Young People's Experiences of Participation in Clinical Trials: Reasons for Taking Part.

Given the lack of knowledge about safety and efficacy of many treatments for children, pediatric clinical trials are important, but recruitment for pediatric research is difficult. Little is known about children's perspective on participating in trials. The purpose of this study was to understand the experiences and motivations of young people who took part in clinical trials. This is a qualitative interview study of 25 young people aged 10-23 who were invited to take part in clinical trials. Interviews were audio or video recorded and analyzed using framework analysis. Young peoples' motivations were both personal benefit and helping others. Both incentives appeared to be more complex than expected. We introduce the terms "network of exchange" and "intergenerational solidarity" to describe these motivations. To improve recruitment, professionals should be more open about research opportunities, provide better information, and give young people feedback after the trial has ended.

Apo J/clusterin expression and secretion: evidence for 15-deoxy-Δ(12,14)-PGJ(2)-dependent mechanism.

Cyclooxygenase-2 (Cox-2) and Apo J/clusterin are involved in inflammatory resolution and have each been reported to inhibit NF-κB signalling. Using a well-validated rat pheochromocytoma (PC12) cell culture model of Cox-2 over-expression the current study investigated inter-dependence between Cox-2 and clusterin with respect to induction of expression and impact on NF-κB signalling. Both gene expression and immunoblot analysis confirmed that intracellular and secreted levels of clusterin were elevated in Cox-2 over-expressing cells (PCXII). Clusterin expression was increased in control (PCMT) cells in a time- and dose-dependent manner by 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), but not PGE(2), and inhibited in PCXII cells by pharmacological Cox inhibition. In PCXII cells, inhibition of two transcription factors known to be activated by 15d-PGJ(2), heat shock factor 1 (HSF-1) and peroxisome proliferator activated receptor (PPAR)γ, by transcription factor oligonucleotide decoy and antagonist (GW9662) treatment, respectively, reduced clusterin expression. While PCXII cells exhibited reduced TNF-α-induced cell surface ICAM-1 expression, IkB phosphorylation and degradation were similar to control cells. With respect to the impact of Cox-2-dependent clusterin upregulation on NF-κB signalling, basal levels of IκB were similar in control and PCXII cells, and no evidence for a physical association between clusterin and phospho-IκB was obtained. Moreover, while PCXII cells exhibited reduced NF-κB transcriptional activity, this was not restored by clusterin knock-down. These results indicate that Cox-2 induces clusterin in a 15d-PGJ(2)-dependent manner, and via activation of HSF-1 and PPARγ. However, the results do not support a model whereby Cox-2/15d-PGJ(2)-dependent inhibition of NF-κB signalling involves clusterin.

Increased circulating CC chemokine levels in the metabolic syndrome are reduced by low-dose atorvastatin treatment: evidence from a randomized controlled trial.

OBJECTIVE: Central obesity and insulin resistance are key components of the metabolic syndrome, which is associated with an increased risk of cardiovascular disease. In obesity, CC chemokines, such as monocyte chemotactic protein-1 (MCP-1), macrophage inhibitory protein-1ß (MIP-1ß) and eotaxin-1 and their respective receptors, are critically involved in peripheral monocyte activation and adipose tissue infiltration. The aim of the current study was to examine whether low-dose atorvastatin (10 mg/d) treatment modulated serum levels of CC chemokines in metabolic syndrome subjects. MATERIALS AND METHODS: Serum levels of MCP-1, eotaxin-1, MIP-1ß, C reactive protein (CRP) and interleukin-6 (IL-6) were measured in lean control and metabolic syndrome subjects at baseline, and following a 6-week randomized placebo-controlled clinical trial of atorvastatin (10 mg/d). Peripheral CD14(+) monocytes were isolated and mRNA levels of MCP-1, MIP-1 ß and CCR5 determined. RESULTS: Serum MCP-1 (P = 0·02), eotaxin-1 (P = 0·02) and MIP-1ß (P = 0·03), CRP (P < 0·001) and IL-6 (P = 0·006) were significantly increased in metabolic syndrome in comparison with lean controls. Furthermore, CD14(+) peripheral monocyte mRNA expression of the chemokine receptor, CCR5, of which MIP-1ß and eotaxin-1 are ligands, was increased two-fold in the metabolic syndrome group (P = 0·03). In addition to the expected improvements in lipid profile, atorvastatin treatment significantly reduced circulating eotaxin-1 (P < 0·05), MIP-1ß (P < 0·05) levels and CD14(+) peripheral monocyte CCR5 mRNA expression (P = 0·02). CONCLUSION: These results support a model whereby atorvastatin treatment, by inhibiting CD14(+) monocyte CCR5 expression, may inhibit monocyte trafficking, reduce chronic inflammation and, thus, lower circulating levels of CC chemokines.

