Goal attainment, adjustment and disengagement in the first year after stroke: A qualitative study.

Understanding stroke survivor responses to attainable and unattainable goals is important so that rehabilitation staff can optimally support ongoing recovery and adaption. In this qualitative study, we aimed to investigate (i) stroke survivor's experiences of goal attainment, adjustment and disengagement in the first year after stroke and (ii) whether the Goal setting and Action Planning (G-AP) framework supported different pathways to goal attainment. In-depth interviews were conducted with eighteen stroke survivors' to explore their experiences and views. Interview data were transcribed verbatim and analysed using a Framework approach to examine themes within and between participants. Stroke survivors reported that attaining personal goals enabled them to resume important activities, reclaim a sense of self and enhance emotional wellbeing. Experiences of goal-related setbacks and failure facilitated understanding and acceptance of limitations and informed adjustment of, or disengagement from, unattainable goals. Use of the G-AP framework supported stroke survivors to (i) identify personal goals, (ii) initiate and sustain goal pursuit, (iii) gauge progress and (iv) make informed decisions about continued goal pursuit, adjustment or disengagement. Stroke survivor recovery involves attainment of original and adjusted or alternative goals. The G-AP framework can support these different pathways to goal attainment.

Home-based intervention to test and start (HITS) protocol: a cluster-randomized controlled trial to reduce HIV-related mortality in men and HIV incidence in women through increased coverage of HIV treatment.

BACKGROUND: To realize the full benefits of treatment as prevention in many hyperendemic African contexts, there is an urgent need to increase uptake of HIV testing and HIV treatment among men to reduce the rate of HIV transmission to (particularly young) women. This trial aims to evaluate the effect of two interventions - micro-incentives and a tablet-based male-targeted HIV decision support application - on increasing home-based HIV testing and linkage to HIV care among men with the ultimate aim of reducing HIV-related mortality in men and HIV incidence in young women. METHODS/DESIGN: This is a cluster randomized trial of 45 communities (clusters) in a rural area in the uMkhanyakude district of KwaZulu Natal, South Africa (2018-2021). The study is built upon the Africa Health Research Institute (AHRI)'s HIV testing platform, which offers annual home-based rapid HIV testing to individuals aged 15 years and above. In a 2 × 2 factorial design, individuals aged ≥15 years living in the 45 clusters are randomly assigned to one of four arms: i) a financial micro-incentive (food voucher) (n = 8); ii) male-targeted HIV specific decision support (EPIC-HIV) (n = 8); iii) both the micro incentives and male-targeted decision support (n = 8); and iv) standard of care (n = 21). The EPIC-HIV application is developed and delivered via a tablet to encourage HIV testing and linkage to care among men. A mixed method approach is adopted to supplement the randomized control trial and meet the study aims. DISCUSSION: The findings of this trial will provide evidence on the feasibility and causal impact of two interventions - micro-incentives and a male-targeted HIV specific decision support - on uptake of home-based HIV testing, linkage to care, as well as population health outcomes including population viral load, HIV related mortality in men, and HIV incidence in young women (15-30 years of age). TRIAL REGISTRATION: This trial was registered on 28 November 2018 on, identifier https://clinicaltrials.gov/ .

The intervention process in the European Fans in Training (EuroFIT) trial: a mixed method protocol for evaluation.

BACKGROUND: EuroFIT is a gender-sensitised, health and lifestyle program targeting physical activity, sedentary time and dietary behaviours in men. The delivery of the program in football clubs, led by the clubs' community coaches, is designed to both attract and engage men in lifestyle change through an interest in football or loyalty to the club they support. The EuroFIT program will be evaluated in a multicentre pragmatic randomised controlled trial (RCT), for which ~1000 overweight men, aged 30-65 years, will be recruited in 15 top professional football clubs in the Netherlands, Norway, Portugal and the UK. The process evaluation is designed to investigate how implementation within the RCT is achieved in the various football clubs and countries and the processes through which EuroFIT affects outcomes. METHODS: This mixed methods evaluation is guided by the Medical Research Council (MRC) guidance for conducting process evaluations of complex interventions. Data will be collected in the intervention arm of the EuroFIT trial through: participant questionnaires (n = 500); attendance sheets and coach logs (n = 360); observations of sessions (n = 30); coach questionnaires (n = 30); usage logs from a novel device for self-monitoring physical activity and non-sedentary behaviour (SitFIT); an app-based game to promote social support for physical activity outside program sessions (MatchFIT); interviews with coaches (n = 15); football club representatives (n = 15); and focus groups with participants (n = 30). Written standard operating procedures are used to ensure quality and consistency in data collection and analysis across the participating countries. Data will be analysed thematically within datasets and overall synthesis of findings will address the processes through which the program is implemented in various countries and clubs and through which it affects outcomes, with careful attention to the context of the football club. DISCUSSION: The process evaluation will provide a comprehensive account of what was necessary to implement the EuroFIT program in professional football clubs within a trial setting and how outcomes were affected by the program. This will allow us to re-appraise the program's conceptual base, optimise the program for post-trial implementation and roll out, and offer suggestions for the development and implementation of future initiatives to promote health and wellbeing through professional sports clubs. TRIAL REGISTRATION: ISRCTN81935608 . Registered on 16 June 2015.

