The kinetics of αIIbβ3 activation determines the size and stability of thrombi in mice: implications for antiplatelet therapy.

Two major pathways contribute to Ras-proximate-1-mediated integrin activation in stimulated platelets. Calcium and diacyglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI, RasGRP2) mediates the rapid but reversible activation of integrin αIIbβ3, while the adenosine diphosphate receptor P2Y12, the target for antiplatelet drugs like clopidogrel, facilitates delayed but sustained integrin activation. To establish CalDAG-GEFI as a target for antiplatelet therapy, we compared how each pathway contributes to thrombosis and hemostasis in mice. Ex vivo, thrombus formation at arterial or venous shear rates was markedly reduced in CalDAG-GEFI(-/-) blood, even in the presence of exogenous adenosine diphosphate and thromboxane A(2). In vivo, thrombosis was virtually abolished in arterioles and arteries of CalDAG-GEFI(-/-) mice, while small, hemostatically active thrombi formed in venules. Specific deletion of the C1-like domain of CalDAG-GEFI in circulating platelets also led to protection from thrombus formation at arterial flow conditions, while it only marginally increased blood loss in mice. In comparison, thrombi in the micro- and macrovasculature of clopidogrel-treated wild-type mice grew rapidly and frequently embolized but were hemostatically inactive. Together, these data suggest that inhibition of the catalytic or the C1 regulatory domain in CalDAG-GEFI will provide strong protection from athero-thrombotic complications while maintaining a better safety profile than P2Y12 inhibitors like clopidogrel.

A novel transport mechanism for MOMP in Chlamydophila pneumoniae and its putative role in immune-therapy

Major outer membrane proteins (MOMPs) of Gram negative bacteria are one of the most intensively studied membrane proteins. MOMPs are essential for maintaining the structural integrity of bacterial outer membranes and in adaptation of parasites to their hosts. There is evidence to suggest a role for purified MOMP from Chlamydophila pneumoniae and corresponding MOMP-derived peptides in immune-modulation, leading to a reduced atherosclerotic phenotype in apoE−/− mice via a characteristic dampening of MHC class II activity. The work reported herein tests this hypothesis by employing a combination of homology modelling and docking to examine the detailed molecular interactions that may be responsible. A three-dimensional homology model of the C. pneumoniae MOMP was constructed based on the 14 transmembrane β-barrel crystal structure of the fatty acid transporter from Escherichia coli, which provides a plausible transport mechanism for MOMP. Ligand docking experiments were used to provide details of the possible molecular interactions driving the binding of MOMP-derived peptides to MHC class II alleles known to be strongly associated with inflammation. The docking experiments were corroborated by predictions from conventional immuno-informatic algorithms. This work supports further the use of MOMP in C. pneumoniae as a possible vaccine target and the role of MOMP-derived peptides as vaccine candidates for immune-therapy in chronic inflammation that can result in cardiovascular events.

Evaluation of reach and grasp robot-assisted therapy suggests similar functional recovery patterns on proximal and distal arm segments in sub-acute hemiplegia

This paper provides some additional evidence in support of the hypothesis that robot therapies are clinically beneficial in neurorehabilitation. Although only 4 subjects were included in the study, the design of the intervention and the measures were done so as to minimise bias. The results are presented as single case studies, and can only be interpreted as such due to the study size. The intensity of intervention was 16 hours and the therapy philosophy (based on Carr and Shepherd) was that coordinated movements are preferable to joint based therapies, and that coordinating distal movements (in this case grasps) helps not only to recover function in these areas, but has greater value since the results are immediately transferable to daily skills such as reach and grasp movements.

Serotonin transporter [corrected] methylation and response to cognitive behaviour therapy in children with anxiety disorders

Anxiety disorders that are the most commonly occurring psychiatric disorders in childhood, are associated with a range of social and educational impairments and often continue into adulthood. Cognitive behaviour therapy (CBT) is an effective treatment option for the majority of cases, although up to 35-45% of children do not achieve remission. Recent research suggests that some genetic variants may be associated with a more beneficial response to psychological therapy. Epigenetic mechanisms such as DNA methylation work at the interface between genetic and environmental influences. Furthermore, epigenetic alterations at the serotonin transporter (SERT) promoter region have been associated with environmental influences such as stressful life experiences. In this study, we measured DNA methylation upstream of SERT in 116 children with an anxiety disorder, before and after receiving CBT. Change during treatment in percentage DNA methylation was significantly different in treatment responders vs nonresponders. This effect was driven by one CpG site in particular, at which responders increased in methylation, whereas nonresponders showed a decrease in DNA methylation. This is the first study to demonstrate differences in SERT methylation change in association with response to a purely psychological therapy. These findings confirm that biological changes occur alongside changes in symptomatology following a psychological therapy such as CBT.