Restoration of adipose function in obese glucose-tolerant men following pioglitazone treatment is associated with CCAAT enhancer-binding protein ß up-regulation.

Obese AT (adipose tissue) exhibits increased macrophage number. Pro-inflammatory CD16+ peripheral monocyte numbers are also reported to increase with obesity. The present study was undertaken to simultaneously investigate obesity-associated changes in CD16+ monocytes and ATMs (AT macrophages). In addition, a pilot randomized placebo controlled trial using the PPAR (peroxisome-proliferator-activated receptor) agonists, pioglitazone and fenofibrate was performed to determine their effects on CD14+/CD16+ monocytes, ATM and cardiometabolic and adipose dysfunction indices. Obese glucose-tolerant men (n=28) were randomized to placebo, pioglitazone (30 mg/day) and fenofibrate (160 mg/day) for 12 weeks. A blood sample was taken to assess levels of serum inflammatory markers and circulating CD14+/CD16+ monocyte levels via flow cytometry. A subcutaneous AT biopsy was performed to determine adipocyte cell surface and ATM number, the latter was determined via assessment of CD68 expression by IHC (immunohistochemistry) and real-time PCR. Subcutaneous AT mRNA expression of CEBPß (CCAAT enhancer-binding protein ß), SREBP1c (sterol-regulatory-element-binding protein 1c), PPARγ2, IRS-1 (insulin receptor substrate-1), GLUT4 (glucose transporter type 4) and TNFα (tumour necrosis factor α) were also assessed. Comparisons were made between obese and lean controls (n=16) at baseline, and pre- and post-PPAR agonist treatment. Obese individuals had significantly increased adipocyte cell surface, percentage CD14+/CD16+ monocyte numbers and ATM number (all P=0.0001). Additionally, serum TNF-α levels were significantly elevated (P=0.017) and adiponectin levels reduced (total: P=0.0001; high: P=0.022) with obesity. ATM number and percentage of CD14+/CD16+ monocytes correlated significantly (P=0.05). Pioglitazone improved adiponectin levels significantly (P=0.0001), and resulted in the further significant enlargement of adipocytes (P=0.05), without effect on the percentage CD14+/CD16+ or ATM number. Pioglitazone treatment also significantly increased subcutaneous AT expression of CEBPß mRNA. The finding that improvements in obesity-associated insulin resistance following pioglitazone were associated with increased adipocyte cell surface and systemic adiponectin levels, supports the centrality of AT to the cardiometabolic derangement underlying the development of T2D (Type 2 diabetes) and CVD (cardiovascular disease).

A preliminary evaluation of a massage program for children who have been sexually abused and their nonabusing mothers.

The aim of this study was to conduct a pilot evaluation of the Mosac Massage Program, a novel program that uses massage to address some of the difficulties faced by children who have been sexually abused and their nonabusing parents. Interviews were conducted with four participating mothers immediately before and after the program. Benefits included improved bonding and communication between mother and child and a relaxing and enjoyable therapy for both mother and child. The program appeared to be a useful complement to talking therapies. Further evaluations are needed to confirm the potential benefits.

Upregulation of oxidative stress markers in human microvascular endothelial cells by complexes of serum albumin and digestion products of glycated casein.