Findings from a pilot Randomised trial of an Asthma Internet Self-management Intervention (RAISIN).

OBJECTIVE: To evaluate the feasibility of a phase 3 randomised controlled trial (RCT) of a website (Living Well with Asthma) to support self-management. DESIGN AND SETTING: Phase 2, parallel group, RCT, participants recruited from 20 general practices across Glasgow, UK. Randomisation through automated voice response, after baseline data collection, to website access for minimum 12 weeks or usual care. PARTICIPANTS: Adults (age≥16 years) with physician diagnosed, symptomatic asthma (Asthma Control Questionnaire (ACQ) score ≥1). People with unstable asthma or other lung disease were excluded. INTERVENTION: 'Living Well with Asthma' is a desktop/laptop compatible interactive website designed with input from asthma/ behaviour change specialists, and adults with asthma. It aims to support optimal medication management, promote use of action plans, encourage attendance at asthma reviews and increase physical activity. OUTCOME MEASURES: Primary outcomes were recruitment/retention, website use, ACQ and mini-Asthma Quality of Life Questionnaire (AQLQ). Secondary outcomes included patient activation, prescribing, adherence, spirometry, lung inflammation and health service contacts after 12 weeks. Blinding postrandomisation was not possible. RESULTS: Recruitment target met. 51 participants randomised (25 intervention group). Age range 16-78 years; 75% female; 28% from most deprived quintile. 45/51 (88%; 20 intervention group) followed up. 19 (76% of the intervention group) used the website, for a mean of 18 min (range 0-49). 17 went beyond the 2 'core' modules. Median number of logins was 1 (IQR 1-2, range 0-7). No significant difference in the prespecified primary efficacy measures of ACQ scores (-0.36; 95% CI -0.96 to 0.23; p=0.225), and mini-AQLQ scores (0.38; -0.13 to 0.89; p=0.136). No adverse events. CONCLUSIONS: Recruitment and retention confirmed feasibility; trends to improved outcomes suggest use of Living Well with Asthma may improve self-management in adults with asthma and merits further development followed by investigation in a phase 3 trial. TRIAL REGISTRATION NUMBER: ISRCTN78556552; Results.

The importance of evaluating the physicochemical and toxicological properties of a contaminant for remediating environments affected by chemical incidents.

In the event of a major chemical incident or accident, appropriate tools and technical guidance need to be available to ensure that a robust approach can be adopted for developing a remediation strategy. Remediation and restoration strategies implemented in the aftermath of a chemical incident are a particular concern for public health. As a result an innovative methodology has been developed to help design an effective recovery strategy in the aftermath of a chemical incident that has been developed; the UK Recovery Handbook for Chemical Incidents (UKRHCI). The handbook consists of a six-step decision framework and the use of decision trees specifically designed for three different environments: food production systems, inhabited areas and water environments. It also provides a compendium of evidence-based recovery options (techniques or methods for remediation) that should be selected in relation to their efficacy for removing contaminants from the environment. Selection of effective recovery options in this decision framework involves evaluating the physicochemical and toxicological properties of the chemical(s) involved. Thus, the chemical handbook includes a series of tables with relevant physicochemical and toxicological properties that should be assessed in function of the environment affected. It is essential that the physicochemical properties of a chemical are evaluated and interpreted correctly during the development of a remedial plan in the aftermath of a chemical incident to ensure an effective remedial response. This paper presents a general overview of the key physicochemical and toxicological properties of chemicals that should be evaluated when developing a recovery strategy. Information on how physicochemical properties have impacted on previous remedial responses reported in the literature is also discussed and a number of challenges for remediation are highlighted to include the need to develop novel approaches to remediate sites contaminated by mixtures of chemicals as well as methods for interpreting chemical reactions in different environmental matrices to include how climate change may affect the speciation and mobility of chemicals in the environment.