Clinical predictors of response to cognitive-behavioural therapy in pediatric anxiety disorders: the Genes for Treatment (GXT) Study

Objective The Genes for Treatment study is an international, multisite collaboration exploring the role of genetic, demographic, and clinical predictors in response to cognitive-behavioral therapy (CBT) in pediatric anxiety disorders. The current article, the first from the study, examined demographic and clinical predictors of response to CBT. We hypothesized that the child’s gender, type of anxiety disorder, initial severity and comorbidity, and parents’ psychopathology would significantly predict outcome. Method A sample of 1,519 children 5 to 18 years of age with a primary anxiety diagnosis received CBT across 11 sites. Outcome was defined as response (change in diagnostic severity) and remission (absence of the primary diagnosis) at each time point (posttreatment, 3-, 6-, and/or 12-month follow-up) and analyzed using linear and logistic mixed models. Separate analyses were conducted using data from posttreatment and follow-up assessments to explore the relative importance of predictors at these time points. Results Individuals with social anxiety disorder (SoAD) had significantly poorer outcomes (poorer response and lower rates of remission) than those with generalized anxiety disorder (GAD). Although individuals with specific phobia (SP) also had poorer outcomes than those with GAD at posttreatment, these differences were not maintained at follow-up. Both comorbid mood and externalizing disorders significantly predicted poorer outcomes at posttreatment and follow-up, whereas self-reported parental psychopathology had little effect on posttreatment outcomes but significantly predicted response (although not remission) at follow-up. Conclusion SoAD, nonanxiety comorbidity, and parental psychopathology were associated with poorer outcomes after CBT. The results highlight the need for enhanced treatments for children at risk for poorer outcomes.

Aberrant brain responses to emotionally valent words is normalised after cognitive behavioural therapy in female depressed adolescents

AbstractBackground Depression in adolescence is debilitating with high recurrence in adulthood, yet its pathophysiological mechanism remains enigmatic. To examine the interaction between emotion, cognition and treatment, functional brain responses to sad and happy distractors in an affective go/no-go task were explored before and after Cognitive Behavioural Therapy (CBT) in depressed female adolescents, and healthy participants. Methods Eighty-two Depressed and 24 healthy female adolescents, aged 12 to 17 years, performed a functional magnetic resonance imaging (fMRI) affective go/no-go task at baseline. Participants were instructed to withhold their responses upon seeing happy or sad words. Among these participants, 13 patients had CBT over approximately 30 weeks. These participants and 20 matched controls then repeated the task. Results At baseline, increased activation in response to happy relative to neutral distractors was observed in the orbitofrontal cortex in depressed patients which was normalized after CBT. No significant group differences were found behaviourally or in brain activation in response to sad distractors. Improvements in symptoms (mean: 9.31, 95% CI: 5.35-13.27) were related at trend-level to activation changes in orbitofrontal cortex. Limitations In the follow-up section, a limited number of post-CBT patients were recruited. Conclusions To our knowledge, this is the first fMRI study addressing the effect of CBT in adolescent depression. Although a bias toward negative information is widely accepted as a hallmark of depression, aberrant brain hyperactivity to positive distractors was found and normalised after CBT. Research, assessment and treatment focused on positive stimuli could be a future consideration. Moreover, a pathophysiological mechanism distinct from adult depression may be suggested and awaits further exploration.