The extent of absorption of dietary advanced glycation end products (AGEs) is not fully known. The possible physiological impact of these absorbed components on inflammatory processes has been studied little and was the aim of this investigation. Aqueous solutions of bovine casein and glucose were heated at 95 degrees C for 5 h to give AGE-casein (AGE-Cas). Simulated stomach and small intestine digestion of AGE-Cas and dialysis (molecular mass cutoff of membrane = 1 kDa) resulted in a low molecular mass (LMM) fraction of digestion products, which was used to prepare bovine serum albumin (BSA)-LMM-AGE-Cas complexes. Stimulation of human microvascular endothelial cells with BSA-LMM-AGE-Cas complexes significantly increased mRNA expression of the receptor of AGE (RAGE), galectin-3 (AGE-R3), tumor necrosis factor alpha, and a marker of the mitogen-activated protein kinase pathway (MAPK-1), as well as p65NF-kappaB activation. Cells treated with LMM digestion products of AGE-Cas significantly increased AGE-R3 mRNA expression. Intracellular reactive oxygen species production increased significantly in cells challenged with BSA-LMM-AGE-Cas and LMM-AGE-Cas. In conclusion, in an in vitro cell system, digested dietary AGEs complexed with serum albumin play a role in the regulation of RAGE and downstream inflammatory pathways. AGE-R3 may protect against these effects.

The effectiveness of the Training and Support Program for parents of children with disabilities: a randomized controlled trial.

OBJECTIVE: The Training and Support Program (TSP) was designed to equip parents of children with disabilities with a simple massage skill for use with their children in the home environment. The effectiveness of the TSP was examined in a randomized controlled trial with a wait-list control group. METHODS: Parents were trained in massage by suitably qualified therapists in eight weekly sessions, each lasting 1 h. The sample comprised 188 parents who were randomized to an intervention group (n=95), who attended the TSP with their children immediately, or a control group (n=93), who were offered the TSP after 4 months of follow-up. Data were collected by self-administered questionnaires at baseline and at 4-month follow-up. RESULTS: The majority of participants were mothers (88%), with a partner (88%), and White European (82%); 40% worked full-time or part-time, and 34% had health problems (e.g., chronic fatigue, cancer, and arthritis). The TSP demonstrated statistically significant positive effects on parental self-efficacy (PSE) for managing children's psychosocial well-being and depressed mood (0.004 and 0.007). There were trends toward improvement on parental satisfaction with life (P=.053), global health (P=.065), and parental ratings of children's sleeping (P=.074) and mobility (P=.012). Effect sizes were small (0.11-0.23). Levels of anxiety, depression, and perceived stress were all higher than published norms. CONCLUSION: The TSP is an effective means of improving PSE and depressed mood. Additional means of supporting parents need to be investigated.

Training parents of children with life-long and life-limiting conditions in the art of massage.

The aim of this study was to explore the experience of being a massage therapist on the Training and Support Programme (TSP) in relation to Continued Professional Development (CPD). The TSP instructs parents caring for children with life-long and life-limiting conditions in simple massage techniques. Data were collected by semi-structured interviews with six massage therapists who had worked on the TSP for between 112 and 4 years. Therapists reported a number of beneficial gains including increased knowledge about 'disabilities' in general and a greater understanding of caring for children with life-long and life-limiting conditions, more patience, enhanced confidence of their practice, ability to adapt, and compassion. All therapists felt privileged to be a part of the process of change that occurred for parents and their children during the TSP. The results of this study will add to the scarce literature concerning massage therapists' CPD and provide insight into their experiences of working with parents and their children with a range of life-long and life-limiting conditions.

Psychosocial well-being of parents of children with ataxia who attended the Training and Support Programme: a 12-month follow-up.

The aim of this study was to investigate the impact of a Training and Support Programme (TSP) for parents of children with ataxia, 12 months after commencing the programme. The TSP provides instruction in basic massage to parents of children with disability and life limiting conditions. Questionnaires were mailed at 12-month follow-up to 27 parents who had completed a questionnaire at 4-month follow-up. Of the 14 parents who responded, the median age was 46 years (range 37-57 years), 11 were female and 6 were still massaging their children at 12-month follow-up. Eight children were male, median age 14 years (range 8.3-22.0 years). Results revealed trends towards improvements in parental satisfaction with life and improvements in children's sleeping and bowel movements for those who were still massaging their children at 12-month follow-up. Results suggest that it may be useful to offer parents support and encouragement in the year after attending the TSP, if they wish to continue to massage their children.