Factors influencing recovery and restoration following a chemical incident.

Chemicals are an important part of our society. A wide range of chemicals are discharged into the environment every day from residential, commercial and industrial sources. Many of these discharges do not pose a threat to public health or the environment. However, global events have shown that chemical incidents or accidents can have severe consequences on human health, the environment and society. It is important that appropriate tools and technical guidance are available to ensure that a robust and efficient approach to developing a remediation strategy is adopted. The purpose of remediation is to protect human health from future exposure and to return the affected area back to normal as soon as possible. There are a range of recovery options (techniques or methods for remediation) that are applicable to a broad range of chemicals and incidents. Recovery options should be evaluated according to their appropriateness and efficacy for removing contaminants from the environment; however economic drivers and social and political considerations often influence decision makers on which remedial actions are implemented during the recovery phase of a chemical incident. To date, there is limited information in the literature on remediation strategies and recovery options that have been implemented following a chemical incident, or how successful they have been. Additional factors that can affect the approach taken for recovery are not well assessed or understood by decision makers involved in the remediation and restoration of the environment following a chemical incident. The identification of this gap has led to the development of the UK Recovery Handbook for Chemical Incidents to provide a framework for choosing an effective recovery strategy. A compendium of practical evidence-based recovery options (techniques or methods for remediation) for inhabited areas, food production systems and water environments has also been developed and is included in the chemical handbook. This paper presents the key factors that should be considered when developing a recovery strategy with respect to how these may impact on its effectiveness. The paper also highlights the importance of these factors through an evaluation of recovery strategies implemented following real chemical incidents that have been reported in the literature.

Recent advances to address European Union Health Security from cross border chemical health threats.

The European Union (EU) Decision (1082/2013/EU) on serious cross border threats to health was adopted by the European Parliament in November 2013, in recognition of the need to strengthen the capacity of Member States to coordinate the public health response to cross border threats, whether from biological, chemical, environmental events or events which have an unknown origin. Although mechanisms have been in place for years for reporting cross border health threats from communicable diseases, this has not been the case for incidents involving chemicals and/or environmental events. A variety of collaborative EU projects have been funded over the past 10 years through the Health Programme to address gaps in knowledge on health security and to improve resilience and response to major incidents involving chemicals. This paper looks at the EU Health Programme that underpins recent research activities to address gaps in resilience, planning, responding to and recovering from a cross border chemical incident. It also looks at how the outputs from the research programme will contribute to improving public health management of transnational incidents that have the potential to overwhelm national capabilities, putting this into context with the new requirements as the Decision on serious cross border threats to health as well as highlighting areas for future development.

Responding to biological incidents--what are the current issues in remediation of the contaminated environment?

Since 2000 there have been a number of biological incidents resulting in environmental contamination with Bacillus anthracis, the causative agent of anthrax. These incidents include the US anthrax attacks in 2001, the US and UK drumming incidents in 2006-2008 and more recently, anthrax contamination of heroin in 2009/2010 and 2012/2013. Remediation techniques used to return environments to normal have varied between incidents, with different decontamination technologies being employed. Many factors need to be considered before a remediation strategy or recovery option can be implemented, including; cost, time (length of application), public perception of risk, and sampling strategies (and results) to name a few. These incidents have demonstrated that consolidated guidance for remediating biologically contaminated environments in the aftermath of a biological incident was required. The UK Recovery Handbook for Biological Incidents (UKRHBI) is a project led by Public Health England (PHE), formerly the Health Protection Agency (HPA) to provide guidance and advice on how to remediate the environment following a biological incident or outbreak of infection, and is expected to be published in 2015.

Hospital Episode Statistics data analysis of postoperative venous thromboembolus in patients undergoing urological surgery: a review of 126,891 cases.