Young Children's Ability to Engage in Cognitive Therapy Tasks: Associations With Age and Educational Experience

Abstract. In two linked studies we examined children’s performance on tasks required for participation in cognitive therapy. In Study 1 we piloted some new tasks with children aged 5 to 11 years. In study 2 the effects of IQ, age and educational experience were examined in children aged 5 to 7 years. In study 1, 14 children aged 5 to 11 completed three tasks related to cognitive therapy; generating post-event attributions, naming emotions, and linking thoughts and feelings. Study 2 used a between-subjects design in which 72 children aged 5, 6, or 7 years from two primary schools completed the three tasks and the Block Design and Vocabulary sub-tests from the WISC III or WPPSI-R. Children were tested individually during the school day. All measures were administered on the same occasion. In study 2 administration order of the cognitive therapy task and the WISC III/WPPSI-R were randomized. The majority of children demonstrated some ability on each of the three tasks. In study 2, performance was associated with school and with IQ but not with age. There were no gender differences. Children attending a school with an integrated thinking skills programme and those with a higher 1Q were more successful on the cognitive therapy tasks. These results suggest that many young children could engage in cognitive therapy given age-appropriate materials. The effects of training in relevant meta-cognitive skills on children’s ability to use concepts in CBT may warrant further research. Keywords: Cognitive behaviour therapy, young children, cognitive development

Letters in cognitive analytic therapy: The patient's experience

Patient perspectives on how therapeutic letters contributed to their experience of cognitive analytic therapy (CAT) were investigated. Eight patients took part in semistructured interviews. A grounded, thematic analysis of their accounts suggested four general processes. First, letters offered a tangible, lasting framework for the assimilation of a new perspective about themselves and their relationships and facilitated coping with a complex range of emotions and risks this awareness required. Second, they demonstrated therapists’ commitment to patients’ growth. Third, they helped to teach participants about the therapy process as an example of an interpersonal exchange. Fourth, they helped participants consider how they wished to share personal information. These data offer a more complex understanding of this standard CAT intervention. Although some findings are consistent with CAT theory, the range of emotional dilemmas associated with letters has not received specific attention. Clinical implications are discussed.

Cognitive Therapy Abilities in People with Learning Disabilities

Background  There is a need to develop and adapt therapies for use with people with learning disabilities who have mental health problems. Aims  To examine the performance of people with learning disabilities on two cognitive therapy tasks (emotion recognition and discrimination among thoughts, feelings and behaviours). We hypothesized that cognitive therapy task performance would be significantly correlated with IQ and receptive vocabulary, and that providing a visual cue would improve performance. Method  Fifty-nine people with learning disabilities were assessed on the Wechsler Abbreviated Scale of Intelligence (WASI), the British Picture Vocabulary Scale-II (BPVS-II), a test of emotion recognition and a task requiring participants to discriminate among thoughts, feelings and behaviours. In the discrimination task, participants were randomly assigned to a visual cue condition or a no-cue condition. Results  There was considerable variability in performance. Emotion recognition was significantly associated with receptive vocabulary, and discriminating among thoughts, feelings and behaviours was significantly associated with vocabulary and IQ. There was no effect of the cue on the discrimination task. Conclusion  People with learning disabilities with higher IQs and good receptive vocabulary were more likely to be able to identify different emotions and to discriminate among thoughts, feelings and behaviours. This implies that they may more easily understand the cognitive model. Structured ways of simplifying the concepts used in cognitive therapy and methods of socialization and education in the cognitive model are required to aid participation of people with learning disabilities.

Genome-wide association study of response to cognitive behavioural therapy in children with anxiety disorders

Background Anxiety disorders are common, and cognitive–behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent. Aims To perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980). Method Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up. Results No variants passed a genome-wide significance threshold (P = 5×10−8) in either analysis. Four variants met criteria for suggestive significance (P<5×10−6) in association with response post-treatment, and three variants in the 6-month follow-up analysis. Conclusions This is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts.

