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BackgroundInternet-delivered self-help programmes with added therapist guidance have shown efficacy in social anxiety disorder, but unguided self-help has been insufficiently studied.AimsTo evaluate the efficacy of guided and unguided self-help for social anxiety disorder.MethodParticipants followed a cognitive–behavioural self-help programme in the form of either pure bibliotherapy or an internet-based treatment with therapist guidance and online group discussions. A subsequent trial was conducted to evaluate treatment specificity. Participants (n = 235) were randomised to one of three conditions in the first trial, or one of four conditions in the second.ResultsPure bibliotherapy and the internet-based treatment were better than waiting list on measures of social anxiety, general anxiety, depression and quality of life. The internet-based therapy had the highest effect sizes, but directly comparable effects were noted for bibliotherapy augmented with online group discussions. Gains were well maintained a year later.ConclusionsUnguided self-help through bibliotherapy can produce enduring improvement for individuals with social anxiety disorder.

Severe health anxiety is characterised by a persistent and exaggerated fear of serious illness, based on misinterpretations of bodily symptoms. It is a common condition, especially in medical settings, and associated with functional disability. The disorder exhibits features similar to obsessive-compulsive disorder, panic disorder and generalised anxiety disorder and can be conceptualised as an anxiety disorder.

Internet-delivered cognitive behavior therapy (ICBT) is a relatively novel treatment format with the potential to increase accessibility of evidence-based care. However, little is known about the feasibility and efficacy of ICBT in children and adolescents. We conducted a comprehensive systematic review and meta-analysis of ICBT for children and adolescents to provide an overview of the field and assess the efficacy of these interventions. A systematic literature search of six electronic databases was performed to identify ICBT intervention studies for children with a psychiatric condition, such as social anxiety disorder, or a somatic condition, such as chronic pain. Two reviewers independently rated study quality. Twenty-five studies, targeting 11 different disorders, were included in the review. Study quality and presentation of treatment variables, such as therapist time and treatment adherence, varied largely. Twenty-four studies (N=1882) were included in the meta-analysis and ICBT yielded moderate between-group effect sizes when compared with waitlist, g=0.62, 95% CI [0.41, 0.84]. The results suggest that CBT for psychiatric and somatic conditions in children and adolescents can be successfully adapted to an internet-delivered format.

Social anxiety disorder (SAD) is characterized by a marked and persistent fear of being scrutinized by others in social situations. It is highly prevalent and follows a chronic course for many affected if untreated. Treatment with cognitive behavior therapy (CBT) has been shown to be highly effective for SAD with responder rates of 50–75 %. For more than a decade, Internet-based CBT (ICBT) has been researched and evidence has been provided by four independent research groups. In essence, most forms of ICBT for SAD can generally be described as therapist-guided Internet-based self-help CBT where a named therapist guides the client through the treatment. The treatments are manualized and highly structured comprising 5–15 modules or lessons, which are the equivalent of sessions in face-to-face CBT. The existing treatments for SAD all have vital features in common including that they are based in CBT, comprise the same interventions as have been shown to be effective in face-to-face CBT, have large amount of psychoeducational material, and use asynchronous text messages as the main communication between patient and therapist. ICBT for SAD has been proven to be effective in at least 16 randomized trials and found to be non-inferior to face-to-face CBT. A few studies suggest that ICBT is a cost-effective treatment. Since SAD is known to appear at an early age in most cases, one central future challenge is to increase the body of knowledge on ICBT for children and adolescents. For adults, ICBT for SAD is clearly an effective treatment and a promising option for increasing accessibility to evidence-based psychological treatment.

Truls Gråberg,1 Lovisa Strömmer,1 Erik Hedman,2 Mehmet Uzunel,3 Ewa Ehrenborg,4 Ann-Charlotte Wikström5 1Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, 2Department of Clinical Pharmacology, Karolinska University Hospital, 3Division of Therapeutic Immunology, Department of Laboratory Medicine, 4Atherosclerosis Research Unit, Department of Medicine, Solna, 5Unit of Translational Immunology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden Introduction: An assay to determine glucocorticoid (GC) responsiveness in humans could be used to monitor GC non-responsiveness in states of GC insufficiency and could provide a tool to adapt GC treatment to individual patients. We propose an ex vivo assay to test GC responsiveness in peripheral leukocytes. The assay was evaluated in a human experimental model of surgery-induced inflammation. Patients and methods: Changes in expression of the GC-regulated genes GILZ, IL1R2, FKBP5, and HLA-DR and glucocorticoid receptor alpha (GRα) were determined by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in peripheral leukocytes from surgical patients and healthy blood donors (total n=60) in response to low (1 nM) and high (1 µM) dexamethasone (DEX). The final selection of a suitable endogenous control gene was based on the studies of stability during DEX treatment and inflammation. Correlations between pre- and postoperative GC-induced gene expression, the postoperative systemic inflammatory and metabolic response (CRP, IL-6, white blood cell count, cytokines, resistin, free fatty acids, glucose, insulin, and adiponectin), and the clinical outcome were analyzed. The length of stay in the intensive care unit (ICU-LOS), the length of stay in the hospital, and postoperative complications were used to measure clinical outcome. Results: When the blood donors were compared to the patients, there were no significant differences in the regulation of the genes in response to DEX, except for GRα. Preoperative, but not postoperative, gene regulation of GILZ and GRαwas negatively correlated to ICU-LOS (P

Objectives Although the short-term outcome of therapist-guided internet-based cognitive–behavioural therapy (ICBT) for treating social anxiety disorder (SAD) has been well studied, little research has been undertaken on the sustainability of treatment gains, especially under clinically representative conditions. Further, there is some debate whether delivering psychological treatment via the internet may be suitable for more severely ill patients. Design Longitudinal multilevel growth-modelling of long-term (1–4 years) follow-up cohort data. Setting An outpatient psychiatric clinic specialised in internet interventions. Participants 446 adults having been treated for SAD. Primary and secondary outcome measures Primary outcomes were estimated improvement rate and Cohen9s d effect size on the self-rated Liebowitz Social Anxiety Disorder Scale. Secondary outcome measures were change in comorbid depressive symptoms and health-related quality of life. Results A large treatment effect was observed on the primary outcome measure after treatment (d=0.8 (95% CI 0.7 to 0.9)), with continued long-term improvements (d=1.2 (95% CI 1.0 to 1.3)). However, the rate of change varied significantly between individuals over time. A faster rate of improvement was observed among patients with higher illness severity, whereas having a family history of social anxiety was related to worse response. Long-term improvements were also observed in comorbid depressive symptoms (d=0.7 (95% CI 0.5 to 0.8)) and health-related quality of life (d=−0.3 (95% CI −0.4 to −0.1)). Conclusions These findings provide evidence for the long-term effectiveness of ICBT for SAD in routine clinical practice, even for more severe cases.