INTRODUCTION: Current guidelines on venous thromboembolism (VTE) prevention do not reflect the potential varying risk for patients undergoing different urological procedures. Our study aimed to establish the procedure specific rate of postoperative VTE in patients undergoing urological surgery. METHODS: Hospital Episode Statistics were obtained for all patients undergoing common urological procedures between April 2009 and April 2010. This cohort was followed up to identify all patients reattending with either deep vein thrombosis (DVT) or pulmonary embolism (PE) within 12 months. RESULTS: A total of 126,891 individuals underwent urological surgery during the study period. This included 89,628 men (70.6%) and 37,236 women (29.3%) with a mean age of 65.2 years. At the 12-month follow-up, 839 patients (0.66%) were readmitted with VTE. Of these, 373 (0.29%) were admitted with DVT and 466 (0.37%) with PE. The procedure-specific rate of VTE varied significantly between 2.86% following cystectomy and 0.23% following urethral dilatation. Procedures performed in the lithotomy position carried a significantly lower risk of VTE than those performed in the supine position (0.60% vs 1.28%, p <0.0001). Furthermore, of all procedures performed in the lithotomy position, those performed on benign conditions carried a significantly lower risk than those performed on malignant disease (0.52% vs 0.79%, p <0.0001). CONCLUSIONS: Procedure specific rates of postoperative VTE vary widely among patients undergoing urological procedures. These findings suggest the potential benefit of prolonging the use of thromboprophylaxis in high-risk patients but also exploring the apparent lack of need for routine thromboprophylaxis in patients undergoing low-risk procedures.

Countering health threats by chemicals with a potential terrorist background--creating a rapid alert system for Europe.

BACKGROUND: The acronym "ASHT" stands for "Alerting System and Development of a Health Surveillance System for the Deliberate Release of Chemicals by Terrorists". Imagine this scenario: 15 patients with respiratory symptoms following a concert in Rome and 12 patients coughing after lunch in a cafeteria in the Czech Republic; are these events related? Today these events would never be connected as there is no mechanism to allow EU Member States to share this type of information effectively. The main objective of the ASHT project was to improve data sharing between EU Member States. In part, this was achieved by an internet accessible EU-wide alerting system with the aim to detect the deliberate (i.e. criminal or terrorist) or accidental release of chemicals. Nevertheless more information from police, fire brigades and health professionals is needed. METHODS: Description of the design, development, functionality and testing of the relational database system called "RAS-CHEM" (Rapid Alert System for Chemicals). RESULTS: A database structure appropriate for the description of "events" with sophisticated retrieval functions was developed. For evaluation purposes 37 events were entered into the database including 29 scenarios and 8 historical mass intoxications. The alert level was "background information" for 21 events, "suspected mass intoxication" for 6 cases and "confirmed mass intoxication" for 10 events. CONCLUSION: The RAS-CHEM database works and will be integrated into the Health Emergency Operations Facility (HEOF) with other European Rapid Alert Systems. Poisons centres receive a large number of enquiries and could be important sentinels in this field of toxicovigilance.

Attenuation of muscle atrophy by an N-terminal peptide of the receptor for proteolysis-inducing factor (PIF).

BACKGROUND: Atrophy of skeletal muscle in cancer cachexia has been attributed to a tumour-produced highly glycosylated peptide called proteolysis-inducing factor (PIF). The action of PIF is mediated through a high-affinity membrane receptor in muscle. This study investigates the ability of peptides derived from the 20 N-terminal amino acids of the receptor to neutralise PIF action both in vitro and in vivo. METHODS: Proteolysis-inducing factor was purified from the MAC16 tumour using an initial pronase digestion, followed by binding on DEAE cellulose, and the pronase was inactivated by heating to 80°C, before purification of the PIF using affinity chromatography. In vitro studies were carried out using C(2)C(12) murine myotubes, while in vivo studies employed mice bearing the cachexia-inducing MAC16 tumour. RESULTS: The process resulted in almost a 23,000-fold purification of PIF, but with a recovery of only 0.004%. Both the D- and L-forms of the 20mer peptide attenuated PIF-induced protein degradation in vitro through the ubiquitin-proteosome proteolytic pathway and increased expression of myosin. In vivo studies showed that neither the D- nor the L-peptides significantly attenuated weight loss, although the D-peptide did show a tendency to increase lean body mass. CONCLUSION: These results suggest that the peptides may be too hydrophilic to be used as therapeutic agents, but confirm the importance of the receptor in the action of the PIF on muscle protein degradation.

Modifiable and fixed factors predicting quality of life in people with colorectal cancer.

