Integrin β3 Crosstalk with VEGFR Accommodating Tyrosine Phosphorylation as a Regulatory Switch

Integrins mediate cell adhesion, migration, and survival by connecting intracellular machinery with the surrounding extracellular matrix. Previous studies demonstrated the importance of the interaction between β3 integrin and VEGF type 2 receptor (VEGFR2) in VEGF-induced angiogenesis. Here we present in vitro evidence of the direct association between the cytoplasmic tails (CTs) of β3 and VEGFR2. Specifically, the membrane-proximal motif around 801YLSI in VEGFR2 mediates its binding to non-phosphorylated β3CT, accommodating an α-helical turn in integrin bound conformation. We also show that Y747 phosphorylation of β3 enhances the above interaction. To demonstrate the importance of β3 phosphorylation in endothelial cell functions, we synthesized β3CT-mimicking Y747 phosphorylated and unphosphorylated membrane permeable peptides. We show that a peptide containing phospho-Y747 but not F747 significantly inhibits VEGF-induced signaling and angiogenesis. Moreover, phospho-Y747 peptide exhibits inhibitory effect only in WT but not in β3 integrin knock-out or β3 integrin knock-in cells expressing β3 with two tyrosines substituted for phenylalanines, demonstrating its specificity. Importantly, these peptides have no effect on fibroblast growth factor receptor signaling. Collectively these data provide novel mechanistic insights into phosphorylation dependent cross-talk between integrin and VEGFR2

Behavioural activation by mental health nurses for late-life depression in primary care: a randomized controlled trial

Background: Depressive symptoms are common in older adults. The effectiveness of pharmacological treatments and the availability of psychological treatments in primary care are limited. A behavioural approach to depression treatment might be beneficial to many older adults but such care is still largely unavailable. Behavioural Activation (BA) protocols are less complicated and more easy to train than other psychological therapies, making them very suitable for delivery by less specialised therapists. The recent introduction of the mental health nurse in primary care centres in the Netherlands has created major opportunities for improving the accessibility of psychological treatments for late-life depression in primary care. BA may thus address the needs of older patients while improving treatment outcome and lowering costs.The primary objective of this study is to compare the effectiveness and cost-effectiveness of BA in comparison with treatment as usual (TAU) for late-life depression in Dutch primary care. A secondary goal is to explore several potential mechanisms of change, as well as predictors and moderators of treatment outcome of BA for late-life depression. Methods/design: Cluster-randomised controlled multicentre trial with two parallel groups: a) behavioural activation, and b) treatment as usual, conducted in primary care centres with a follow-up of 52 weeks. The main inclusion criterion is a PHQ-9 score > 9. Patients are excluded from the trial in case of severe mental illness that requires specialized treatment, high suicide risk, drug and/or alcohol abuse, prior psychotherapy, change in dosage or type of prescribed antidepressants in the previous 12 weeks, or moderate to severe cognitive impairment. The intervention consists of 8 weekly 30-min BA sessions delivered by a trained mental health nurse. Discussion: We expect BA to be an effective and cost-effective treatment for late-life depression compared to TAU. BA delivered by mental health nurses could increase the availability and accessibility of non-pharmacological treatments for late-life depression in primary care. Trial registration: This study is retrospectively registered in the Dutch Clinical Trial Register NTR6013on August 25th 2016. © 2017 The Author(s)

A systematic review of parental involvement in cognitive behavioural therapy for adolescent anxiety disorders

Anxiety disorders are common among adolescents and lead to poor long-term outcomes. Cognitive Behavioural Therapy (CBT) is an evidenced-based intervention for adolescent anxiety disorders, but little is known about whether and how parents should be involved. This systematic review evaluated how parents have been involved and associated treatment outcomes in studies of CBT for adolescent anxiety disorders. Electronic systematic searches were conducted in PsycINFO, Embase, CINAHL, Medline, AMED databases, to identify studies investigating CBT for adolescent anxiety disorder(s) that included parents in treatment. Twenty-three studies were identified. Parents were involved in treatment in a number of different ways: by attending separate parent sessions, joint parent-adolescent sessions, or both, or through provision of a workbook while attending some adolescent sessions. Content varied but was most typically aimed at the parent developing an understanding of core CBT components and skills to help them manage their adolescent’s anxiety and avoidance. Treatment outcomes indicate that CBT with parental involvement is an effective intervention for adolescent anxiety disorders, however it is not possible to draw conclusions regarding whether parental involvement (generally or in any particular form) enhances treatment outcomes. Poor reporting and methodological issues also limit the conclusions. Further research is required to identify whether there are particular types of parental involvement in CBT that bring clinical benefits to adolescents with anxiety disorders generally, as well as in particular circumstances