Internet-based cognitive-behavioral therapy (ICBT) has received increased attention as an innovative approach to improve access to evidence-based psychological treatments. Although the efficacy of ICBT for social anxiety disorder has been established in several studies, there is limited knowledge of its effectiveness and application in clinical psychiatric care. The purpose of this study was to evaluate the effectiveness of ICBT in the treatment of social anxiety disorder and to determine the significance of patient adherence and the clinic's years of experience in delivering ICBT.A longitudinal cohort study was conducted using latent growth curve modeling of patients (N = 654) treated with ICBT at an outpatient psychiatric clinic between 2009 and 2013. The primary outcome measure was the Liebowitz Social Anxiety Scale-Self-Rated.Significant reductions in symptoms of social anxiety were observed after treatment (effect size d = 0.86, 99% CI [0.74, 0.98]). Improvements were sustained at 6-month follow-up (d = 1.15, 99% CI [0.99, 1.32]). Patient adherence had a positive effect on the rate of improvement. A positive association between the clinic's years of experience with ICBT and treatment outcome was also observed.This study suggests that ICBT for social anxiety disorder is effective when delivered within the context of a unit specialized in Internet-based psychiatric care and may be considered as a treatment alternative for implementation within the mental health care system.

In this report, we describe a newly developed method for isolating outer membranes from Synechocystis sp. PCC 6803 cells. The purity of the outer membrane fraction was verified by immunoblot analysis using antibodies against membrane-specific marker proteins. We investigated the protein composition of the outer membrane using two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry followed by database identification. Forty-nine proteins were identified corresponding to 29 different gene products. All of the identified proteins have a putative N-terminal signal peptide. About 40% of the proteins identified represent hypothetical proteins with unknown function. Among the proteins identified are a Toc75 homologue, a protein that was initially found in the outer envelope of chloroplasts in pea, as well as TolC, putative porins, and a pilus protein. Other proteins identified include ABC transporters and GumB, which has a suggested function in carbohydrate export. A number of proteases such as HtrA were also found in the outer membrane of Synechocystis sp. PCC 6803.

Background Health anxiety can be viewed as a dimensional phenomenon where severe health anxiety in form of DSM-IV hypochondriasis represents a cut-off where the health anxiety becomes clinically significant. Three of the most reliable and used self-report measures of health anxiety are the Health Anxiety Inventory (HAI), the Illness Attitude Scales (IAS) and the Whiteley Index (WI). Identifying the optimal cut-offs for classification of presence of a diagnosis of severe health anxiety on these measures has several advantages in clinical and research settings. The aim of this study was therefore to investigate the HAI, IAS and WI as proximal diagnostic instruments for severe health anxiety defined as DSM-IV hypochondriasis. Methods We investigated sensitivity, specificity and predictive value on the HAI, IAS and WI using a total of 347 adult participants of whom 158 had a diagnosis of severe health anxiety, 97 had obsessive-compulsive disorder and 92 were healthy non-clinical controls. Diagnostic assessments were conducted using the Anxiety Disorder Interview Schedule. Results Optimal cut-offs for identifying a diagnosis of severe health anxiety was 67 on the HAI, 47 on the IAS, and 5 on the WI. Sensitivity and specificity were high, ranging from 92.6 to 99.4%. Positive and negative predictive values ranged from 91.6 to 99.4% using unadjusted prevalence rates. Conclusions The HAI, IAS and WI have very good properties as diagnostic indicators of severe health anxiety and can be used as cost-efficient proximal estimates of the diagnosis. Funding Agencies|Karolinska Insititutet; Stockholm County Council

Background.Internet interventions are assumed to be cost-effective. However, it is unclear how strong this evidence is, and what the quality of this evidence is.Method.A comprehensive literature search (1990–2014) in Medline, EMBASE, the Cochrane Central Register of Controlled Trials, NHS Economic Evaluations Database, NHS Health Technology Assessment Database, Office of Health Economics Evaluations Database, Compendex and Inspec was conducted. We included economic evaluations alongside randomized controlled trials of Internet interventions for a range of mental health symptoms compared to a control group, consisting of a psychological or pharmaceutical intervention, treatment-as-usual (TAU), wait-list or an attention control group.Results.Of the 6587 abstracts identified, 16 papers met the inclusion criteria. Nine studies featured a societal perspective. Results demonstrated that guided Internet interventions for depression, anxiety, smoking cessation and alcohol consumption had favourable probabilities of being more cost-effective when compared to wait-list, TAU, group cognitive behaviour therapy (CBGT), attention control, telephone counselling or unguided Internet CBT. Unguided Internet interventions for suicide prevention, depression and smoking cessation demonstrated cost-effectiveness compared to TAU or attention control. In general, results from cost-utility analyses using more generic health outcomes (quality of life) were less favourable for unguided Internet interventions. Most studies adhered reasonably to economic guidelines.Conclusions.Results of guided Internet interventions being cost-effective are promising with most studies adhering to publication standards, but more economic evaluations are needed in order to determine cost-effectiveness of Internet interventions compared to the most cost-effective treatment currently available.

Background The World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) is a widespread measure of disability and functional impairment, which is bundled with the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) for use in psychiatry. Administering psychometric scales via the Internet is an effective way to reach respondents and allow for convenient handling of data. Objective The aim was to study the psychometric properties of the 12-item self-report WHODAS 2.0 when administered online to individuals with anxiety and stress disorders. The WHODAS 2.0 was hypothesized to exhibit high internal consistency and be unidimensional. We also expected the WHODAS 2.0 to show high 2-week test-retest reliability, convergent validity (correlations approximately .50 to .90 with other self-report measures of functional impairment), that it would differentiate between patients with and without exhaustion disorder, and that it would respond to change in primary symptom domain. Methods We administered the 12-item self-report WHODAS 2.0 online to patients with anxiety and stress disorders (N=160) enrolled in clinical trials of cognitive behavior therapy, and analyzed psychometric properties within a classical test theory framework. Scores were compared with well-established symptom and disability measures, and sensitivity to change was studied from pretreatment to posttreatment assessment. Results The 12-item self-report WHODAS 2.0 showed high internal consistency (Cronbach alpha=.83-.92), high 2-week test-retest reliability (intraclass correlation coefficient=.83), adequate construct validity, and was sensitive to change. We found preliminary evidence for a three-factorial structure, but one strong factor accounted for a clear majority of the variance. Conclusions We conclude that the 12-item self-report WHODAS 2.0 is a psychometrically sound instrument when administered online to individuals with anxiety and stress disorders, but that it is probably fruitful to also report the three subfactors to facilitate comparisons between studies. Trial Registration Clinicaltrials.gov NCT02540317; https://clinicaltrials.gov/ct2/show/NCT02540317 (Archived by WebCite at http://www.webcitation.org/6vQEdYAem); Clinicaltrials.gov NCT02314065; https://clinicaltrials.gov/ct2/show/NCT02314065 (Archived by WebCite at http://www.webcitation.org/6vQEjlUU8)