BACKGROUND: People with colorectal cancer have impaired quality of life (QoL). We investigated what factors were most highly associated with it. METHODS: Four hundred and ninety-six people with colorectal cancer completed questionnaires about QoL, functioning, symptoms, co-morbidity, cognitions and personal and social factors. Disease, treatment and co-morbidity data were abstracted from case notes. Multiple linear regression identified modifiable and unmodifiable factors independently predictive of global quality of life (EORTC-QLQ-C30). RESULTS: Of unmodifiable factors, female sex (P<0.001), more self-reported co-morbidities (P=0.006) and metastases at diagnosis (P=0.036) significantly predicted poorer QoL, but explained little of the variability in the model (R(2)=0.064). Adding modifiable factors, poorer role (P<0.001) and social functioning (P=0.003), fatigue (P=0.001), dyspnoea (P=0.001), anorexia (P<0.001), depression (P<0.001) and worse perceived consequences (P=0.013) improved the model fit considerably (R(2)=0.574). Omitting functioning subscales resulted in recent diagnosis (P=0.002), lower perceived personal control (P=0.020) and travel difficulties (P<0.001) becoming significant predictors. CONCLUSION: Most factors affecting QoL are modifiable, especially symptoms (fatigue, anorexia, dyspnoea) and depression. Beliefs about illness are also important. Unmodifiable factors, including metastatic (or unstaged) disease at diagnosis, have less impact. There appears to be potential for interventions to improve QoL in patients with colorectal cancer.

Factors contributing to the time taken to consult with symptoms of lung cancer: a cross-sectional study.

OBJECTIVES: To determine what factors are associated with the time people take to consult with symptoms of lung cancer, with a focus on those from rural and socially deprived areas. METHODS: A cross-sectional quantitative interview survey was performed of 360 patients with newly diagnosed primary lung cancer in three Scottish hospitals (two in Glasgow, one in NE Scotland). Supplementary data were obtained from medical case notes. The main outcome measures were the number of days from (1) the date participant defined first symptom until date of presentation to a medical practitioner; and (2) the date of earliest symptom from a symptom checklist (derived from clinical guidelines) until date of presentation to a medical practitioner. RESULTS: 179 participants (50%) had symptoms for more than 14 weeks before presenting to a medical practitioner (median 99 days; interquartile range 31-381). 270 participants (75%) had unrecognised symptoms of lung cancer. There were no significant differences in time taken to consult with symptoms of lung cancer between rural and/or deprived participants compared with urban and/or affluent participants. Factors independently associated with increased time before consulting about symptoms were living alone, a history of chronic obstructive pulmonary disease (COPD) and longer pack years of smoking. Haemoptysis, new onset of shortness of breath, cough and loss of appetite were significantly associated with earlier consulting, as were a history of chest infection and renal failure. CONCLUSION: For many people with lung cancer, regardless of location and socioeconomic status, the time between symptom onset and consultation was long enough to plausibly affect prognosis. Long-term smokers, those with COPD and/or those living alone are at particular risk of taking longer to consult with symptoms of lung cancer and practitioners should be alert to this.

Induction of protein degradation in skeletal muscle by a phorbol ester involves upregulation of the ubiquitin-proteasome proteolytic pathway.

Although muscle atrophy is common to a number of disease states there is incomplete knowledge of the cellular mechanisms involved. In this study murine myotubes were treated with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) to evaluate the role of protein kinase C (PKC) as an upstream intermediate in protein degradation. TPA showed a parabolic dose-response curve for the induction of total protein degradation, with an optimal effect at a concentration of 25 nM, and an optimal incubation time of 3 h. Protein degradation was attenuated by co-incubation with the proteasome inhibitor lactacystin (5 microM), suggesting that it was mediated through the ubiquitin-proteasome proteolytic pathway. TPA induced an increased expression and activity of the ubiquitin-proteasome pathway, as evidenced by an increased functional activity, and increased expression of the 20S proteasome alpha-subunits, the 19S subunits MSS1 and p42, as well as the ubiquitin conjugating enzyme E2(14k), also with a maximal effect at a concentration of 25 nM and with a 3 h incubation time. There was also a reciprocal decrease in the cellular content of the myofibrillar protein myosin. TPA induced activation of PKC maximally at a concentration of 25 nM and this effect was attenuated by the PKC inhibitor calphostin C (300 nM), as was also total protein degradation. These results suggest that stimulation of PKC in muscle cells initiates protein degradation through the ubiquitin-proteasome pathway. TPA also induced degradation of the inhibitory protein, I-kappaBalpha, and increased nuclear accumulation of nuclear factor-kappaB (NF-kappaB) at the same time and concentrations as those inducing proteasome expression. In addition inhibition of NF-kappaB activation by resveratrol (30 microM) attenuated protein degradation induced by TPA. These results suggest that the induction of proteasome expression by TPA may involve the transcription factor NF-kappaB.

