuse. A particularly strong association with social security benefit was also found (odds ratio 4.0, p<0.001). CONCLUSIONS: The prevalence of a history of sleep events is similar in PNES and epilepsy, and is of no value in discriminating between the two, although a history of events occurring exclusively during sleep does suggest epileptic seizures. The clinical associations found indicate that a combination of psychopathological and external influences may be important in determining whether or not a patient with PNES gives a history of events during sleep.

Use of short term video EEG in the diagnosis of attack disorders.

BACKGROUND: Distinguishing epileptic from psychogenic non-epileptic seizures (PNES) often requires video electroencephalography (EEG) recording. Inpatient recording is a limited resource; some evidence suggests that short term video EEG (SVEEG) is useful, but its role in practice has yet to be evaluated. OBJECTIVE: To assess the usefulness of SVEEG in the diagnosis of attack disorders. METHODS: One hundred and forty three SVEEG recordings were performed during an 18 month period. RESULTS: A diagnostic event was recorded in 72 of 143 (50.3%): PNES (n = 51), epilepsy (n = 7), or other attacks, such as movement disorders (n = 14). CONCLUSIONS: SVEEG is a robust and useful diagnostic technique, which complements existing resources.

The role of androgens in development of the scrotum of the grey short-tailed Brazilian opossum ( Monodelphis domestica).

In eutherian mammals, sex differentiation is initiated by expression of the testis-determining gene on the Y chromosome. Subsequent phenotypic development of the reproductive tract and genitalia depends on the production of hormones by the differentiated testis. In marsupials the mechanisms of phenotypic development may vary from this pattern, as differentiation of the scrotal primordia has been shown to occur before that of the gonad. Thus, the development of the scrotum in the marsupial has been regarded as an androgen-independent process. We have sought to clarify the ontogeny of scrotal development and the appearance of androgen receptor immunoreactivity by examining Monodelphis domesticaembryos/pups from 1 day prior to birth until 2 days after birth. We have also used immunocytochemistry to determine the expression of the key steroidogenic enzyme 3beta-hydroxysteroid dehydrogenase as an indicator of when the developing gonad may be capable of synthesizing androgens. Expression of this enzyme was first detected in the gonads and adrenals of both sexes 1 day prior to birth and before the appearance of scrotal bulges. Androgen receptor immunoreactivity was detected in the scrotal anlagen of male opossum pups as early as 1 day following birth. This finding is significantly earlier than previous reports and coincides with the appearance 1 day after birth of distinct scrotal bulges. Androgen receptor immunoreactivity was also observed in the genital tubercles of male pups, but not female pups, 2 days after birth. These results suggest that androgens may play an important role in the development of the male genitalia at a much earlier stage than that indicated by previously published work and that scrotal development in this species may not be androgen-independent.

Species differences in the ovarian distribution of 3beta-hydroxysteroid dehydrogenase/delta5-->4 isomerase (3beta-HSD) in two marsupials: the brushtail possum Trichosurus vulpecula and the grey, short-tailed opossum Monodelphis domestica.

The ovarian distribution of the steroidogenic enzyme 3beta-hydroxysteroid dehydrogenase/delta(5-->4) isomerase (3beta-HSD) was investigated by immunocytochemistry in two marsupial species throughout the reproductive cycle, using a rabbit polyclonal antibody raised against human placental 3beta-HSD. In the polyoestrous and polyovular South American opossum Monodelphis domestica, immunostaining was positive for 3beta-HSD in the adrenal cortex, the ovarian interstitial tissue, the corpus luteum and the granulosa cells of antral and atretic follicles. The theca interna was weakly positive for 3beta-HSD, but only in late preantral to early antral stages of follicular development. The adrenal medulla and smaller preantral follicles were completely negative for 3beta-HSD. In contrast, in the polyoestrous and monovular Australian brushtail possum Trichosurus vulpecula, immunostaining showed a strong positive reaction for 3beta-HSD in the theca, whereas the granulosa layer remained predominantly negative for 3beta-HSD except in the largest follicles. The atretic follicles were completely negative for 3beta-HSD. The ovaries of pregnant animals contained grossly enlarged, persistent, antral follicles, which reacted positively for 3beta-HSD. The function of these follicles in T. vulpecula and the 3beta-HSD-positive atretic follicles in M. domestica has not been determined. The differences between the two marsupials represent species variations. The situation in M. domestica does not represent a marsupial-eutherian dichotomy as previously conjectured.

Direct compression of the failing heart reestablishes maximal mechanical efficiency.

BACKGROUND: In failing hearts, homeostatic mechanisms contrive to maximize stroke work and maintain normal arterial blood pressure at the expense of energetic efficiency. In contrast dobutamine reestablishes maximal mechanical efficiency by promoting energetically optimal loading conditions. However, dobutamine also wastefully increases nonmechanical oxygen consumption. We investigated whether direct mechanical cardiac compression would reestablish maximal mechanical efficiency without the oxygen-wasting effect. METHODS: The pressure-volume relationship and myocardial oxygen consumption were derived in sheep using left ventricular pressure and volume from manometer-tipped and conductance catheters, and coronary flow from Transonics flow probe. RESULTS: Propranolol hydrochloride and atropine sulfate were administered to reduce ejection fraction to 21% when ventricular elastance fell to 1.35 mm Hg/mL and mechanical efficiency to 79% of maximal. Low-pressure direct mechanical compression of the failing heart restored mechanical efficiency to 94% of maximal and realigned optimal left ventricular end-systolic pressure with operating left ventricular end-systolic pressure without altering nonmechanical oxygen consumption. CONCLUSIONS: We conclude that direct cardiac compression restores mechanical efficiency to normal maximum without wasting energy on additional nonmechanical activity.

Cardiomyoplasty reduces myocardial oxygen consumption: implications for direct mechanical compression.

BACKGROUND: This study investigates the possibility of reducing myocardial oxygen consumption by dynamic cardiomyoplasty in chronic heart failure. The sheep model used is relevant for cardiac assist using direct mechanical cardiac compression. METHODS: In 7 sheep, heart failure was induced by staged intracoronary microembolization followed by dynamic cardiomyoplasty. Six months later, the effect of latissimus dorsi muscle stimulation in the 2:1 mode (on, cardiomyoplasty; off, control) was studied. Left ventricular pressure-volume loops were obtained by conductance, micromanometer, and inferior vena cava occlusion catheter. Myocardial oxygen consumption was derived from left main coronary artery blood flow and oxygen content of arterial and coronary sinus blood. RESULTS: Cardiomyoplasty had no significant effect on left ventricular hemodynamic variables such as end-systolic pressure. However, cardiomyoplasty increased stroke volume and ejection fraction significantly by 11% +/- 12% and 11% +/- 10%, respectively. Although pressure-volume area and external work did not increase with cardiomyoplasty, myocardial oxygen consumption decreased by 21% +/- 11%. Therefore, cardiomyoplasty increased myocardial efficiency (external work/myocardial oxygen consumption) by 16% +/- 13%. CONCLUSIONS: Despite limited hemodynamic improvement from dynamic cardiac compression by cardiomyoplasty in sheep with chronic heart failure, myocardial oxygen consumption was significantly reduced. These findings provide a rationale for reverse remodeling of the failing heart using direct mechanical compression.