ObjectivesSocial anxiety disorder (SAD) can be effectively treated with internet-delivered cognitive behavioural therapy (ICBT), but studies on long-term cost minimisation from a healthcare provider perspective in comparison to an evidence-based control treatment of therapeutic equivalence are lacking. The objective of the study was to determine whether ICBT reduces healthcare costs and use of healthcare resources compared with cognitive behavioural group therapy (CBGT).DesignA cost-minimisation study alongside a randomised controlled trial where participants (n=126) with SAD were randomised to ICBT or to CBGT. Costs measured from a healthcare provider perspective were estimated using time-driven activity-based costing alongside health status over 4 years from baseline measured with EQ-5D.SettingA psychiatric outpatient clinic in Stockholm, Sweden.ParticipantsParticipants were 126 individuals with SAD.Primary outcome measuresChanges in EQ-5D and costs.InterventionsParticipants received either CBGT or ICBT for a duration of 15 weeks.ResultsICBT minimised healthcare costs and demonstrated health improvements within the non-inferiority margin. Assuming a practical work capacity for personnel varying between 100%, 80% and 50% of theoretical full capacity, the cost for ICBT varied in the range between 400€, 463€ and 654 €, while the cost for CBGT varied between 699€, 806€ and 1134€. Within-group effect size was −0.36 (95% CI −0.70 to −0.01) for ICBT and −0.25 (95% CI −0.60 to 0.10) for CBGT. Mean use of effective psychologist time in ICBT was 189.60 (SD=53.77) minutes compared with 499.78 (SD=30.91) in the CBGT group.ConclusionsIn treatment of SAD, ICBT is equally effective but is associated with more efficient staff utilisation and less costs compared with CBGT. From a healthcare provider perspective, ICBT is an advantageous treatment option.Trial registration number

Severe health anxiety can be effectively treated with exposure-based Internet-delivered cognitive behavior therapy (ICBT), but information about which factors that predict outcome is scarce. Using data from a recently conducted RCT comparing ICBT (n = 79) with Internet-delivered behavioral stress management (IBSM) (n = 79) the presented study investigated predictors of treatment outcome. Analyses were conducted using a two-step linear regression approach and the dependent variable was operationalized both as end state health anxiety at post-treatment and as baseline-to post-treatment improvement. A hypothesis driven approach was used where predictors expected to influence outcome were based on a previous predictor study by our research group. As hypothesized, the results showed that baseline health anxiety and treatment adherence predicted both end state health anxiety and improvement. In addition, anxiety sensitivity, treatment credibility, and working alliance were significant predictors of health anxiety improvement. Demographic variables, i.e. age, gender, marital status, computer skills, educational level, and having children, had no significant predictive value. We conclude that it is possible to predict a substantial proportion of the outcome variance in ICBT and IBSM for severe health anxiety. The findings of the present study can be of high clinical value as they provide information about factors of importance for outcome in the treatment of severe health anxiety.

BackgroundExposure-based cognitive–behavioural therapy (CBT) delivered via the internet has been shown to be effective for severe health anxiety (hypochondriasis) but has not been compared with an active, effective and credible psychological treatment, such as behavioural stress management (BSM).AimsTo investigate two internet-delivered treatments – exposure-based CBTv.BSM – for severe health anxiety in a randomised controlled trial (trial registration: NCT01673035).MethodParticipants (n= 158) with a principal diagnosis of severe health anxiety were allocated to 12 weeks of exposure-based CBT (n= 79) or BSM (n= 79) delivered via the internet. The Health Anxiety Inventory (HAI) was the primary outcome.ResultsInternet-delivered exposure-based CBT led to a significantly greater improvement on the HAI compared with BSM. However, both treatment groups made large improvements on the HAI (pre-to-post-treatment Cohen'sd: exposure-based CBT, 1.78; BSM, 1.22).ConclusionsExposure-based CBT delivered via the internet is an efficacious treatment for severe health anxiety.Declarations of interestNone.

BackgroundAs relapse after completed cognitive behavior therapy (CBT) for obsessive–compulsive disorder (OCD) is common, many treatment protocols include booster programs to improve the long-term effects. However, the effects of booster programs are not well studied. In this study, we investigated the long-term efficacy of Internet-based CBT (ICBT) with therapist support for OCD with or without an Internet-based booster program.MethodA total of 101 participants were included in the long-term follow-up analysis of ICBT. Of these, 93 were randomized to a booster program or no booster program. Outcome assessments were collected at 4, 7, 12 and 24 months after receiving ICBT.ResultsThe entire sample had sustained long-term effects from pre-treatment to all follow-up assessments, with large within-group effect sizes (Cohen's d = 1.58–2.09). The booster group had a significant mean reduction in OCD symptoms compared to the control condition from booster baseline (4 months) to 7 months, but not at 12 or 24 months. Participants in the booster group improved significantly in terms of general functioning at 7, 12 and 24 months, and had fewer relapses. Kaplan–Meier analysis also indicated a significantly slower relapse rate in the booster group.ConclusionsThe results suggest that ICBT has sustained long-term effects and that adding an Internet-based booster program can further improve long-term outcome and prevent relapse for some OCD patients.

Although cognitive interventions for obsessive-compulsive disorder (OCD) have been tested in randomized trials, there are few trials that have tested the specific mechanisms of cognitive interventions, i.e. how they achieve their effects. In this study, we aimed to investigate the mediating effects of a short cognitive intervention in the treatment of OCD and used data from a recently conducted randomized controlled trial where 101 participants were allocated to either Internet-based CBT (ICBT) or to a control condition. Obsessive beliefs were measured at pre-treatment, at the time they had received the cognitive intervention, and also at post-treatment. Weekly OCD symptoms were measured throughout the 10 weeks of treatment. We hypothesized that (1) the ICBT group would have greater reductions in obsessive beliefs (controlling for change in OCD symptoms) after completing the cognitive intervention, and that (2) this reduction would, in turn, predict greater OCD symptom reduction throughout the rest of the treatment period. Contrary to our expectations, the longitudinal mediation analysis indicated that (1) being randomized to ICBT actually increased the degree of obsessive beliefs after receiving the cognitive intervention at weeks 1-3, and (2) increase in obsessive beliefs predicted better outcome later in treatment. However, when repeating the analysis using cross-sectional data at post-treatment, the results were in line with the initial hypotheses. Results were replicated when the control condition received ICBT. We conclude that, although obsessive beliefs were significantly reduced at post-treatment for the ICBT group, early increase rather than decrease in obsessive beliefs predicted favourable outcome.This study investigated the impact of cognitive interventions on obsessive beliefs for patients with obsessive-compulsive disorder. Results showed that a sudden increase in obsessive beliefs is not an indicator of worse treatment response. On the contrary, it is more likely that the patient is better off when having this sudden increase. Clinicians should not be alarmed if the patient has a sudden increase in obsessive beliefs, but we do recommend the clinician to investigate the reasons for this further.