The Training and Support Programme for parents of children with Cerebral Palsy: a process evaluation.

The aim of this process evaluation was to better understand the practice implications of an intervention designed to train parents to massage their children with Cerebral Palsy. Seventy parents completed the Training and Support Programme (TSP) with their children. Data were collected by Home Record Sheets and Observation Sheets completed by parents and therapists, respectively. Implications for practice included therapist's sensitivity to the needs of each parent and child, the need for flexibility in the delivery of the TSP, and the implementation of strategies to ensure the TSP ran smoothly. Such strategies may be of value in the delivery of other similar interventions.

The influence of the training and support programme on the self-efficacy and psychological well-being of parents of children with disabilities: a controlled trial.

The purpose of the study was to examine the effectiveness of an intervention for parents of children with disabilities in a controlled study focusing on parents' self-efficacy, psychological well-being and perceptions of change in children's sleeping, eating and mobility. The Training and Support Programme (TSP) was designed to equip parents with a simple massage skill that they could use with their children in the home environment. Parents were trained in massage by therapeutic massage therapists in 8-weekly sessions, each lasting 1h. The sample comprised 95 parents (49 in the Intervention Group, 46 in the Waiting-list Control Group) who attended the TSP with their children. Data were collected by self-administered questionnaires at baseline (before commencing the TSP), and at 8-week follow-up. The TSP demonstrated statistically significant positive effects on parents' anxious mood, self-efficacy for managing children's psychosocial well-being, self-efficacy in giving massage therapy, and perceptions of children's sleeping and eating. Relatively high levels of psychological distress were found among parents, particularly mothers. Overall, findings suggest that wider implementation of the Programme is warranted, and greater attention needs to paid to the psychological well-being of parents caring for children with disabilities.

Exploring a massage intervention for parents and their children with autism: the implications for bonding and attachment.

This exploratory study aimed to address two questions: (1) What does touch mean between parents and their children with autism on completion of a massage intervention? (2) Do parents feel that their relationship with their children has changed on completion of a massage intervention? Fourteen parents agreed to be interviewed. Data were collected before the massage intervention (baseline), immediately after the massage intervention and 16 weeks from baseline and were analysed using interpretative phenomenological analysis. At baseline, parents felt distressed that they felt unable to get 'close' to their children. After the intervention, parents reported feeling physically and emotionally closer to their children. Children expressed a range of cues to initiate massage at home. These benefits were maintained at follow-up for parents who continued to use massage at home. In conclusion, giving massage to children with autism may help to enhance the emotional bond between parent and child.

An Individualized Yoga Programme for Multiple Sclerosis: A Case Study.

PURPOSE: Despite the evidence that yoga is beneficial for people with multiple sclerosis (MS), substantial in-depth qualitative studies of yoga and MS-and individualized yoga programmes (IYP), in particular-are lacking. The aims of this paper are (a) to conduct a case study on an IYP for one participant with MS in terms of her experience of yoga and how yoga affected her particular symptoms of MS, and (b) to better understand the unique and changing needs of someone with MS in the context of an IYP. DESIGN AND METHOD: Data collected for this study were sourced from a qualitative case study design with data collected via a participant diary completed over the 24-week duration of an IYP; an exit interview after the final IYP session; and weekly records completed by the yoga teacher. Data were analysed using thematic analysis. FINDINGS: Over the course of the IYP, the female participant experienced an increased awareness of negative thoughts and feelings about MS and how it affected her and her body. As the programme progressed, she began to work through these feelings and, by the end of the programme, reported experiencing improvements in muscle tone, strength, balance, psychological wellbeing, and confidence. CONCLUSION: Our findings highlight the importance of a programme individualized to meet the complex health and psychological needs of individuals with MS.

High glucose decreases intracellular glutathione concentrations and upregulates inducible nitric oxide synthase gene expression in intestinal epithelial cells.