Individual differences in first- and second-order temporal judgment

The ability of subjects to identify and reproduce brief temporal intervals is influenced by many factors whether they be stimulus-based, task-based or subject-based. The current study examines the role individual differences play in subsecond and suprasecond timing judgments, using the schizoptypy personality scale as a test- case approach for quantifying a broad range of individual differences. In two experiments, 129 (Experiment 1) and 141 (Experiment 2) subjects completed the O-LIFE personality questionnaire prior to performing a modified temporal-bisect ion task. In the bisection task, subjects responded to two identical instantiations of a luminance grating presented in a 4deg window, 4deg above fixation for 1.5 s Experiment 1) or 3 s (Experiment 2). Subjects initiated presentation with a button- press, and released the button when they considered the stimulus to be half-way through (750/1500 ms). Subjects were then asked to indicate their ‘most accurate estimate’ of the two intervals. In this way we measure both performance on the task (a first-order measure) and the subjects’ knowledge of their performance (a second-order measure). In Experiment 1 the effect of grating-drift and feedback on performance was also examined. Experiment 2 focused on the static/no-feedback condition. For the group data, Experiment 1 showed a significant effect of presentation order in the baseline condition (no feedback), which disappeared when feedback was provided. Moving the stimulus had no effect on perceived duration. Experiment 2 showed no effect of stimulus presentation order. This elimination of the subsecond order-effect was at the expense of accuracy, as the mid-point of the suprasecond interval was generally underestimated. Response precision increased as a proportion of total duration, reducing the variance below that predicted by Weber’s law. This result is consistent with a breakdown of the scalar properties of time perception in the early suprasecond range. All subjects showed good insight into their own performance, though that insight did not necessarily correlate with the veridical bisection point. In terms of personality, we found evidence of significant differences in performance along the Unusual Experiences subscale, of most theoretical interest here, in the subsecond condition only. There was also significant correlation with Impulsive Nonconformity and Cognitive Disorganisation in the sub- and suprasecond conditions, respectively. Overall, these data support a partial dissocation of timing mechanisms at very short and slightly longer intervals. Further, these results suggest that perception is not the only critical mitigator of confidence in temporal experience, since individuals can effectively compensate for differences in perception at the level of metacognition in early suprasecond time. Though there are individual differences in performance, these are perhaps less than expected from previous reports and indicate an effective timing mechanism dealing with brief durations independent of the influence of significant personality trait differences

Optimising the acceptability and feasibility of Acceptance and Commitment Therapy for treatment-resistant generalised anxiety disorder in older adults

BACKGROUND:generalised anxiety disorder (GAD) is common in later life with a prevalence of 3-12%. Many only partially respond to cognitive behavioural therapy or pharmacotherapy and can be classified as treatment resistant. These patients experience poor quality of life, and are at increased risk of comorbid depression, falls and loneliness. Acceptance and commitment therapy (ACT) is an emerging therapy, which may be particularly suited to this population, but has not been tailored to their needs. OBJECTIVES:to optimise the acceptability and feasibility of ACT for older adults with treatment-resistant GAD. DESIGN:a person-based approach to ground the adapted ACT intervention in the perspectives and lives of those who will use it. METHODS:first, we conducted qualitative interviews with 15 older adults with GAD and 36 healthcare professionals to develop guiding principles to inform the intervention. Second, we consulted service users and clinical experts and interviewed the same 15 older adults using 'think aloud' techniques to enhance its acceptability and feasibility. RESULTS:in Stage 1, older adults' concerns and needs were categorised in four themes: 'Expert in one's own condition', 'Deep seated coping strategies', 'Expert in therapy' and 'Support with implementation'. In Stage 2, implications for therapy were identified that included an early focus on values and ACT as a collaborative partnership, examining beliefs around 'self as worrier' and the role of avoidance, validating and accommodating individuals' knowledge and experience and compensating for age-related cognitive changes. DISCUSSION:Our systematic approach combined rigour and transparency to develop a therapeutic intervention tailored to the specific needs of older adults with treatment-resistant GAD

A scoping review investigating the use of exposure for the treatment and targeted prevention of anxiety and related disorders in young people

Background: Cognitive Behavioural Therapy (CBT) is the gold standard intervention for anxiety and related mental health disorders among young people; however, the efficacy of individual elements of CBT (e.g., exposure to feared stimuli) have received little scrutiny. Aims: This scoping review, informed by three stakeholder groups and a scientific advisory group, aimed to identify the nature and extent of the available research literature on the efficacy of exposure to feared stimuli, moderators of effectiveness in young people aged 14-24 years. Method: Three international stakeholder groups composed of clinicians (N = 8), parents/carers (N = 5) and youth with lived experience of anxiety (N = 7) provided input into study design and results. Using the PRISMA extension for scoping reviews, a search of MEDLINE/Ovid, PsycINFO, PubMed, CINAHL, SCOPUS, EMBASE, ERIC, and Health Collection (informit) was conducted using terms related to anxiety, ages 14 to 24, and exposure. Results: From 3508 unique abstracts, 64 papers were included for the review. While there was evidence for the efficacy of exposure as a treatment for youth anxiety disorders, fundamental gaps in knowledge of exposure in this age group were identified. Most studies examined post-traumatic stress disorder, obsessive-compulsive disorder, and specific phobias with no randomised clinical trials uniquely evaluating exposure for the treatment of DSM-5 anxiety disorders. Exposure was typically delivered accompanied by other anxiety management techniques. A multitude of optimisation strategies have been tested, yet only one of these effects (timing relative to sleep) showed preliminary evidence of replication. Conclusions: A systematic and theoretically driven program of research investigating the efficacy of exposure in young people and factors that moderate its efficacy, along with methods to overcome barriers for delivery, is urgently needed.</p