Why cancer patients choose in-patient complementary therapy in palliative care: a qualitative study at Arokhayasala Hospice in Thailand

Cancer patients often choose complementary and alternative medicine (CAM) in palliative care, often in addition to conventional treatment and without medical advice or approval. Herbal medicines (HM) are the most commonly used type of CAM, but rarely available on an in-patient basis for palliative care. The motivations which lead very ill patients to travel far to receive such therapies are not clear. A qualitative study was therefore carried out to investigate influences on choosing to attend a CAM herbal hospice, to identify cancer patients’ main concerns about end-of-life care. Semi-structured interviews with 32 patients were conducted and analysed using thematic analysis. Patients were recruited from Arokhayasala, a Buddhist cancer hospice in Thailand which provides CAM, in the form of HM, a restricted diet, Thai yoga, deep-breathing exercises, meditation, chanting, Dhamma, laughter and music therapy, free-of-charge. The main factors influencing decision-making were a positive attitude towards HMs and previous use of them, dissatisfaction with conventional treatment, the home environment and their relationships with hospital doctors. Patients’ own perceptions and experiences were more important in making the decision to use CAM, and especially HM, in palliative cancer care than referral by healthcare professionals or scientific evidence of efficacy. Patients were prepared to travel far and live away from home to receive such care, especially as it was cost-free. In view of patients’ previously stated satisfaction with the regime at the Arokhayasala, these findings may be relevant to the provision of in-patient cancer palliative care to other patients.

Protocol for a feasibility study of a self help cognitive behavioural therapy resource for the reduction of dental anxiety in young people

Background Childhood dental anxiety is very common, with 10–20 % of children and young people reporting high levels of dental anxiety. It is distressing and has a negative impact on the quality of life of young people and their parents as well as being associated with poor oral health. Affected individuals may develop a lifelong reliance on general anaesthetic or sedation for necessary dental treatment thus requiring the support of specialist dental services. Children and young people with dental anxiety therefore require additional clinical time and can be costly to treat in the long term. The reduction of dental anxiety through the use of effective psychological techniques is, therefore, of high importance. However, there is a lack of high-quality research investigating the impact of cognitive behavioural therapy (CBT) approaches when applied to young people’s dental anxiety. Methods/design The first part of the study will develop a profile of dentally anxious young people using a prospective questionnaire sent to a consecutive sample of 100 young people referred to the Paediatric Dentistry Department, Charles Clifford Dental Hospital, in Sheffield. The second part will involve interviewing a purposive sample of 15–20 dental team members on their perceptions of a CBT self-help resource for dental anxiety, their opinions on whether they might use such a resource with patients, and their willingness to recruit participants to a future randomised controlled trial (RCT) to evaluate the resource. The third part of the study will investigate the most appropriate outcome measures to include in a trial, the acceptability of the resource, and retention and completion rates of treatment with a sample of 60 dentally anxious young people using the CBT resource. Discussion This study will provide information on the profile of dentally anxious young people who could potentially be helped by a guided self-help CBT resource. It will gain the perceptions of dental care team members of guided self-help CBT for dental anxiety in young people and their willingness to recruit participants to a trial. Acceptability of the resource to participants and retention and completion rates will also be investigated to inform a future RCT.

Antimicrobial Photodynamic Therapy in the Non-Surgical Treatment of Aggressive Periodontitis: Cytokine Profile in Gingival Crevicular Fluid, Preliminary Results

Background: Aggressive periodontitis is a specific form of periodontal disease that is characterized by rapid attachment loss and bone destruction. Cytokine profiles are of considerable value when studying disease course during treatment. The aim of this trial was to investigate cytokine levels in the gingival crevicular fluid (GCF) of patients with aggressive periodontitis, after treatment with photodynamic therapy (PDT) or scaling and root planing (SRP), in a split-mouth design on -7, 0, +1, +7, +30, and +90 days. Methods: Ten patients were randomly treated with PDT using a laser source associated with a photosensitizer or SRP with hand instruments. GCF samples were collected, and the concentrations of tumor necrosis factor-alpha (TNF-alpha) and receptor activator of nuclear factor-kappa B ligand (RANKL) were determined by enzyme-linked immunosorbent assays. The data were analyzed using generalized estimating equations to test the associations among treatments, evaluated parameters, and experimental times (alpha = 0.05). Results: Non-surgical periodontal treatment with PDT or SRP led to statistically significant reductions in TNF-alpha level 30 days following treatment. There were similar levels of TNF-alpha and RANKL at the different time points in both groups, with no statistically significant differences. Conclusion: SRP and PDT had similar effects on crevicular TNF-alpha and RANKL levels in patients with aggressive periodontitis. J Periodontol 2009;80:98-105.