Diabetes is associated with oxidative stress and increased concentrations of inflammatory cytokines. The aim of the study was to assess the effects of inflammatory cytokines and oxidative stress associated with increased glucose concentrations on inducible nitric oxide synthase (iNOS) promoter activity in intestinal epithelial cells. High-glucose (25 mmol/l) conditions reduced glutathione (GSH) concentrations in the human intestinal epithelial cell line, DLD-1. Addition of the antioxidant, alpha-lipoic acid, resulted in the restoration of GSH concentrations to normal. Upregulation of basal iNOS promoter activity was observed when cells were incubated in high glucose alone. This effect was significantly reduced by the addition of the antioxidant, alpha-lipoic acid, and completely blocked with inhibition of nuclear factor kappa B (NFkappaB) activity. Stimulation of cytokines (interleukin-1 beta, tumour necrosis factor-alpha, interferon-gamma) induced iNOS promoter activity in all conditions and this was accompanied by an increase in nitric oxide (NO) production. Inhibition of NFkappaB activity decreased, but did not completely inhibit, cytokine-induced iNOS promoter activity and subsequent production of NO. In conclusion, iNOS promoter activity induced by high concentrations of glucose is mediated in part through intracellular GSH and NFkappaB.

Differences in mitochondrial and nuclear DNA status of high-density and low-density sperm fractions after density centrifugation preparation.

OBJECTIVE: To determine the mitochondrial DNA and nuclear DNA fragmentation of sperm populations separated by using discontinuous density gradient. DESIGN: Analysis of mitochondrial and nuclear DNA status of sperm from high and low density layers. SETTING: Regional fertility center. PATIENT(S): Twenty-eight men who presented for an initial infertility investigation. MAIN OUTCOME MEASURE(S): Semen was prepared by using discontinuous density gradient (90.0%:45.0%) and subjected to a modified long polymerase chain reaction to assess mitochondrial DNA deletions and to a modified single-cell alkaline gel electrophoresis assay to determine nuclear DNA fragmentation. RESULT(S): The high-density fraction displayed significantly more wild-type mitochondrial DNA (75% of samples) than did the low-density fraction (25% of samples). In the high-density fraction, the incidence of single deletions was higher than that of double or multiple deletions, and the deletions were predominantly small. A strong correlation was observed between nuclear DNA fragmentation and the number and size of mitochondrial DNA deletions. CONCLUSION(S): Density centrifugation isolates a population of sperm with high-quality mitochondrial DNA and nuclear DNA.

Changing eating behaviours to treat childhood obesity in the community using Mandolean: the Community Mandolean randomised controlled trial (ComMando)--a pilot study.

BACKGROUND: Around one in five children in England is obese when they leave primary school. Thus far, it has not been demonstrated that primary care interventions to manage childhood obesity can achieve significant weight reduction. Training obese children to eat more slowly as an adjunct to other healthy lifestyle behaviour change has been shown to increase weight reduction in a hospital setting. OBJECTIVES: This pilot study aimed to test recruitment strategies, treatment adherence, clinic attendance and participants' experiences of using a device [Mandolean® (previously Mandometer®, Mikrodidakt AB, Lund, Sweden)] to slow down speed of eating as an adjunct to dietary and activity advice in treating obesity in primary school-aged children. DESIGN: A two-arm, parallel, randomised controlled trial with a qualitative study embedded within the pilot. Randomisation occurred after informed consent and baseline measures were collected. Participants were randomised by the Bristol Randomised Trials Collaboration randomisation service with allocation stratified by hub and minimised by age of the child, gender, and baseline body mass index (BMI) standard deviation score (BMI z-value) of the child, and by BMI of the study parent (obese/not obese). SETTING: General practices across Bristol, North Somerset and South Gloucestershire primary care trusts. PARTICIPANTS: Children (BMI ≥ 95th percentile) aged 5-11 years and their families. INTERVENTION: Standard care comprised dietary and activity advice by trained practice nurses. Adjunctive Mandolean training (the intervention) educated participants to eat meals more slowly and to rate levels of fullness (satiety). Mandolean is a small computer device attached to a weighing scale that provides visual and oral feedback during meals while generating a visual representation of levels of satiety during the meal. Participants were encouraged to eat their main meal each day from the Mandolean. One parent was also given a Mandolean to use when eating with the child. OUTCOME MEASURES: Outcomes for the pilot were recruitment of 36 families to the trial in the 9-month pilot phase, that meals would be eaten at least five times a week off a Mandolean by 90% of patients randomised to the intervention arm, that 80% of patients in both arms would attend the weight management clinic appointment 3 months post randomisation and that > 60% of children using Mandolean would demonstrate a reduction in speed of eating from baseline within 3 months of randomisation. RESULTS: None of the criteria for progression to the main trial were reached. Despite numerous pathways being available for referral, only 21 (13 to standard care, eight to intervention arm; 58%) of the target 36 families were recruited in the pilot phase. Less than 20% of those randomised to Mandolean used the device at least five times a week. The > 60% target for slowing down of eating speed by 3 months was unmet. Attendance at the weight management clinic in general practice hubs for both arms of the study at 3 months was 44% against a target of 80%. CONCLUSIONS: This pilot trial failed to meet its objectives in terms of recruitment, treatment adherence, demonstration of a reduction in speed of eating in sufficient numbers of children, and attendance at follow-up appointments. Despite a high prevalence of childhood obesity in the geographical area and practices signing up for the trial, this study, like many others, demonstrates a failure of families to engage with and respond to primary care weight management interventions. We need to understand why the target population seems inured to the health message that childhood obesity is a significant health-care issue and identify the barriers to seeking help and then acting on positive health behaviour retraining. Only when we have fully understood the general public's perceptions of childhood obesity and have identified ways of engaging target populations can we hope to develop interventions that can work in a primary or community-based setting. TRIAL REGISTRATION: Current Controlled Trials ISRCTN90561114. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 47. See the NIHR Journals Library website for further project information.