Can be highly effective and is used to increase access to psychological treatment There are two main forms of internet delivered cognitive behavioural therapy—fully automated open access programmes without therapist contact and programmes guided by a therapist, which are conducted in a context similar to that of regular healthcare. This editorial focuses on therapy that is guided by a therapist, with scheduling that mirrors face to face treatment.1 Because the mechanisms for improvement are the same for internet delivered cognitive behavioural therapy as for face to face therapy, the patient should be exposed to the same interventions. So, if exposure to a feared object—such as snakes in patients with a phobia about snakes—is important in face to face therapy, then it is equally important in internet delivered therapy. In essence, internet delivered therapy is not a new treatment in itself but rather a new framework for providing psychological treatments. The patient accesses the treatment through a personal account in a secure internet based treatment platform. The most important elements of the treatment are modules, often eight to 15, whose content reflects that of sessions in face to face therapy and provides …

PurposePatients' problematic substance use prevalence and effects were explored in relation to internet-based cognitive behavioral therapy (ICBT) outcomes for depression, panic disorder and social anxiety disorder.MethodsAt baseline and treatment conclusion, 1601 ICBT patients were assessed with self-rated measures for alcohol and drug use (AUDIT/DUDIT), depressive symptoms (MADRS-S), panic disorder symptoms (PDSS-SR) and social anxiety symptoms (LSAS-SR).ResultsProblematic substance use (AUDIT ≥ 8 for men, ≥ 6 for women; DUDIT ≥ 1) occurred among 32.4% of the patients; 24.1% only alcohol, 4.6% only drugs, and 3.7% combined alcohol and drug use. Hazardous alcohol use and probable alcohol dependence negatively affected panic disorder outcomes, and hazardous drug use led to worse social anxiety outcomes. Depression outcomes were not affected by substance use. Treatment adherence was negatively affected by problematic drug use among men and 25-34 year olds; combined substance use negatively affected adherence for women and 35-64 year olds.ConclusionProblematic substance use does not preclude ICBT treatment but can worsen outcomes, particularly problematic alcohol use for panic disorder patients and hazardous drug use for social anxiety patients. ICBT clinicians should exercise particular caution when treating men and younger patients with problematic drug use, and women or older patients with combined substance use.

Background: Several studies show that psychological treatments relieve symptoms for patients suffering from irritable bowel syndrome (IBS). However, there are no consistent findings that show what patient characteristics make a psychological treatment more or less likely to result in improvement. We have previously conducted a study of a newly developed internet-delivered cognitive behavioral therapy (ICBT) that emphasized exposure to IBS symptoms and IBS-related situations and reduced symptom-related avoidance. The study showed that the treatment led to improvement in IBS symptoms compared to a waiting list and that treatment gains were maintained over a 15-18 month follow-up period. The aim of the present study was to investigate several possible predictors of short-and long-term treatment outcome in terms of symptom improvement, based on data collected in the previously conducted treatment trial. less thanbrgreater than less thanbrgreater thanMethods: Demographics, comorbid psychological distress, IBS-related fear and avoidance behaviors, and IBS-related disability were investigated as predictors of treatment outcome in the sample consisting of 79 participants diagnosed with IBS who had undergone 10 weeks of ICBT. Predictors that were significantly correlated with symptom levels at post-treatment and follow-up were entered into multiple regression analyses that controlled for pre-treatment symptom levels. less thanbrgreater than less thanbrgreater thanResults: There were measures within each domain, i.e., comorbid psychological distress, IBS-related fear and avoidance behaviors, and IBS-related disability, with the exception of demographic data, that were correlated with the symptom levels at post-treatment and follow-up. However, when these were entered into a multiple regression analyses that controlled for pre-treatment levels, none remained a significant predictor of the post-treatment and follow-up symptomatic status. less thanbrgreater than less thanbrgreater thanConclusions: The study did not find any individual characteristics that made patients more or less likely to respond to the exposure-based ICBT. The finding that comorbid psychological distress did not predict outcome is in accordance with previous studies. Reliable predictors for response to any type of psychological treatment for IBS remain to be established.

Acceptance and commitment therapy (ACT) is a promising treatment option for fibromyalgia (FM). Studies have shown that many cognitive behavioral protocols can be transferred to the Internet with sustained efficacy. However, no study has investigated the effect on an Internet-delivered ACT-based protocol for FM. This study evaluated the efficacy, acceptability, and the health economic effects of an Internet-delivered acceptance and values-based exposure treatment for FM.This open pilot trial included 41 self-referred women with a FM diagnosis. The 10-week Internet-delivered treatment included acceptance, mindfulness, work with life-values, and systematic exposure to FM symptoms and FM-related situations. Participants also had regular contact with an assigned online therapist. Assessments were made at pretreatment, post-treatment, and 6-month follow-up.The treatment was completed by 70% of the participants. Attrition rates were low, with 98% completing the post-treatment assessment and 90% completing the 6-month follow-up assessment. Multiple imputations were used to replace missing values. Pre- to post-treatment within-group effect sizes were in the moderate to large range (Cohen's d = 0.62-1.56) on measures of FM symptoms and impact, disability, quality of life, depression, anxiety, fatigue, and psychological flexibility. All improvements were maintained at follow-up. Economical analyses revealed significant societal cost reductions that offset the treatment costs within 2 months of treatment completion.An Internet-delivered psychological treatment based on acceptance and exposure principles seems to be an efficacious, acceptable, and cost-effective treatment for FM. Randomized controlled trials are needed to confirm these results.

Background: Internet-administered self-report measures of social anxiety, depressive symptoms, and sleep difficulties are widely used in clinical trials and in clinical routine care, but data loss is a common problem that could render skewed estimates of symptom levels and treatment effects. One way of reducing the negative impact of missing data could be to use telephone administration of self-report measures as a means to complete the data missing from the online data collection. Objective: The aim of the study was to compare the convergence of telephone and Internet administration of self-report measures of social anxiety, depressive symptoms, and sleep difficulties. Methods: The Liebowitz Social Anxiety Scale-Self-Report (LSAS-SR), Montgomery-Asberg Depression Rating Scale-Self-Rated (MADRS-S), and the Insomnia Severity Index (ISI) were administered over the telephone and via the Internet to a clinical sample (N=82) of psychiatric patients at a clinic specializing in Internet-delivered treatment. Shortened versions of the LSAS-SR and the ISI were used when administered via telephone. Results: As predicted, the results showed that the estimates produced by the two administration formats were highly correlated ( r =.82-.91; P

A significant proportion of the general population suffers from anxiety disorders, often with comorbid psychiatric conditions. Internet-delivered cognitive behavior therapy (ICBT) has been found to be a potent treatment for patients with specific psychiatric conditions. The aim of this trial was to investigate the effectiveness and cost-effectiveness of ICBT when tailoring the treatment to address comorbidities and preferences for primary-care patients with a principal anxiety disorder. One hundred participants were recruited through their primary-care contact and randomized to either treatment or an active control group. The treatment consisted of 7–10 weekly individually assigned modules guided by online therapists. At post-treatment, 46% of the treatment group had achieved clinically significant improvement on the primary outcome measure (CORE-OM) and between-group effect sizes ranged from d = 0.20 to 0.86, with a mean effect of d = 0.59. At one-year follow-up, within-group effect sizes varied between d = 0.53 to 1.00. Cost analysis showed significant reduction of total costs for the ICBT group, the results were maintained at one-year follow-up and the incremental cost-effectiveness ratio favored ICBT compared to control group. Individually tailored ICBT is an effective and cost-effective treatment for primary-care patients with anxiety disorders with or without comorbidities.Trial RegistrationClinicaltrials.gov: NCT01390168.

