Targeting the cell cycle machinery for the treatment of cardiovascular disease

Cardiovascular disease represents a major clinical problem affecting a significant proportion of the world's population and remains the main cause of death in the UK. The majority of therapies currently available for the treatment of cardiovascular disease do not cure the problem but merely treat the symptoms. Furthermore, many cardioactive drugs have serious side effects and have narrow therapeutic windows that can limit their usefulness in the clinic. Thus, the development of more selective and highly effective therapeutic strategies that could cure specific cardiovascular diseases would be of enormous benefit both to the patient and to those countries where healthcare systems are responsible for an increasing number of patients. In this review, we discuss the evidence that suggests that targeting the cell cycle machinery in cardiovascular cells provides a novel strategy for the treatment of certain cardiovascular diseases. Those cell cycle molecules that are important for regulating terminal differentiation of cardiac myocytes and whether they can be targeted to reinitiate cell division and myocardial repair will be discussed as will the molecules that control vascular smooth muscle cell (VSMC) and endothelial cell proliferation in disorders such as atherosclerosis and restenosis. The main approaches currently used to target the cell cycle machinery in cardiovascular disease have employed gene therapy techniques. We will overview the different methods and routes of gene delivery to the cardiovascular system and describe possible future drug therapies for these disorders. Although the majority of the published data comes from animal studies, there are several instances where potential therapies have moved into the clinical setting with promising results.

Threat interpretation in anxious children and their mothers: comparison with nonclinical children and the effects of treatment

Interpretation biases towards threat play a prominent role in cognitive theories of anxiety, and have been identified amongst highly anxious adults and children. Little is known, however, about the development of these cognitive biases although family processes have been implicated. The current study investigated the nature of threat interpretation of anxious children and their mothers through (i) comparison of a clinic and non-clinic population, (ii) analysis of individual differences; and (ill) pre- and post-treatment comparisons. Participants were 27 children with a primary anxiety disorder and 33 children from a non-clinic population and their mothers. Children and mothers completed self-report measures of anxiety and indicated their most likely interpretation of ambiguous scenarios. Clinic and non-clinical groups differed significantly on measures of threat interpretation. Furthermore, mothers' and children's threat interpretation correlated significantly. Following treatment for child anxiety, both children and their mothers reported a reduction in threat interpretation. (c) 2005 Elsevier Ltd. All rights reserved.

A family study of co-morbidity between generalized social phobia and generalized anxiety disorder in a non-clinic sample

Background: High rates of co-morbidity between Generalized Social Phobia (GSP) and Generalized Anxiety Disorder (GAD) have been documented. The reason for this is unclear. Family studies are one means of clarifying the nature of co-morbidity between two disorders. Methods: Six models of co-morbidity between GSP and GAD were investigated in a family aggregation study of 403 first-degree relatives of non-clinical probands: 37 with GSP, 22 with GAD, 15 with co-morbid GSP/GAD, and 41 controls with no history of GSP or GAD. Psychiatric data were collected for probands and relatives. Mixed methods (direct and family history interviews) were utilised. Results: Primary contrasts (against controls) found an increased rate of pure GSP in the relatives of both GSP probands and co-morbid GSP/GAD probands, and found relatives of co-morbid GSP/GAD probands to have an increased rate of both pure GAD and comorbid GSP/GAD. Secondary contrasts found (i) increased GSP in the relatives of GSP only probands compared to the relatives of GAD only probands; and (ii) increased GAD in the relatives of co-morbid GSP/GAD probands compared to the relatives of GSP only probands. Limitations: The study did not directly interview all relatives, although the reliability of family history data was assessed. The study was based on an all-female proband sample. The implications of both these limitations are discussed. Conclusions: The results were most consistent with a co-morbidity model indicating independent familial transmission of GSP and GAD. This has clinical implications for the treatment of patients with both disorders. (C) 2006 Elsevier B.V. All fights reserved.

A follow-up study of characteristics of young people that dropout and continue psychotherapy: service implications for a clinic in the community

Background: The paper reports the findings from a follow-up study of the factors that contribute to whether young people dropout or continue once-weekly psychotherapy at a voluntary sector psychotherapy service for young people aged 12 to 21 years. Method: The study uses data from an ongoing audit of the psychotherapy service that started in 1993; 882 young people were included in the study. Premature termination of treatment was defined as dropping out before the 21st session. Continuation in treatment was defined as remaining in therapy after 20 sessions. Measures and areas of interest used in the study include diagnostic measures, the Youth Self Report Form and Young Adult Self Report Form, demographic characteristics and treatment related information. Results: Young people who continued in treatment were more likely to be older, have anxieties about sexual and relationship issues and have higher scores on self-reported anxiety-depression. Young people who dropped out of treatment were more likely to be younger, have higher self-reported delinquency scores, have a diagnosis of hyperactivity-conduct disorder and be homeless. Conclusions: The study of treatment termination has demonstrated the value of service audit and has led to a significant change in clinical practice.