Expression of the ubiquitin-proteasome pathway and muscle loss in experimental cancer cachexia.

Muscle protein degradation is thought to play a major role in muscle atrophy in cancer cachexia. To investigate the importance of the ubiquitin-proteasome pathway, which has been suggested to be the main degradative pathway mediating progressive protein loss in cachexia, the expression of mRNA for proteasome subunits C2 and C5 as well as the ubiquitin-conjugating enzyme, E2(14k), has been determined in gastrocnemius and pectoral muscles of mice bearing the MAC16 adenocarcinoma, using competitive quantitative reverse transcriptase polymerase chain reaction. Protein levels of proteasome subunits and E2(14k) were determined by immunoblotting, to ensure changes in mRNA were reflected in changes in protein expression. Muscle weights correlated linearly with weight loss during the course of the study. There was a good correlation between expression of C2 and E2(14k) mRNA and protein levels in gastrocnemius muscle with increases of 6-8-fold for C2 and two-fold for E2(14k) between 12 and 20% weight loss, followed by a decrease in expression at weight losses of 25-27%, although loss of muscle protein continued. In contrast, expression of C5 mRNA only increased two-fold and was elevated similarly at all weight losses between 7.5 and 27%. Both proteasome functional activity, and proteasome-specific tyrosine release as a measure of total protein degradation was also maximal at 18-20% weight loss and decreased at higher weight loss. Proteasome expression in pectoral muscle followed a different pattern with increases in C2 and C5 and E2(14k) mRNA only being seen at weight losses above 17%, although muscle loss increased progressively with increasing weight loss. These results suggest that activation of the ubiquitin-proteasome pathway plays a major role in protein loss in gastrocnemius muscle, up to 20% weight loss, but that other factors such as depression in protein synthesis may play a more important role at higher weight loss.

NF-kappaB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin-proteasome system in skeletal muscle.

Loss of skeletal muscle in cancer cachexia has a negative effect on both morbidity and mortality. The role of nuclear factor-kappaB (NF-kappaB) in regulating muscle protein degradation and expression of the ubiquitin-proteasome proteolytic pathway in response to a tumour cachectic factor, proteolysis-inducing factor (PIF), has been studied by creating stable, transdominant-negative, muscle cell lines. Murine C(2)C(12) myoblasts were transfected with plasmids with a CMV promoter that had mutations at the serine phosphorylation sites required for degradation of I-kappaBalpha, an NF-kappaB inhibitory protein, and allowed to differentiate into myotubes. Proteolysis-inducing factor induced degradation of I-kappaBalpha, nuclear accumulation of NF-kappaB and an increase in luciferase reporter gene activity in myotubes containing wild-type, but not mutant, I-kappaBalpha proteins. Proteolysis-inducing factor also induced total protein degradation and loss of the myofibrillar protein myosin in myotubes containing wild-type, but not mutant, plasmids at the same concentrations as those causing activation of NF-kappaB. Proteolysis-inducing factor also induced increased expression of the ubiquitin-proteasome pathway, as determined by 'chymotrypsin-like' enzyme activity, the predominant proteolytic activity of the beta-subunits of the proteasome, protein expression of 20S alpha-subunits and the 19S subunits MSS1 and p42, as well as the ubiquitin conjugating enzyme, E2(14k), in cells containing wild-type, but not mutant, I-kappaBalpha. The ability of mutant I-kappaBalpha to inhibit PIF-induced protein degradation, as well as expression of the ubiquitin-proteasome pathway, confirms that both of these responses depend on initiation of transcription by NF-kappaB.

Induction of proteasome expression in skeletal muscle is attenuated by inhibitors of NF-kappaB activation.