A sudden gain is defined as a large and stable individual improvement occurring between two consecutive treatment sessions. Sudden gains have been shown to predict better long-term improvement in several treatment studies, including cognitive behavioural therapy for depression and anxiety disorders, but have not been studied in the treatment of health anxiety or any form of internet-based cognitive behavioural therapy. The aim of this study was to investigate the role of sudden gains in internet-based cognitive behavioural therapy for severe health anxiety.We examined the occurrence and significance of sudden gains in measures of health anxiety in 81 participants receiving internet-based cognitive behavioural therapy. We compared patients with sudden gains, patients without sudden gains, and patients with gradual gains.Thirteen participants (16%) experienced one sudden gain in health anxiety with individual sudden gains distributed across the treatment. As expected, patients with a sudden gain showed larger improvements than patients without a sudden gain at post-treatment (d = 1.04) and at one-year follow-up (d = 0.91) on measures of health anxiety.Consistent with previous studies, sudden gains in internet-based cognitive behavioural therapy are associated with significantly larger and stable treatment effects up to one-year follow-up.

The aim of this study was to identify mediators of change in a previously published randomized controlled trial that compared Internet-delivered cognitive behavioral treatment based on exposure exercises (ICBT) with Internet-delivered stress management (ISM) for irritable bowel syndrome (IBS). ICBT and ISM targeted distinct proposed mechanisms of illness maintenance and symptom exacerbation, gastrointestinal symptom-specific anxiety (GSA), and stress reactivity, respectively. The original study found that ICBT was more effective than ISM in improving IBS symptoms.Weekly measurements of GSA and stress reactivity (putative mediators) and treatment outcome were obtained from 195 participants with IBS, who had been randomized to ICBT or ISM.Parallel process growth mediational analyses revealed that the larger reduction of IBS symptoms from ICBT compared to ISM was mediated by changes in GSA, αβ = -0.42, 95% CI asymmetric [-0.71, -0.16]. In contrast, changes in stress reactivity did not mediate the difference in outcomes between treatments, αβ = 0.04, 95% CI asymmetric [-0.09, 0.20]. Analyses of the temporal sequence of week-to-week changes in process and outcome measures showed that only GSA displayed a pattern consistent with a causal model in which change in process preceded and contributed to symptom change. Furthermore, engagement in treatment specific activities was related to change in GSA but not to stress reactivity in the ICBT arm, whereas treatment specific activities were not related to change in any of the putative processes in the ISM arm.We conclude that ICBT works through directly targeting GSA, rather than by means of reducing stress reactivity.

Social anxiety disorder (SAD), characterized by fear of being scrutinized by others, has features that that are closely linked to the concept of shame. Despite this, it remains to be investigated whether shame is elevated in persons with SAD, and if cognitive behavior therapy (CBT) for SAD could reduce shame experience. In the present study, we focused on internal shame, i.e. the type of shame that pertains to how we judge ourselves. Although guilt is distinctly different from shame, we also viewed it as important to investigate its role in SAD as the two emotions are highly correlated. The aim of this study was to investigate: (I) if persons with SAD differ from healthy controls on shame and guilt, (II) if shame, guilt, depressive symptoms, and social anxiety are associated in persons with SAD, and (III) if CBT can reduce internal shame in patients with SAD. Firstly, we conducted a case-control study comparing a sample with SAD (n = 67) with two samples of healthy controls, a main sample (n = 72) and a replication sample (n = 22). Secondly, all participants with SAD were treated with CBT and shame, measured with the Test of Self-Conscious affect, was assessed before and after treatment. The results showed that shame was elevated in person with SAD compared to the control replication sample, but not to the main control sample. In addition, shame, social anxiety, and depressive symptoms were significantly associated among participants with SAD. After CBT, participants with SAD had significantly reduced their shame (Cohen's d = 0.44). Guilt was unrelated to social anxiety. We conclude that shame and social anxiety are associated and that it is likely that persons with SAD are more prone to experience shame than persons without SAD. Also, CBT is associated with shame reduction in the treatment of SAD.

According to cognitive-behavioral models of social anxiety disorder (SAD), four of the important maintaining mechanisms are avoidance, self-focused attention, anticipatory processing and post-event cognitive processing. Individual cognitive therapy (ICT) and cognitive behavioral group therapy (CBGT) both have substantial empirical support. However, it is unclear whether they achieve their effects by similar or different mechanisms. The aim of this study was to investigate whether changes in the four maintenance processes mediate clinical improvement in ICT and CBGT for SAD. We analyzed data from participants (N = 94) who received either ICT or CBGT in two separate RCTs. The results showed that ICT had larger effects than CBGT on social anxiety and each of the four potential mediators. More pertinently, moderated mediation analyses revealed significant between-treatment differences. Whereas improvement in ICT was mainly mediated by reductions in avoidance and self-focused attention, improvement in CBGT was mediated by changes in self-focused attention and in anticipatory and post-event processing. These results support the importance of the putative mediators, but suggest that their relative weights are moderated by treatment type.

Objective The role of genetics for predicting the response to cognitive behavior therapy (CBT) for social anxiety disorder (SAD) has only been studied in one previous investigation. The serotonin transporter (5-HTTLPR), the catechol-o-methyltransferase (COMT) val158met, and the tryptophan hydroxylase-2 (TPH2) G-703Tpolymorphisms are implicated in the regulation of amygdala reactivity and fear extinction and therefore might be of relevance for CBT outcome. The aim of the present study was to investigate if these three gene variants predicted response to CBT in a large sample of SAD patients. Method Participants were recruited from two separate randomized controlled CBT trials (trial 1: n = 112, trial 2: n = 202). Genotyping were performed on DNA extracted from blood or saliva samples. Effects were analyzed at follow-up (6 or 12 months after treatment) for both groups and for each group separately at post-treatment. The main outcome measure was the Liebowitz Social Anxiety Scale Self-Report. Results At long-term follow-up, there was no effect of any genotype, or gene × gene interactions, on treatment response. In the subsamples, there was time by genotype interaction effects indicating an influence of the TPH2 G-703T-polymorphism on CBT short-term response, however the direction of the effect was not consistent across trials. Conclusions None of the three gene variants, 5-HTTLPR, COMTval158met and TPH2 G-703T, was associated with long-term response to CBT for SAD. Trial Registration ClinicalTrials.gov (ID-NCT0056496)

Internet-based cognitive behaviour therapy (ICBT) can be equally effective as traditional face-to-face cognitive behaviour therapy (CBT) for treating panic disorder (PD). However, little is known about the predictors and moderators of outcome of ICBT when delivered in psychiatric outpatient settings. This study investigated a selection of outcome predictors and moderators of ICBT for panic disorder based on data from a randomised controlled trial where therapist-guided ICBT was compared with group CBT (GCBT) for panic disorder. Participants (N = 104) received 10 weeks of ICBT or GCBT and were assessed before and after treatment, and after six months. Multiple regression analyses were used to test for significant predictors of treatment outcome. Predictors of positive treatment response for both modalities were having low levels of symptom severity and work impairment. In addition, anxiety sensitivity was found to have a small negative relationship with treatment outcome, suggesting that anxiety sensitivity may slightly enhance treatment response. Treatment modality had a moderating effect on the relationship between domestic impairment and outcome and on the relationship between initial age of onset of panic symptoms and treatment outcome, favouring ICBT for patients having had an early onset of PD symptoms and for patients having a high domestic functional impairment. These results suggest that both ICBT and GCBT are effective treatment modalities for PD and that it is possible to predict a significant proportion of the long-term outcome variance based on clinical variables.