Linoleic acid increases monocyte chemotaxis and adhesion to human aortic endothelial cells through protein kinase C- and cyclooxygenase-2-dependent mechanisms.

The effects of polyunsaturated n-6 linoleic acid on monocyte-endothelial interactions were investigated with particular emphasis on the expression of platelet/endothelial cell adhesion molecule (PECAM)-1 and the role of protein kinase C (PKC) and cyclooxygenase-2 (COX-2). As a diet rich in polyunsaturated fatty acids may favour atherosclerosis in hyperglycaemia, this study was performed in both normal and high-glucose media using human aortic endothelial cells (HAEC). The HAEC were preincubated with normal (5 mM) or high (25 mM) D-glucose for 3 days before addition of fatty acids (0.2 mM) for 3 days. Linoleic acid enhanced PECAM-1 expression independently of tumor necrosis factor (TNF)-α and significantly increased TNF-α-induced monocyte adhesion to HAEC in comparison to the monounsaturated n-9 oleic acid. Chronic glucose treatment (25 mM, 6 days) did not modify the TNF-α-induced or fatty acid-induced changes in monocyte binding. The increase in monocyte binding was accompanied by a significant increase in E-selectin and vascular cell adhesion molecule (VCAM)-1 expression and could be abrogated by an interleukin (IL)-8 neutralising antibody and by the PKC and COX inhibitors. Inhibition of PKC-δ reduced VCAM-1 expression regardless of experimental condition and was accompanied by a significant decrease in monocyte binding. Conditioned medium from linoleic acid-treated HAEC grown in normal glucose conditions significantly increased THP-1 chemotaxis. These results suggest that linoleic acid-induced changes in monocyte chemotaxis and subsequent binding are not solely mediated by changes in adhesion molecule expression but may be due to secreted factors such as IL-8, monocyte chemoattractant protein-1 or prostaglandins (PGs) such as PGE(2), as IL-8 neutralisation and COX-2 inhibition reduced monocyte binding without changes in adhesion molecule expression.

Children's experiences of their participation in a training and support programme involving massage.

This study reports on a research project that aimed to extrapolate the value of the Training and Support Programme (TSP), involving massage, among children with cerebral palsy (CP). Data gathering included information from interviews with a sub-sample of children and the TSP therapist observation forms. Data were analysed using standard thematic content analysis to identify key themes and issues of importance to children. Results showed that children enjoyed the relaxing aspects of massage and reported a number of improvements in their health such as improved muscle relaxation, mobility and bowel movements, and reduced pain. Future studies may need to explore other ways of extrapolating data from this population and similar populations where communication is impaired due to disability, but at the same time ensure that their views are listened to and acted upon.