A randomised controlled trial of cognitive behavioural treatment for obsessive compulsive disorder in children and adolescents

Cognitive behaviour therapy (CBT) for young people with obsessive compulsive disorder (OCD) has become the treatment of first choice. However, the literature is largely based on studies emphasising exposure and response prevention. In this study, we report on a randomised controlled trial of CBT for young people carried out in typical outpatient clinic conditions which focused on cognitions. A randomised controlled trial compares 10 sessions of manualised cognitive behavioural treatment with a 12-week waiting list for adolescents and children with OCD. Assessors were blind to treatment allocation. 21 consecutive patients with OCD aged between 9 and 18 years were recruited. The group who received treatment improved more than a comparison group who waited for 3 months. The second group was treated subsequently using the same protocol and made similar gains. In conclusion, CBT can be delivered effectively to young people with OCD in typical outpatient settings.

Treatment of child anxiety in the context of maternal anxiety disorder: a randomised controlled trial and economic analysis

Background Cognitive–behavioural therapy (CBT) for childhood anxiety disorders is associated with modest outcomes in the context of parental anxiety disorder. Objectives This study evaluated whether or not the outcome of CBT for children with anxiety disorders in the context of maternal anxiety disorders is improved by the addition of (i) treatment of maternal anxiety disorders, or (ii) treatment focused on maternal responses. The incremental cost-effectiveness of the additional treatments was also evaluated. Design Participants were randomised to receive (i) child cognitive–behavioural therapy (CCBT); (ii) CCBT with CBT to target maternal anxiety disorders [CCBT + maternal cognitive–behavioural therapy (MCBT)]; or (iii) CCBT with an intervention to target mother–child interactions (MCIs) (CCBT + MCI). Setting A NHS university clinic in Berkshire, UK. Participants Two hundred and eleven children with a primary anxiety disorder, whose mothers also had an anxiety disorder. Interventions All families received eight sessions of individual CCBT. Mothers in the CCBT + MCBT arm also received eight sessions of CBT targeting their own anxiety disorders. Mothers in the MCI arm received 10 sessions targeting maternal parenting cognitions and behaviours. Non-specific interventions were delivered to balance groups for therapist contact. Main outcome measures Primary clinical outcomes were the child’s primary anxiety disorder status and degree of improvement at the end of treatment. Follow-up assessments were conducted at 6 and 12 months. Outcomes in the economic analyses were identified and measured using estimated quality-adjusted life-years (QALYs). QALYS were combined with treatment, health and social care costs and presented within an incremental cost–utility analysis framework with associated uncertainty. Results MCBT was associated with significant short-term improvement in maternal anxiety; however, after children had received CCBT, group differences were no longer apparent. CCBT + MCI was associated with a reduction in maternal overinvolvement and more confident expectations of the child. However, neither CCBT + MCBT nor CCBT + MCI conferred a significant post-treatment benefit over CCBT in terms of child anxiety disorder diagnoses [adjusted risk ratio (RR) 1.18, 95% confidence interval (CI) 0.87 to 1.62, p = 0.29; adjusted RR CCBT + MCI vs. control: adjusted RR 1.22, 95% CI 0.90 to 1.67, p = 0.20, respectively] or global improvement ratings (adjusted RR 1.25, 95% CI 1.00 to 1.59, p = 0.05; adjusted RR 1.20, 95% CI 0.95 to 1.53, p = 0.13). CCBT + MCI outperformed CCBT on some secondary outcome measures. Furthermore, primary economic analyses suggested that, at commonly accepted thresholds of cost-effectiveness, the probability that CCBT + MCI will be cost-effective in comparison with CCBT (plus non-specific interventions) is about 75%. Conclusions Good outcomes were achieved for children and their mothers across treatment conditions. There was no evidence of a benefit to child outcome of supplementing CCBT with either intervention focusing on maternal anxiety disorder or maternal cognitions and behaviours. However, supplementing CCBT with treatment that targeted maternal cognitions and behaviours represented a cost-effective use of resources, although the high percentage of missing data on some economic variables is a shortcoming. Future work should consider whether or not effects of the adjunct interventions are enhanced in particular contexts. The economic findings highlight the utility of considering the use of a broad range of services when evaluating interventions with this client group. Trial registration Current Controlled Trials ISRCTN19762288. Funding This trial was funded by the Medical Research Council (MRC) and Berkshire Healthcare Foundation Trust and managed by the National Institute for Health Research (NIHR) on behalf of the MRC–NIHR partnership (09/800/17) and will be published in full in Health Technology Assessment; Vol. 19, No. 38.