Our research group has developed an internet-delivered cognitive behavioral treatment (ICBT) for irritable bowel syndrome (IBS). We compared ICBT with internet-delivered stress management (ISM) for IBS to assess whether the effects of ICBT are specific.This was a randomized controlled trial, including 195 self-referred participants diagnosed with IBS. The treatment interventions lasted for 10 weeks and included an online therapist contact. The ICBT emphasized acceptance of symptoms through exposure to IBS symptoms and related negative feelings. The ICBT also included mindfulness training. The ISM emphasized symptom control through relaxation techniques, dietary adjustments, and problem-solving skills. Severity of IBS symptoms was measured with the gastrointestinal symptom rating scale-IBS version (GSRS-IBS). Credibility of the treatments and expectancy of improvement were assessed with the treatment credibility scale. The participants' perceived therapeutic alliance with their online therapist was measured with the working alliance inventory.At post-treatment and 6-month follow-up, 192 (99%) and 169 (87%) participants returned data, respectively. At post-treatment and 6-month follow-up, we found significant differences on the GSRS-IBS, favoring ICBT. The difference on GSRS-IBS scores was 4.8 (95% confidence interval (CI): 1.2-8.4) at post-treatment and 5.9 (95% CI: 1.9-9.9) at 6-month follow-up. There were no significant differences on the treatment credibility scale or the working alliance inventory between the groups.Internet-delivered CBT has specific effects that cannot be attributed only to treatment credibility, expectancy of improvement, therapeutic alliance, or attention. Furthermore, a treatment based on exposure exercises specifically tailored for IBS may be a better treatment option than general stress and symptom management for IBS patients. ICBT is a promising treatment modality for IBS as it can be offered to IBS patients in much larger scale than conventional psychological treatments.

Social anxiety disorder (SAD) is highly prevalent and associated with a substantial societal economic burden, primarily due to high costs of productivity loss. Cognitive behavior group therapy (CBGT) is an effective treatment for SAD and the most established in clinical practice. Internet-based cognitive behavior therapy (ICBT) has demonstrated efficacy in several trials in recent years. No study has however investigated the cost-effectiveness of ICBT compared to CBGT from a societal perspective, i.e. an analysis where both direct and indirect costs are included. The aim of the present study was to investigate the cost-effectiveness of ICBT compared to CBGT from a societal perspective using a prospective design. We conducted a randomized controlled trial where participants with SAD were randomized to ICBT (n=64) or CBGT (n=62). Economic data were assessed at pre-treatment, immediately following treatment and six months after treatment. Results showed that the gross total costs were significantly reduced at six-month follow-up, compared to pre-treatment in both treatment conditions. As both treatments were equivalent in reducing social anxiety and gross total costs, ICBT was more cost-effective due to lower intervention costs. We conclude that ICBT can be more cost-effective than CBGT in the treatment of SAD and that both treatments reduce societal costs for SAD.

Background: Internet-based cognitive behavior therapy (ICBT) has shown promising effects in the treatment of irritable bowel syndrome (IBS). However, to date no study has used a design where participants have been sampled solely from a clinical population. We aimed to investigate the acceptability, effectiveness, and cost-effectiveness of ICBT for IBS using a consecutively recruited sample from a gastroenterological clinic. less thanbrgreater than less thanbrgreater thanMethods: Sixty-one patients were randomized to 10 weeks of ICBT (n = 30) or a waiting list control (n = 31). The ICBT was guided by an online therapist and emphasized acceptance of symptoms through exposure and mindfulness training. Severity of IBS symptoms was measured with the Gastrointestinal symptom rating scale - IBS version (GSRS-IBS). Patients in both groups were assessed at pre- and post-treatment while only the ICBT group was assessed 12 months after treatment completion. Health economic data were also gathered at all assessment points and analyzed using bootstrap sampling. less thanbrgreater than less thanbrgreater thanResults: Fifty of 61 patients (82%) completed the post-treatment assessment and 20 of 30 patients (67%) in the ICBT group were assessed at 12-month follow-up. The ICBT group demonstrated significantly (p andlt; .001) larger improvements on the IBS-related outcome scales than the waiting list group. The between group effect size on GSRS-IBS was Cohens d = 0.77 (95% CI: 0.19-1.34). Similar effects were noted on measures of quality of life and IBS-related fear and avoidance behaviors. Improvements in the ICBT group were maintained at 12-month follow-up. The ICBT condition was found to be more cost-effective than the waiting list, with an 87% chance of leading to reduced societal costs combined with clinical effectiveness. The cost-effectiveness was sustained over the 12-month period. less thanbrgreater than less thanbrgreater thanConclusions: ICBT proved to be a cost-effective treatment when delivered to a sample recruited from a gastroenterological clinic. However, many of the included patients dropped out of the study and the overall treatment effects were smaller than previous studies with referred and self-referred samples. ICBT may therefore be acceptable and effective for only a subset of clinical patients. Study dropout seemed to be associated with severe symptoms and large impairment. Objective and empirically validated criteria to select which patients to offer ICBT should be developed. Funding Agencies|Stockholm City Council||Stockholm Centre for Psychiatry Research, Linkoping University||Soderstrom-Konigska Foundation||Bror Gadelius Foundation

Background: Irritable Bowel Syndrome (IBS) is highly prevalent and is associated with a substantial economic burden. Cognitive behavior therapy (CBT) has been shown to be effective in treating IBS. The aim of this study was to evaluate the cost-effectiveness of a new treatment alternative, internet-delivered CBT based on exposure and mindfulness exercises. Methods: Participants (N = 85) with IBS were recruited through self-referral and were assessed via a telephone interview and self-report measures on the internet. Participants were randomized to internet-delivered CBT or to a discussion forum. Economic data was assessed at pre-, post- and at 3-month and 1 year follow-up. Results: Significant cost reductions were found for the treatment group at $16,806 per successfully treated case. The cost reductions were mainly driven by reduced work loss in the treatment group. Results were sustained at 3-month and 1 year follow-up. Conclusions: Internet-delivered CBT appears to generate health gains in IBS treatment and is associated with cost-savings from a societal perspective. Original Publication:Erik Andersson, Brjann Ljotsson, Filip Smit, Björn Paxling, Erik Hedman, Nils Lindefors, Gerhard Andersson and Christian Ruck, Cost-effectiveness of internet-based cognitive behavior therapy for irritable bowel syndrome: results from a randomized controlled trial, 2011, BMC PUBLIC HEALTH, (11), 215.http://dx.doi.org/10.1186/1471-2458-11-215Licensee: BioMed Centralhttp://www.biomedcentral.com/