The potential for inhibitors of nuclear factor-kappaB (NF-kappaB) activation to act as inhibitors of muscle protein degradation in cancer cachexia has been evaluated both in vitro and in vivo. Activation of NF-kappaB is important in the induction of proteasome expression and protein degradation by the tumour factor, proteolysis-inducing factor (PIF), since the cell permeable NF-kappaB inhibitor SN50 (18 microM) attenuated the expression of 20S proteasome alpha-subunits, two subunits of the 19S regulator MSS1 and p42, and the ubiquitin-conjugating enzyme, E2(14k), as well as the decrease in myosin expression in murine myotubes. To assess the potential therapeutic benefit of NF-kappaB inhibitors on muscle atrophy in cancer cachexia, two potential inhibitors were employed; curcumin (50 microM) and resveratrol (30 microM). Both agents completely attenuated total protein degradation in murine myotubes at all concentrations of PIF, and attenuated the PIF-induced increase in expression of the ubiquitin-proteasome proteolytic pathway, as determined by the 'chymotrypsin-like' enzyme activity, proteasome subunits and E2(14k). However, curcumin (150 and 300 mg kg(-1)) was ineffective in preventing weight loss and muscle protein degradation in mice bearing the MAC16 tumour, whereas resveratrol (1 mg kg(-1)) significantly attenuated weight loss and protein degradation in skeletal muscle, and produced a significant reduction in NF-kappaB DNA-binding activity. The inactivity of curcumin was probably due to a low bioavailability. These results suggest that agents which inhibit nuclear translocation of NF-kappaB may prove useful for the treatment of muscle wasting in cancer cachexia.

Role of protein kinase C and NF-kappaB in proteolysis-inducing factor-induced proteasome expression in C(2)C(12) myotubes.

Proteolysis-inducing factor (PIF) is a sulphated glycoprotein produced by cachexia-inducing tumours, which initiates muscle protein degradation through an increased expression of the ubiquitin-proteasome proteolytic pathway. The role of kinase C (PKC) in PIF-induced proteasome expression has been studied in murine myotubes as a surrogate model of skeletal muscle. Proteasome expression induced by PIF was attenuated by 4alpha-phorbol 12-myristate 13-acetate (100 nM) and by the PKC inhibitors Ro31-8220 (10 microM), staurosporine (300 nM), calphostin C (300 nM) and Gö 6976 (200 microM). Proteolysis-inducing factor-induced activation of PKC(alpha), with translocation from the cytosol to the membrane at the same concentration as that inducing proteasome expression, and this effect was attenuated by calphostin C. Myotubes transfected with a constitutively active PKC(alpha) (pCO(2)) showed increased expression of proteasome activity, and a longer time course, compared with their wild-type counterparts. In contrast, myotubes transfected with a dominant-negative PKC(alpha) (pKS1), which showed no activation of PKC(alpha) in response to PIF, exhibited no increase in proteasome activity at any time point. Proteolysis-inducing factor-induced proteasome expression has been suggested to involve the transcription factor nuclear factor-kappaB (NF-kappaB), which may be activated through PKC. Proteolysis-inducing factor induced a decrease in cytosolic I-kappaBalpha and an increase in nuclear binding of NF-kappaB in pCO(2), but not in pKS1, and the effect in wild-type cells was attenuated by calphostin C, confirming that it was mediated through PKC. This suggests that PKC may be involved in the phosphorylation and degradation of I-kappaBalpha, induced by PIF, necessary for the release of NF-kappaB from its inactive cytosolic complex.

Assessment of impact of information booklets on use of healthcare services: randomised controlled trial.

OBJECTIVES: To investigate the effect of patient information booklets on overall use of health services, on particular types of use, and on possible interactions between use, deprivation category of the area in which respondents live, and age. To investigate the possibility of a differential effect on health service use between two information booklets. DESIGN: Randomised controlled trial of two patient information booklets (covering the management and treatment of minor illness). SETTING: 20 general practices in Lothian, Scotland. PARTICIPANTS: Random sample of patients from the community health index (n=4878) and of those contacting out of hours services (n=4530) in the previous 12 months in each of the study general practices. INTERVENTION: Booklets were posted to participants in intervention groups (3288 were sent What Should I Do?; 3127 were sent Health Care Manual). Patients randomised to control group (2993) did not receive a booklet. MAIN OUTCOME MEASURES: Use of health services audited from patients' general practice notes in 12 months after receipt of booklet. RESULTS: Receipt of either booklet had no significant effect on health service use compared with a control group. However, nine out of ten matched practices allocated to receive Health Care Manual had reduced consultation rates compared with matched practices allocated to What Should I Do? CONCLUSION: Widespread distribution of information booklets about the management of minor illness is unlikely to reduce demand for health services.