Background: Cognitive behavior therapy (CBT) is widely regarded as an effective treatment for obsessive compulsive disorder (OCD), but access to CBT therapists is limited. Internet-based CBT (ICBT) with therapist support is a way to increase access to CBT but has not been developed or tested for OCD. The aim of this study was to evaluate ICBT for OCD. less thanbrgreater than less thanbrgreater thanMethod: An open trial where patients (N = 23) received a 15-week ICBT program with therapist support consisting of psychoeducation, cognitive restructuring and exposure with response prevention. The primary outcome was the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), which was assessed by a psychiatrist before and immediately after treatment. Secondary outcomes were self-rated measures of OCD symptoms, depressive symptoms, general functioning, anxiety and quality of life. All assessments were made at baseline and post-treatment. less thanbrgreater than less thanbrgreater thanResults: All participants completed the primary outcome measure at all assessment points. There were reductions in OCD symptoms with a large within-group effect size (Cohens d = 1.56). At post-treatment, 61% of participants had a clinically significant improvement and 43% no longer fulfilled the diagnostic criteria of OCD. The treatment also resulted in statistically significant improvements in self-rated OCD symptoms, general functioning and depression. less thanbrgreater than less thanbrgreater thanConclusions: ICBT with therapist support reduces OCD symptoms, depressive symptoms and improves general functioning. Randomized trials are needed to confirm the effectiveness of this new treatment format. Funding Agencies|Swedish Research Council||Soderstromska-Konigska Foundation||Stockholm County Council

The aim of this study was to investigate if cognitive behavior therapy (CBT) based on exposure and mindfulness exercises delivered via the Internet would be effective in treating participants with irritable bowel syndrome (IBS). Participants were recruited through self-referral. Eighty-six participants were included in the study and randomized to treatment or control condition (an online discussion forum). One participant was excluded after randomization. The main outcome measure was IBS-symptom severity and secondary measures included IBS-related quality of life, GI-specific anxiety, depression and general functioning. Participants were assessed at pre-treatment, post-treatment and 3 month follow-up (treatment condition only). Four participants (5% of total sample) in the treatment condition did not participate in post-treatment assessment. Participants in the treatment condition reported a 42% decrease and participants in the control group reported a 12% increase in primary IBS-symptoms. Compared to the control condition, participants in the treatment group improved on all secondary outcome measures with a large between group effect size on quality of life (Cohen's d = 1.21). We conclude that CBT-based on exposure and mindfulness delivered via the Internet can be effective in treating IBS-patients, alleviating the total burden of symptoms and increasing quality of life.

We conducted a study of a group therapy based on exposure and mindfulness in the treatment of irritable bowel syndrome (IBS). Out of 49 outpatients, most of whom were referred from gastroenterological clinics, 34 entered into the 10-week treatment. Patients were assessed before, immediately after and 6 months after treatment. The assessments consisted of a gastrointestinal symptom diary, self-report questionnaires covering quality of life, gastrointestinal specific anxiety, general functioning, and a psychiatric interview. At post-treatment, the mean reduction in symptoms was 41% and 50% of patients showed clinically significant improvement in symptom level. Patients also showed marked improvement on other outcome measures. Treatment gains were maintained at follow-up. The results support the use of exposure and mindfulness based strategies in the treatment of IBS, but further randomised studies are needed to confirm the efficacy of the treatment.

The glucocorticoid receptor (GR) forms part of a multiprotein complex consisting of chaperones and proteins active in glucocorticoid signaling and other pathways. By immunoaffinity purification of GR, followed by Edman sequencing and Western blotting, we identified the FMS-like tyrosine kinase 3 (Flt3) as a GR-interacting protein in rat liver and hepatoma cells. Flt3 interacts with both non-liganded and liganded GR. The DNA-binding domain of GR is sufficient for Flt3 interaction as shown by GST-pull down experiments. Studies of the effects of Flt3 and its ligand FL in glucocorticoid-driven reporter-gene assays in Cos7 cells, show that co-transfection with Flt3 and FL potentiates glucocorticoid effects. Treatment with FL had no effect on GR location and Dex induced translocation of GR was unaffected by FL. In summary, GR and Flt3 interact, affecting GR signaling. This novel cross-talk between GR and a hematopoietic growth factor might also imply glucocorticoid effects on Flt3-mediated signaling.

Health anxiety is characterized by a persistent and debilitating worry of somatic illness, as well as of avoidance behaviours. However, little is known of the cognitive mechanisms involved. We hypothesized that a higher degree of health anxiety would relate to an altered interpretation of other people’s health status and that this would be driven by disgust and a fear for becoming sick. We recruited 225 participants with a varying degree of health anxiety (of which 132 were patients suffering from severe health anxiety). The participants rated facial photographs of other individuals with a varying degree of appeared sickness. A higher degree of health anxiety was related to perceiving other people as less healthy, being more contagious, and that they had a higher risk of becoming infected if meeting these people (p’s .05), particularly if people looked more sick. Health anxiety was also related to increased feelings of disgust and anxiety of other people (p’s .05). Our data supports that disgust and cognitive biases of other peoples’ health status are significant features of severe health anxiety. We propose that a heightened sensitivity to whether other people are contagious (pathogenic threats) or not, have been beneficial throughout evolution, allowing for “disease avoidance”, but that this can have debilitating effects in a society with many people and a high demand for social interactions.

It is unclear whether d-cycloserine (DCS), a partial N-methyl-d-aspartate agonist that enhances fear extinction, can augment the effects of exposure-based cognitive behavioral therapy (CBT) for obsessive-compulsive disorder (OCD).To examine whether DCS augments the effects of CBT for OCD and to explore (post hoc) whether concomitant antidepressant medication moderates the effects of DCS.A 12-week, double-blind randomized clinical trial with 3-month follow-up conducted at an academic medical center between September 4, 2012, and September 26, 2013. Participants included 128 adult outpatients with a primary diagnosis of OCD and a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of 16 or higher. Concurrent antidepressant medication was permitted if the dose had been stable for at least 2 months prior to enrollment and remained unchanged during the trial. The main analysis was by intention-to-treat population.All participants received a previously validated Internet-based CBT protocol over 12 weeks and were randomized to receive either 50 mg of DCS or placebo, administered 1 hour before each of 5 exposure and response prevention tasks.Clinician-administered Y-BOCS score at week 12 and at 3-month follow-up. Remission was defined as a score of 12 or lower on the Y-BOCS.In the primary intention-to-treat analyses, DCS did not augment the effects of CBT compared with placebo (mean [SD] clinician-rated Y-BOCS score, DCS: 13.86 [6.50] at week 12 and 12.35 [7.75] at 3-month follow-up; placebo: 11.77 [5.95] at week 12 and 12.37 [6.68] at 3-month follow-up) but showed a significant interaction with antidepressants (clinician-rated Y-BOCS, B = -1.08; Z = -2.79; P = .005). Post hoc analyses revealed that antidepressants significantly impaired treatment response in the DCS group but not the placebo group, at both posttreatment and follow-up (clinician-rated Y-BOCS: t62 = -3.00; P = .004; and t61 = -3.49; P .001, respectively). In the DCS group, a significantly greater proportion of antidepressant-free patients achieved remission status at follow-up (60% [95% CI, 45%-74%]) than antidepressant-medicated patients (24% [95% CI, 9%-48%]) (P = .008). Antidepressants had no effect in the placebo group (50% [95% CI, 36%-64%] remission rate in both groups).The findings suggest that antidepressants may interact with DCS to block its facilitating effect on fear extinction. Use of DCS may be a promising CBT augmentation strategy but only in antidepressant-free patients with OCD.clinicaltrials.gov Identifier: NCT01649895.

In this study, we used ob/ob mice as a model to investigate the effects of long-term estradiol administration on insulin sensitivity and to explore the mechanisms that underlie the antidiabetic effects of estrogen on mouse liver. Female ob/ob mice were randomly divided into two groups and given estradiol (100 microg/kg.d) or vehicle alone for 4 wk. Estrogen administration improved glucose tolerance and insulin response to glucose in ob/ob mice. Moreover, insulin resistance and liver triglyceride levels were decreased in response to estrogen administration. Microarray analysis revealed that expression of genes involved in hepatic lipid biosynthesis was decreased in ob/ob mouse livers after estradiol treatment. Further searches for direct estrogen target genes revealed increased hepatic mRNA expression of signal transducer and activator of transcription 3 (Stat3) and several known Stat3 target genes in ob/ob livers after long-term estradiol treatment. Furthermore, Stat3 and phosphorylated Stat3 protein is induced in ob/ob mouse liver after long-term estrogen treatment. We also present data showing that Stat3 is rapidly induced by estradiol in mouse livers. This, together with data showing recruitment of ERalpha to the promoter of Stat3 in vivo, suggests that Stat3 is a direct target gene for estradiol. In conclusion, estradiol treatment improves glucose tolerance and insulin sensitivity in ob/ob mice. We propose that this may be mediated, at least partially, via estrogen stimulation of the hepatic expression of Stat3, leading to decreased expression of hepatic lipogenic genes, and thereby to antidiabetic effects.

The glucocorticoid receptor (GR) acts as a ligand dependent transcription factor but can also cross talk with other signaling pathways via protein-protein interactions. In this paper we describe methods to study novel cytosolic GR interacting proteins, using mAb based immunoaffinity chromatography of GR from rat liver cytosol. Co-purifying proteins were identified by 2-DE in combination with MALDI-TOF-MS. Non-liganded/non-activated and in vitro liganded/activated GR, respectively, co-purifies with specific sets of proteins. Of these 34 were conclusively identified, seven have previously been reported to be part of the GR-complex, revealing 27 new possible interacting candidates for the GR-complex. Of the novel GR interacting proteins the major vault protein, TATA binding interacting protein 49a and glycoprotein PP63 were of special interest. Furthermore, using 2-D DIGE we show that the set of proteins interacting with non-liganded GR is distinctly different in protein amount compared to the proteins found with liganded/activated GR. This suggests the presence of different GR complexes in the cell, which was further substantiated by the finding of several separate GR native protein complexes, "GR-receptosomes", using blue native gel electrophoresis. Our findings suggest the existence of several new mechanisms for GR signaling and regulation.

the association with foregut symptoms. Methods: We conducted a retrospective review of the medical notes and electronic patient records for all children diagnosed with JHS (Beighton score >4/9) referred to the syncope service based at Hammersmith Hospital. The study period was June 2011 to October 2013. Cardiovascular autonomic function was evaluated using the tilt table test. Results: A total of 53 children were recruited with a median age range of 15.2 yrs (range 8.1yrs-18.7 yrs). The gender distribution was 28 females (53%) and 25 males (47%). All patients had autonomic nervous system-related symptoms including postural dizziness or syncope (53%), palpitations (40%), migraine (25%) and chest pain (19%). Of the 53 JHS patients with autonomic symptoms, 48 (91%) patients had GI-related symptoms. 45 (85%) of these patients had confirmed cardiovascular autonomic dysfunction on tilt testing. All these patients also complained of foregut symptoms, predominantly nausea and bloating. Summary: Foregut dysfunction was a co-morbid presentation in all JHS patients with cardiovascular dysautonomia. Conclusion: Children with JHS presenting with foregut symptoms are likely to have associated cardiovascular autonomic dysfunction. Recognition of these symptoms by paediatricians is important as formal evaluation and treatment of the dysautonomia may improve the quality of life for these patients. Further studies are required to evaluate the objective improvement of GI symptoms following treatment for dysautonomia.

Introduction Anxiety disorders are highly prevalent and among the leading causes of the global disease burden. Cognitive behaviour therapy (CBT) is an effective treatment, but demand is high and resources to deliver CBT are scarce. Embracing new technologies to meet these growing needs, there is an emergent evidence base of the efficacy of internet-based CBT (ICBT). Objectives Evaluating (1) treatment effects, (2) cost-effectiveness and (3) cost-utility of ICBT for panic disorder. Aims To evaluate clinical effectiveness and health economics of ICBT for patients within regular psychiatric care. Methods Longitudinal analysis of 570 patients diagnosed with panic disorder that have been treated between 2007 and 2012 at an ICBT unit within regular psychiatric care. The ICBT was therapist-guided and lasted for three months. Clinical outcome measures were improvements in symptom severity and health related quality of life. Economic outcome measures were direct and indirect costs and incremental cost-effectiveness ratios (ICER). Results Analyses of treatment outcome suggest significant reductions in primary symptoms of panic disorder and that ICBT is an economically and clinically effective treatment for panic disorder leading to improvement of symptom severity and quality of life for these patients. Conclusions The findings of this study can aid decision makers when considering options of evidence-based treatment delivery formats within psychiatric care.

The dopamine system has been suggested to play a role in social anxiety disorder (SAD), partly based on molecular imaging studies showing reduced levels of striatal dopaminergic markers in patients compared with control subjects. However, the dopamine system has not been examined in frontal and limbic brain regions proposed to be central in the pathophysiology of SAD. In the present study, we hypothesized that extrastriatal dopamine D2-receptor (D2-R) levels measured using positron emission tomography (PET) would predict symptom reduction after cognitive behavior therapy (behavior). Nine SAD patients were examined using high-resolution PET and the high-affinity D2-R antagonist radioligand [C-11]FLB 457, before and after 15 weeks of CBT. Symptom levels were assessed using the anxiety subscale of Liebowitz Social Anxiety Scale (LSAS(anx)). At posttreatment, there was a statistically significant reduction of social anxiety symptoms (Po0.005). Using a repeated measures analysis of covariance, significant effects for time and time x LSAS(anx) change on D2-R-binding potential (BPND) were shown (P